[{"_id":"8353","project":[{"name":"Revealing the functional mechanism of Mrp antiporter, an ancestor of complex I","grant_number":"24741","_id":"26169496-B435-11E9-9278-68D0E5697425"}],"date_created":"2020-09-09T14:27:01Z","supervisor":[{"id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A","last_name":"Sazanov","full_name":"Sazanov, Leonid A","orcid":"0000-0002-0977-7989"}],"file_date_updated":"2021-09-16T12:40:56Z","page":"191","article_processing_charge":"No","date_published":"2020-09-09T00:00:00Z","date_updated":"2023-09-07T13:14:09Z","title":"Biochemical and structural investigation of the Mrp antiporter, an ancestor of complex I","month":"09","oa":1,"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","acknowledgement":"I acknowledge the scientific service units of the IST Austria for providing resources by the Life Science Facility, the Electron Microscopy Facility and the high-performance computer cluster. Special thanks to the cryo-EM specialists Valentin Hodirnau and Daniel Johann Gütl for spending many hours with me in front of the microscope and for supporting me to collect the data presented here. I also want to thank Professor Masahiro Ito for providing plasmid DNA\r\nencoding Mrp from Anoxybacillus flavithermus WK1. I am a recipient of a DOC Fellowship of the Austrian Academy of Sciences.","related_material":{"record":[{"status":"public","relation":"part_of_dissertation","id":"8284"}]},"alternative_title":["ISTA Thesis"],"publisher":"Institute of Science and Technology Austria","day":"09","doi":"10.15479/AT:ISTA:8353","oa_version":"None","year":"2020","author":[{"last_name":"Steiner","full_name":"Steiner, Julia","orcid":"0000-0003-0493-3775","id":"3BB67EB0-F248-11E8-B48F-1D18A9856A87","first_name":"Julia"}],"department":[{"_id":"LeSa"}],"publication_identifier":{"issn":["2663-337X"]},"degree_awarded":"PhD","ddc":["572"],"acknowledged_ssus":[{"_id":"LifeSc"},{"_id":"EM-Fac"},{"_id":"ScienComp"}],"file":[{"date_updated":"2021-09-16T12:40:56Z","content_type":"application/pdf","file_size":117547589,"checksum":"2388d7e6e7a4d364c096fa89f305c3de","relation":"main_file","access_level":"open_access","file_name":"Thesis_Julia_Steiner_pdfA.pdf","file_id":"8354","date_created":"2020-09-09T14:22:35Z","creator":"jsteiner"},{"date_created":"2020-09-09T14:23:25Z","creator":"jsteiner","file_id":"8355","file_name":"Thesis_Julia_Steiner.docx","access_level":"closed","checksum":"ba112f957b7145462d0ab79044873ee9","relation":"source_file","date_updated":"2020-09-15T08:48:37Z","content_type":"application/vnd.openxmlformats-officedocument.wordprocessingml.document","file_size":223328668}],"type":"dissertation","citation":{"ama":"Steiner J. Biochemical and structural investigation of the Mrp antiporter, an ancestor of complex I. 2020. doi:10.15479/AT:ISTA:8353","chicago":"Steiner, Julia. “Biochemical and Structural Investigation of the Mrp Antiporter, an Ancestor of Complex I.” Institute of Science and Technology Austria, 2020. https://doi.org/10.15479/AT:ISTA:8353.","ista":"Steiner J. 2020. Biochemical and structural investigation of the Mrp antiporter, an ancestor of complex I. Institute of Science and Technology Austria.","mla":"Steiner, Julia. Biochemical and Structural Investigation of the Mrp Antiporter, an Ancestor of Complex I. Institute of Science and Technology Austria, 2020, doi:10.15479/AT:ISTA:8353.","apa":"Steiner, J. (2020). Biochemical and structural investigation of the Mrp antiporter, an ancestor of complex I. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:8353","short":"J. Steiner, Biochemical and Structural Investigation of the Mrp Antiporter, an Ancestor of Complex I, Institute of Science and Technology Austria, 2020.","ieee":"J. Steiner, “Biochemical and structural investigation of the Mrp antiporter, an ancestor of complex I,” Institute of Science and Technology Austria, 2020."},"publication_status":"published","abstract":[{"lang":"eng","text":"Mrp (Multi resistance and pH adaptation) are broadly distributed secondary active antiporters that catalyze the transport of monovalent ions such as sodium and potassium outside of the cell coupled to the inward translocation of protons. Mrp antiporters are unique in a way that they are composed of seven subunits (MrpABCDEFG) encoded in a single operon, whereas other antiporters catalyzing the same reaction are mostly encoded by a single gene. Mrp exchangers are crucial for intracellular pH homeostasis and Na+ efflux, essential mechanisms for H+ uptake under alkaline environments and for reduction of the intracellular concentration of toxic cations. Mrp displays no homology to any other monovalent Na+(K+)/H+ antiporters but Mrp subunits have primary sequence similarity to essential redox-driven proton pumps, such as respiratory complex I and membrane-bound hydrogenases. This similarity reinforces the hypothesis that these present day redox-driven proton pumps are descended from the Mrp antiporter. The Mrp structure serves as a model to understand the yet obscure coupling mechanism between ion or electron transfer and proton translocation in this large group of proteins. In the thesis, I am presenting the purification, biochemical analysis, cryo-EM analysis and molecular structure of the Mrp complex from Anoxybacillus flavithermus solved by cryo-EM at 3.0 Å resolution. Numerous conditions were screened to purify Mrp to high homogeneity and to obtain an appropriate distribution of single particles on cryo-EM grids covered with a continuous layer of ultrathin carbon. A preferred particle orientation problem was solved by performing a tilted data collection. The activity assays showed the specific pH-dependent\r\nprofile of secondary active antiporters. The molecular structure shows that Mrp is a dimer of seven-subunit protomers with 50 trans-membrane helices each. The dimer interface is built by many short and tilted transmembrane helices, probably causing a thinning of the bacterial membrane. The surface charge distribution shows an extraordinary asymmetry within each monomer, revealing presumable proton and sodium translocation pathways. The two largest\r\nand homologous Mrp subunits MrpA and MrpD probably translocate one proton each into the cell. The sodium ion is likely being translocated in the opposite direction within the small subunits along a ladder of charged and conserved residues. Based on the structure, we propose a mechanism were the antiport activity is accomplished via electrostatic interactions between the charged cations and key charged residues. The flexible key TM helices coordinate these\r\nelectrostatic interactions, while the membrane thinning between the monomers enables the translocation of sodium across the charged membrane. The entire family of redox-driven proton pumps is likely to perform their mechanism in a likewise manner."}],"status":"public","has_accepted_license":"1","language":[{"iso":"eng"}]},{"author":[{"first_name":"Andreea","last_name":"Andrei","full_name":"Andrei, Andreea"},{"first_name":"Yavuz","full_name":"Öztürk, Yavuz","last_name":"Öztürk"},{"full_name":"Khalfaoui-Hassani, Bahia","last_name":"Khalfaoui-Hassani","first_name":"Bahia"},{"last_name":"Rauch","full_name":"Rauch, Juna","first_name":"Juna"},{"last_name":"Marckmann","full_name":"Marckmann, Dorian","first_name":"Dorian"},{"full_name":"Trasnea, Petru Iulian","last_name":"Trasnea","id":"D560034C-10C4-11EA-ABF4-A4B43DDC885E","first_name":"Petru Iulian"},{"last_name":"Daldal","full_name":"Daldal, Fevzi","first_name":"Fevzi"},{"first_name":"Hans-Georg","last_name":"Koch","full_name":"Koch, Hans-Georg"}],"isi":1,"year":"2020","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"publication_identifier":{"eissn":["20770375"]},"department":[{"_id":"LeSa"}],"day":"01","publisher":"MDPI","oa_version":"Published Version","doi":"10.3390/membranes10090242","quality_controlled":"1","language":[{"iso":"eng"}],"has_accepted_license":"1","status":"public","publication_status":"published","abstract":[{"lang":"eng","text":"Copper (Cu) is an essential trace element for all living organisms and used as cofactor in key enzymes of important biological processes, such as aerobic respiration or superoxide dismutation. However, due to its toxicity, cells have developed elaborate mechanisms for Cu homeostasis, which balance Cu supply for cuproprotein biogenesis with the need to remove excess Cu. This review summarizes our current knowledge on bacterial Cu homeostasis with a focus on Gram-negative bacteria and describes the multiple strategies that bacteria use for uptake, storage and export of Cu. We furthermore describe general mechanistic principles that aid the bacterial response to toxic Cu concentrations and illustrate dedicated Cu relay systems that facilitate Cu delivery for cuproenzyme biogenesis. Progress in understanding how bacteria avoid Cu poisoning while maintaining a certain Cu quota for cell proliferation is of particular importance for microbial pathogens because Cu is utilized by the host immune system for attenuating pathogen survival in host cells."}],"article_type":"original","ddc":["570"],"citation":{"ama":"Andrei A, Öztürk Y, Khalfaoui-Hassani B, et al. Cu homeostasis in bacteria: The ins and outs. Membranes. 2020;10(9). doi:10.3390/membranes10090242","chicago":"Andrei, Andreea, Yavuz Öztürk, Bahia Khalfaoui-Hassani, Juna Rauch, Dorian Marckmann, Petru Iulian Trasnea, Fevzi Daldal, and Hans-Georg Koch. “Cu Homeostasis in Bacteria: The Ins and Outs.” Membranes. MDPI, 2020. https://doi.org/10.3390/membranes10090242.","ista":"Andrei A, Öztürk Y, Khalfaoui-Hassani B, Rauch J, Marckmann D, Trasnea PI, Daldal F, Koch H-G. 2020. Cu homeostasis in bacteria: The ins and outs. Membranes. 10(9), 242.","mla":"Andrei, Andreea, et al. “Cu Homeostasis in Bacteria: The Ins and Outs.” Membranes, vol. 10, no. 9, 242, MDPI, 2020, doi:10.3390/membranes10090242.","apa":"Andrei, A., Öztürk, Y., Khalfaoui-Hassani, B., Rauch, J., Marckmann, D., Trasnea, P. I., … Koch, H.-G. (2020). Cu homeostasis in bacteria: The ins and outs. Membranes. MDPI. https://doi.org/10.3390/membranes10090242","short":"A. Andrei, Y. Öztürk, B. Khalfaoui-Hassani, J. Rauch, D. Marckmann, P.I. Trasnea, F. Daldal, H.-G. Koch, Membranes 10 (2020).","ieee":"A. Andrei et al., “Cu homeostasis in bacteria: The ins and outs,” Membranes, vol. 10, no. 9. MDPI, 2020."},"type":"journal_article","file":[{"checksum":"ceb43d7554e712dea6f36f9287271737","relation":"main_file","date_updated":"2020-09-28T11:36:50Z","content_type":"application/pdf","file_size":4612258,"file_name":"2020_Membranes_Andrei.pdf","success":1,"access_level":"open_access","file_id":"8583","creator":"dernst","date_created":"2020-09-28T11:36:50Z"}],"date_published":"2020-09-01T00:00:00Z","article_processing_charge":"No","month":"09","title":"Cu homeostasis in bacteria: The ins and outs","date_updated":"2023-08-22T09:34:06Z","date_created":"2020-09-28T08:59:26Z","external_id":{"isi":["000581446000001"]},"_id":"8579","file_date_updated":"2020-09-28T11:36:50Z","publication":"Membranes","issue":"9","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","intvolume":" 10","oa":1,"article_number":"242","volume":10,"scopus_import":"1"},{"date_updated":"2023-08-22T09:33:09Z","title":"Cryo-EM structure of the entire mammalian F-type ATP synthase","month":"11","article_processing_charge":"No","date_published":"2020-11-01T00:00:00Z","publication":"Nature Structural and Molecular Biology","page":"1077-1085","_id":"8581","external_id":{"isi":["000569299400004"],"pmid":["32929284"]},"date_created":"2020-09-28T08:59:27Z","related_material":{"link":[{"description":"News on IST Homepage","url":"https://ist.ac.at/en/news/structure-of-atpase-solved/","relation":"press_release"}]},"volume":27,"intvolume":" 27","acknowledgement":"We thank J. Novacek from CEITEC (Brno, Czech Republic) for assistance with collecting the FEI Krios dataset and iNEXT for providing access to CEITEC. We thank the IST Austria EM facility for access and assistance with collecting the FEI Glacios dataset. Data processing was performed at the IST high-performance computing cluster. This work has been supported by iNEXT EM HEDC (proposal 4506), funded by the Horizon 2020 Programme of the European Commission.","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","issue":"11","scopus_import":"1","department":[{"_id":"LeSa"}],"publication_identifier":{"eissn":["15459985"],"issn":["15459993"]},"year":"2020","author":[{"full_name":"Pinke, Gergely","last_name":"Pinke","first_name":"Gergely","id":"4D5303E6-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Zhou","orcid":"0000-0002-1864-8951","full_name":"Zhou, Long","first_name":"Long","id":"3E751364-F248-11E8-B48F-1D18A9856A87"},{"id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A","full_name":"Sazanov, Leonid A","orcid":"0000-0002-0977-7989","last_name":"Sazanov"}],"isi":1,"doi":"10.1038/s41594-020-0503-8","oa_version":"None","publisher":"Springer Nature","day":"01","abstract":[{"lang":"eng","text":"The majority of adenosine triphosphate (ATP) powering cellular processes in eukaryotes is produced by the mitochondrial F1Fo ATP synthase. Here, we present the atomic models of the membrane Fo domain and the entire mammalian (ovine) F1Fo, determined by cryo-electron microscopy. Subunits in the membrane domain are arranged in the ‘proton translocation cluster’ attached to the c-ring and a more distant ‘hook apparatus’ holding subunit e. Unexpectedly, this subunit is anchored to a lipid ‘plug’ capping the c-ring. We present a detailed proton translocation pathway in mammalian Fo and key inter-monomer contacts in F1Fo multimers. Cryo-EM maps of F1Fo exposed to calcium reveal a retracted subunit e and a disassembled c-ring, suggesting permeability transition pore opening. We propose a model for the permeability transition pore opening, whereby subunit e pulls the lipid plug out of the c-ring. Our structure will allow the design of drugs for many emerging applications in medicine."}],"publication_status":"published","pmid":1,"status":"public","language":[{"iso":"eng"}],"quality_controlled":"1","citation":{"ama":"Pinke G, Zhou L, Sazanov LA. Cryo-EM structure of the entire mammalian F-type ATP synthase. Nature Structural and Molecular Biology. 2020;27(11):1077-1085. doi:10.1038/s41594-020-0503-8","chicago":"Pinke, Gergely, Long Zhou, and Leonid A Sazanov. “Cryo-EM Structure of the Entire Mammalian F-Type ATP Synthase.” Nature Structural and Molecular Biology. Springer Nature, 2020. https://doi.org/10.1038/s41594-020-0503-8.","mla":"Pinke, Gergely, et al. “Cryo-EM Structure of the Entire Mammalian F-Type ATP Synthase.” Nature Structural and Molecular Biology, vol. 27, no. 11, Springer Nature, 2020, pp. 1077–85, doi:10.1038/s41594-020-0503-8.","ista":"Pinke G, Zhou L, Sazanov LA. 2020. Cryo-EM structure of the entire mammalian F-type ATP synthase. Nature Structural and Molecular Biology. 27(11), 1077–1085.","apa":"Pinke, G., Zhou, L., & Sazanov, L. A. (2020). Cryo-EM structure of the entire mammalian F-type ATP synthase. Nature Structural and Molecular Biology. Springer Nature. https://doi.org/10.1038/s41594-020-0503-8","short":"G. Pinke, L. Zhou, L.A. Sazanov, Nature Structural and Molecular Biology 27 (2020) 1077–1085.","ieee":"G. Pinke, L. Zhou, and L. A. Sazanov, “Cryo-EM structure of the entire mammalian F-type ATP synthase,” Nature Structural and Molecular Biology, vol. 27, no. 11. Springer Nature, pp. 1077–1085, 2020."},"type":"journal_article","acknowledged_ssus":[{"_id":"EM-Fac"},{"_id":"ScienComp"}],"article_type":"original"},{"acknowledgement":"We thank J. Novacek (CEITEC Brno) and V.-V. Hodirnau (IST Austria) for their help with collecting cryo-EM datasets. We thank the IST Life Science and Electron Microscopy Facilities for providing equipment. This work has been supported by iNEXT,project number 653706, funded by the Horizon 2020 program of the European Union. This article reflects only the authors’view,and the European Commission is not responsible for any use that may be made of the information it contains. CIISB research infrastructure project LM2015043 funded by MEYS CR is gratefully acknowledged for the financial support of the measurements at the CF Cryo-electron Microscopy and Tomography CEITEC MU.This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement no. 665385","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","issue":"6516","oa":1,"intvolume":" 370","article_number":"eabc4209","volume":370,"scopus_import":"1","ec_funded":1,"date_published":"2020-10-30T00:00:00Z","article_processing_charge":"No","month":"10","date_updated":"2023-08-22T12:35:38Z","title":"The coupling mechanism of mammalian respiratory complex I","date_created":"2020-11-08T23:01:23Z","external_id":{"isi":["000583031800004"],"pmid":["32972993"]},"project":[{"name":"International IST Doctoral Program","call_identifier":"H2020","_id":"2564DBCA-B435-11E9-9278-68D0E5697425","grant_number":"665385"}],"_id":"8737","file_date_updated":"2020-11-26T18:47:58Z","publication":"Science","quality_controlled":"1","language":[{"iso":"eng"}],"pmid":1,"status":"public","has_accepted_license":"1","abstract":[{"lang":"eng","text":"Mitochondrial complex I couples NADH:ubiquinone oxidoreduction to proton pumping by an unknown mechanism. Here, we present cryo-electron microscopy structures of ovine complex I in five different conditions, including turnover, at resolutions up to 2.3 to 2.5 angstroms. Resolved water molecules allowed us to experimentally define the proton translocation pathways. Quinone binds at three positions along the quinone cavity, as does the inhibitor rotenone that also binds within subunit ND4. Dramatic conformational changes around the quinone cavity couple the redox reaction to proton translocation during open-to-closed state transitions of the enzyme. In the induced deactive state, the open conformation is arrested by the ND6 subunit. We propose a detailed molecular coupling mechanism of complex I, which is an unexpected combination of conformational changes and electrostatic interactions."}],"publication_status":"published","article_type":"original","acknowledged_ssus":[{"_id":"LifeSc"},{"_id":"EM-Fac"}],"ddc":["572"],"citation":{"ieee":"D. Kampjut and L. A. Sazanov, “The coupling mechanism of mammalian respiratory complex I,” Science, vol. 370, no. 6516. American Association for the Advancement of Science, 2020.","short":"D. Kampjut, L.A. Sazanov, Science 370 (2020).","apa":"Kampjut, D., & Sazanov, L. A. (2020). The coupling mechanism of mammalian respiratory complex I. Science. American Association for the Advancement of Science. https://doi.org/10.1126/science.abc4209","ista":"Kampjut D, Sazanov LA. 2020. The coupling mechanism of mammalian respiratory complex I. Science. 370(6516), eabc4209.","mla":"Kampjut, Domen, and Leonid A. Sazanov. “The Coupling Mechanism of Mammalian Respiratory Complex I.” Science, vol. 370, no. 6516, eabc4209, American Association for the Advancement of Science, 2020, doi:10.1126/science.abc4209.","chicago":"Kampjut, Domen, and Leonid A Sazanov. “The Coupling Mechanism of Mammalian Respiratory Complex I.” Science. American Association for the Advancement of Science, 2020. https://doi.org/10.1126/science.abc4209.","ama":"Kampjut D, Sazanov LA. The coupling mechanism of mammalian respiratory complex I. Science. 2020;370(6516). doi:10.1126/science.abc4209"},"type":"journal_article","file":[{"file_id":"8820","date_created":"2020-11-26T18:47:58Z","creator":"lsazanov","relation":"main_file","checksum":"658ba90979ca9528a2efdfac8547047a","file_size":7618987,"content_type":"application/pdf","date_updated":"2020-11-26T18:47:58Z","file_name":"Full_manuscript_with_SI_opt_red.pdf","access_level":"open_access","success":1}],"author":[{"full_name":"Kampjut, Domen","last_name":"Kampjut","id":"37233050-F248-11E8-B48F-1D18A9856A87","first_name":"Domen"},{"full_name":"Sazanov, Leonid A","orcid":"0000-0002-0977-7989","last_name":"Sazanov","id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A"}],"isi":1,"year":"2020","department":[{"_id":"LeSa"}],"publication_identifier":{"eissn":["10959203"]},"day":"30","publisher":"American Association for the Advancement of Science","oa_version":"Submitted Version","doi":"10.1126/science.abc4209"},{"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","oa":1,"status":"public","abstract":[{"text":"The mitochondrial respiratory chain, formed by five protein complexes, utilizes energy from catabolic processes to synthesize ATP. Complex I, the first and the largest protein complex of the chain, harvests electrons from NADH to reduce quinone, while pumping protons across the mitochondrial membrane. Detailed knowledge of the working principle of such coupled charge-transfer processes remains, however, fragmentary due to bottlenecks in understanding redox-driven conformational transitions and their interplay with the hydrated proton pathways. Complex I from Thermus thermophilus encases 16 subunits with nine iron–sulfur clusters, reduced by electrons from NADH. Here, employing the latest crystal structure of T. thermophilus complex I, we have used microsecond-scale molecular dynamics simulations to study the chemo-mechanical coupling between redox changes of the iron–sulfur clusters and conformational transitions across complex I. First, we identify the redox switches within complex I, which allosterically couple the dynamics of the quinone binding pocket to the site of NADH reduction. Second, our free-energy calculations reveal that the affinity of the quinone, specifically menaquinone, for the binding-site is higher than that of its reduced, menaquinol forma design essential for menaquinol release. Remarkably, the barriers to diffusive menaquinone dynamics are lesser than that of the more ubiquitous ubiquinone, and the naphthoquinone headgroup of the former furnishes stronger binding interactions with the pocket, favoring menaquinone for charge transport in T. thermophilus. Our computations are consistent with experimentally validated mutations and hierarchize the key residues into three functional classes, identifying new mutation targets. Third, long-range hydrogen-bond networks connecting the quinone-binding site to the transmembrane subunits are found to be responsible for proton pumping. Put together, the simulations reveal the molecular design principles linking redox reactions to quinone turnover to proton translocation in complex I.","lang":"eng"}],"related_material":{"record":[{"id":"8040","relation":"used_in_publication","status":"public"}]},"main_file_link":[{"open_access":"1"}],"type":"research_data_reference","citation":{"short":"C. Gupta, U. Khaniya, C. Chan, F. Dehez, M. Shekhar, M.R. Gunner, L.A. Sazanov, C. Chipot, A. Singharoy, (2020).","apa":"Gupta, C., Khaniya, U., Chan, C., Dehez, F., Shekhar, M., Gunner, M. R., … Singharoy, A. (2020). Charge transfer and chemo-mechanical coupling in respiratory complex I. American Chemical Society. https://doi.org/10.1021/jacs.9b13450.s002","ieee":"C. Gupta et al., “Charge transfer and chemo-mechanical coupling in respiratory complex I.” American Chemical Society, 2020.","chicago":"Gupta, Chitrak, Umesh Khaniya, Chun Chan, Francois Dehez, Mrinal Shekhar, M. R. Gunner, Leonid A Sazanov, Christophe Chipot, and Abhishek Singharoy. “Charge Transfer and Chemo-Mechanical Coupling in Respiratory Complex I.” American Chemical Society, 2020. https://doi.org/10.1021/jacs.9b13450.s002.","ama":"Gupta C, Khaniya U, Chan C, et al. Charge transfer and chemo-mechanical coupling in respiratory complex I. 2020. doi:10.1021/jacs.9b13450.s002","mla":"Gupta, Chitrak, et al. Charge Transfer and Chemo-Mechanical Coupling in Respiratory Complex I. American Chemical Society, 2020, doi:10.1021/jacs.9b13450.s002.","ista":"Gupta C, Khaniya U, Chan C, Dehez F, Shekhar M, Gunner MR, Sazanov LA, Chipot C, Singharoy A. 2020. Charge transfer and chemo-mechanical coupling in respiratory complex I, American Chemical Society, 10.1021/jacs.9b13450.s002."},"author":[{"first_name":"Chitrak","last_name":"Gupta","full_name":"Gupta, Chitrak"},{"first_name":"Umesh","last_name":"Khaniya","full_name":"Khaniya, Umesh"},{"first_name":"Chun","last_name":"Chan","full_name":"Chan, Chun"},{"last_name":"Dehez","full_name":"Dehez, Francois","first_name":"Francois"},{"full_name":"Shekhar, Mrinal","last_name":"Shekhar","first_name":"Mrinal"},{"first_name":"M. R.","last_name":"Gunner","full_name":"Gunner, M. R."},{"id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A","last_name":"Sazanov","full_name":"Sazanov, Leonid A","orcid":"0000-0002-0977-7989"},{"first_name":"Christophe","full_name":"Chipot, Christophe","last_name":"Chipot"},{"full_name":"Singharoy, Abhishek","last_name":"Singharoy","first_name":"Abhishek"}],"date_published":"2020-05-20T00:00:00Z","year":"2020","article_processing_charge":"No","tmp":{"image":"/images/cc_by_nc.png","name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode","short":"CC BY-NC (4.0)"},"month":"05","date_updated":"2023-08-22T07:49:37Z","title":"Charge transfer and chemo-mechanical coupling in respiratory complex I","department":[{"_id":"LeSa"}],"date_created":"2021-04-14T12:05:20Z","day":"20","publisher":"American Chemical Society","_id":"9326","oa_version":"Published Version","doi":"10.1021/jacs.9b13450.s002"},{"volume":1861,"intvolume":" 1861","oa":1,"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","issue":"8","article_number":"148213","scopus_import":"1","month":"08","date_updated":"2023-08-21T06:19:18Z","title":"NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2","article_processing_charge":"No","date_published":"2020-08-01T00:00:00Z","publication":"Biochimica et Biophysica Acta - Bioenergetics","file_date_updated":"2020-07-14T12:48:03Z","external_id":{"pmid":["32335026"],"isi":["000540842000012"]},"date_created":"2020-05-03T22:00:47Z","_id":"7788","pmid":1,"has_accepted_license":"1","status":"public","language":[{"iso":"eng"}],"abstract":[{"text":"Mutations in NDUFS4, which encodes an accessory subunit of mitochondrial oxidative phosphorylation (OXPHOS) complex I (CI), induce Leigh syndrome (LS). LS is a poorly understood pediatric disorder featuring brain-specific anomalies and early death. To study the LS pathomechanism, we here compared OXPHOS proteomes between various Ndufs4−/− mouse tissues. Ndufs4−/− animals displayed significantly lower CI subunit levels in brain/diaphragm relative to other tissues (liver/heart/kidney/skeletal muscle), whereas other OXPHOS subunit levels were not reduced. Absence of NDUFS4 induced near complete absence of the NDUFA12 accessory subunit, a 50% reduction in other CI subunit levels, and an increase in specific CI assembly factors. Among the latter, NDUFAF2 was most highly increased. Regarding NDUFS4, NDUFA12 and NDUFAF2, identical results were obtained in Ndufs4−/− mouse embryonic fibroblasts (MEFs) and NDUFS4-mutated LS patient cells. Ndufs4−/− MEFs contained active CI in situ but blue-native-PAGE highlighted that NDUFAF2 attached to an inactive CI subcomplex (CI-830) and inactive assemblies of higher MW. In NDUFA12-mutated LS patient cells, NDUFA12 absence did not reduce NDUFS4 levels but triggered NDUFAF2 association to active CI. BN-PAGE revealed no such association in LS patient fibroblasts with mutations in other CI subunit-encoding genes where NDUFAF2 was attached to CI-830 (NDUFS1, NDUFV1 mutation) or not detected (NDUFS7 mutation). Supported by enzymological and CI in silico structural analysis, we conclude that absence of NDUFS4 induces near complete absence of NDUFA12 but not vice versa, and that NDUFAF2 stabilizes active CI in Ndufs4−/− mice and LS patient cells, perhaps in concert with mitochondrial inner membrane lipids.","lang":"eng"}],"publication_status":"published","quality_controlled":"1","type":"journal_article","citation":{"short":"M.J.W. Adjobo-Hermans, R. De Haas, P.H.G.M. Willems, A. Wojtala, S.E. Van Emst-De Vries, J.A. Wagenaars, M. Van Den Brand, R.J. Rodenburg, J.A.M. Smeitink, L.G. Nijtmans, L.A. Sazanov, M.R. Wieckowski, W.J.H. Koopman, Biochimica et Biophysica Acta - Bioenergetics 1861 (2020).","apa":"Adjobo-Hermans, M. J. W., De Haas, R., Willems, P. H. G. M., Wojtala, A., Van Emst-De Vries, S. E., Wagenaars, J. A., … Koopman, W. J. H. (2020). NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2. Biochimica et Biophysica Acta - Bioenergetics. Elsevier. https://doi.org/10.1016/j.bbabio.2020.148213","ieee":"M. J. W. Adjobo-Hermans et al., “NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2,” Biochimica et Biophysica Acta - Bioenergetics, vol. 1861, no. 8. Elsevier, 2020.","chicago":"Adjobo-Hermans, Merel J.W., Ria De Haas, Peter H.G.M. Willems, Aleksandra Wojtala, Sjenet E. Van Emst-De Vries, Jori A. Wagenaars, Mariel Van Den Brand, et al. “NDUFS4 Deletion Triggers Loss of NDUFA12 in Ndufs4−/− Mice and Leigh Syndrome Patients: A Stabilizing Role for NDUFAF2.” Biochimica et Biophysica Acta - Bioenergetics. Elsevier, 2020. https://doi.org/10.1016/j.bbabio.2020.148213.","ama":"Adjobo-Hermans MJW, De Haas R, Willems PHGM, et al. NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2. Biochimica et Biophysica Acta - Bioenergetics. 2020;1861(8). doi:10.1016/j.bbabio.2020.148213","ista":"Adjobo-Hermans MJW, De Haas R, Willems PHGM, Wojtala A, Van Emst-De Vries SE, Wagenaars JA, Van Den Brand M, Rodenburg RJ, Smeitink JAM, Nijtmans LG, Sazanov LA, Wieckowski MR, Koopman WJH. 2020. NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2. Biochimica et Biophysica Acta - Bioenergetics. 1861(8), 148213.","mla":"Adjobo-Hermans, Merel J. W., et al. “NDUFS4 Deletion Triggers Loss of NDUFA12 in Ndufs4−/− Mice and Leigh Syndrome Patients: A Stabilizing Role for NDUFAF2.” Biochimica et Biophysica Acta - Bioenergetics, vol. 1861, no. 8, 148213, Elsevier, 2020, doi:10.1016/j.bbabio.2020.148213."},"file":[{"file_size":3826792,"date_updated":"2020-07-14T12:48:03Z","content_type":"application/pdf","checksum":"a9b152381307cf45fe266a8dc5640388","relation":"main_file","access_level":"open_access","file_name":"2020_BBA_Adjobo_Hermans.pdf","file_id":"7798","creator":"dernst","date_created":"2020-05-04T12:25:19Z"}],"article_type":"original","ddc":["570"],"tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"department":[{"_id":"LeSa"}],"publication_identifier":{"issn":["00052728"],"eissn":["18792650"]},"year":"2020","author":[{"first_name":"Merel J.W.","full_name":"Adjobo-Hermans, Merel J.W.","last_name":"Adjobo-Hermans"},{"full_name":"De Haas, Ria","last_name":"De Haas","first_name":"Ria"},{"last_name":"Willems","full_name":"Willems, Peter H.G.M.","first_name":"Peter H.G.M."},{"first_name":"Aleksandra","full_name":"Wojtala, Aleksandra","last_name":"Wojtala"},{"full_name":"Van Emst-De Vries, Sjenet E.","last_name":"Van Emst-De Vries","first_name":"Sjenet E."},{"first_name":"Jori A.","last_name":"Wagenaars","full_name":"Wagenaars, Jori A."},{"last_name":"Van Den Brand","full_name":"Van Den Brand, Mariel","first_name":"Mariel"},{"full_name":"Rodenburg, Richard J.","last_name":"Rodenburg","first_name":"Richard J."},{"last_name":"Smeitink","full_name":"Smeitink, Jan A.M.","first_name":"Jan A.M."},{"first_name":"Leo G.","last_name":"Nijtmans","full_name":"Nijtmans, Leo G."},{"id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A","last_name":"Sazanov","full_name":"Sazanov, Leonid A","orcid":"0000-0002-0977-7989"},{"first_name":"Mariusz R.","full_name":"Wieckowski, Mariusz R.","last_name":"Wieckowski"},{"first_name":"Werner J.H.","last_name":"Koopman","full_name":"Koopman, Werner J.H."}],"isi":1,"oa_version":"Published Version","doi":"10.1016/j.bbabio.2020.148213","day":"01","publisher":"Elsevier"},{"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","issue":"20","intvolume":" 142","volume":142,"related_material":{"record":[{"id":"9326","status":"public","relation":"research_data"},{"relation":"research_data","status":"public","id":"9713"},{"id":"9878","status":"public","relation":"research_data"}]},"scopus_import":"1","date_published":"2020-05-20T00:00:00Z","article_processing_charge":"No","month":"05","date_updated":"2023-08-22T07:49:38Z","title":"Charge transfer and chemo-mechanical coupling in respiratory complex I","date_created":"2020-06-29T07:59:35Z","external_id":{"isi":["000537415600020"],"pmid":["32347721"]},"_id":"8040","page":"9220-9230","publication":"Journal of the American Chemical Society","quality_controlled":"1","language":[{"iso":"eng"}],"status":"public","pmid":1,"publication_status":"published","abstract":[{"lang":"eng","text":"The mitochondrial respiratory chain, formed by five protein complexes, utilizes energy from catabolic processes to synthesize ATP. Complex I, the first and the largest protein complex of the chain, harvests electrons from NADH to reduce quinone, while pumping protons across the mitochondrial membrane. Detailed knowledge of the working principle of such coupled charge-transfer processes remains, however, fragmentary due to bottlenecks in understanding redox-driven conformational transitions and their interplay with the hydrated proton pathways. Complex I from Thermus thermophilus encases 16 subunits with nine iron–sulfur clusters, reduced by electrons from NADH. Here, employing the latest crystal structure of T. thermophilus complex I, we have used microsecond-scale molecular dynamics simulations to study the chemo-mechanical coupling between redox changes of the iron–sulfur clusters and conformational transitions across complex I. First, we identify the redox switches within complex I, which allosterically couple the dynamics of the quinone binding pocket to the site of NADH reduction. Second, our free-energy calculations reveal that the affinity of the quinone, specifically menaquinone, for the binding-site is higher than that of its reduced, menaquinol form—a design essential for menaquinol release. Remarkably, the barriers to diffusive menaquinone dynamics are lesser than that of the more ubiquitous ubiquinone, and the naphthoquinone headgroup of the former furnishes stronger binding interactions with the pocket, favoring menaquinone for charge transport in T. thermophilus. Our computations are consistent with experimentally validated mutations and hierarchize the key residues into three functional classes, identifying new mutation targets. Third, long-range hydrogen-bond networks connecting the quinone-binding site to the transmembrane subunits are found to be responsible for proton pumping. Put together, the simulations reveal the molecular design principles linking redox reactions to quinone turnover to proton translocation in complex I."}],"article_type":"original","citation":{"ieee":"C. Gupta et al., “Charge transfer and chemo-mechanical coupling in respiratory complex I,” Journal of the American Chemical Society, vol. 142, no. 20. American Chemical Society, pp. 9220–9230, 2020.","short":"C. Gupta, U. Khaniya, C.K. Chan, F. Dehez, M. Shekhar, M.R. Gunner, L.A. Sazanov, C. Chipot, A. Singharoy, Journal of the American Chemical Society 142 (2020) 9220–9230.","apa":"Gupta, C., Khaniya, U., Chan, C. K., Dehez, F., Shekhar, M., Gunner, M. R., … Singharoy, A. (2020). Charge transfer and chemo-mechanical coupling in respiratory complex I. Journal of the American Chemical Society. American Chemical Society. https://doi.org/10.1021/jacs.9b13450","mla":"Gupta, Chitrak, et al. “Charge Transfer and Chemo-Mechanical Coupling in Respiratory Complex I.” Journal of the American Chemical Society, vol. 142, no. 20, American Chemical Society, 2020, pp. 9220–30, doi:10.1021/jacs.9b13450.","ista":"Gupta C, Khaniya U, Chan CK, Dehez F, Shekhar M, Gunner MR, Sazanov LA, Chipot C, Singharoy A. 2020. Charge transfer and chemo-mechanical coupling in respiratory complex I. Journal of the American Chemical Society. 142(20), 9220–9230.","chicago":"Gupta, Chitrak, Umesh Khaniya, Chun Kit Chan, Francois Dehez, Mrinal Shekhar, M. R. Gunner, Leonid A Sazanov, Christophe Chipot, and Abhishek Singharoy. “Charge Transfer and Chemo-Mechanical Coupling in Respiratory Complex I.” Journal of the American Chemical Society. American Chemical Society, 2020. https://doi.org/10.1021/jacs.9b13450.","ama":"Gupta C, Khaniya U, Chan CK, et al. Charge transfer and chemo-mechanical coupling in respiratory complex I. Journal of the American Chemical Society. 2020;142(20):9220-9230. doi:10.1021/jacs.9b13450"},"type":"journal_article","isi":1,"author":[{"full_name":"Gupta, Chitrak","last_name":"Gupta","first_name":"Chitrak"},{"first_name":"Umesh","full_name":"Khaniya, Umesh","last_name":"Khaniya"},{"first_name":"Chun Kit","full_name":"Chan, Chun Kit","last_name":"Chan"},{"last_name":"Dehez","full_name":"Dehez, Francois","first_name":"Francois"},{"full_name":"Shekhar, Mrinal","last_name":"Shekhar","first_name":"Mrinal"},{"first_name":"M. R.","last_name":"Gunner","full_name":"Gunner, M. R."},{"full_name":"Sazanov, Leonid A","orcid":"0000-0002-0977-7989","last_name":"Sazanov","id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A"},{"first_name":"Christophe","last_name":"Chipot","full_name":"Chipot, Christophe"},{"last_name":"Singharoy","full_name":"Singharoy, Abhishek","first_name":"Abhishek"}],"year":"2020","publication_identifier":{"eissn":["15205126"],"issn":["00027863"]},"department":[{"_id":"LeSa"}],"day":"20","publisher":"American Chemical Society","oa_version":"None","doi":"10.1021/jacs.9b13450"},{"_id":"9713","publisher":"American Chemical Society ","date_created":"2021-07-23T12:02:39Z","day":"20","doi":"10.1021/jacs.9b13450.s001","oa_version":"Published Version","date_published":"2020-05-20T00:00:00Z","author":[{"full_name":"Gupta, Chitrak","last_name":"Gupta","first_name":"Chitrak"},{"first_name":"Umesh","full_name":"Khaniya, Umesh","last_name":"Khaniya"},{"full_name":"Chan, Chun Kit","last_name":"Chan","first_name":"Chun Kit"},{"full_name":"Dehez, Francois","last_name":"Dehez","first_name":"Francois"},{"first_name":"Mrinal","last_name":"Shekhar","full_name":"Shekhar, Mrinal"},{"full_name":"Gunner, M.R.","last_name":"Gunner","first_name":"M.R."},{"last_name":"Sazanov","orcid":"0000-0002-0977-7989","full_name":"Sazanov, Leonid A","first_name":"Leonid A","id":"338D39FE-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Chipot, Christophe","last_name":"Chipot","first_name":"Christophe"},{"first_name":"Abhishek","last_name":"Singharoy","full_name":"Singharoy, Abhishek"}],"article_processing_charge":"No","year":"2020","date_updated":"2023-08-22T07:49:38Z","title":"Supporting information","department":[{"_id":"LeSa"}],"month":"05","type":"research_data_reference","citation":{"apa":"Gupta, C., Khaniya, U., Chan, C. K., Dehez, F., Shekhar, M., Gunner, M. R., … Singharoy, A. (2020). Supporting information. American Chemical Society . https://doi.org/10.1021/jacs.9b13450.s001","short":"C. Gupta, U. Khaniya, C.K. Chan, F. Dehez, M. Shekhar, M.R. Gunner, L.A. Sazanov, C. Chipot, A. Singharoy, (2020).","ieee":"C. Gupta et al., “Supporting information.” American Chemical Society , 2020.","ama":"Gupta C, Khaniya U, Chan CK, et al. Supporting information. 2020. doi:10.1021/jacs.9b13450.s001","chicago":"Gupta, Chitrak, Umesh Khaniya, Chun Kit Chan, Francois Dehez, Mrinal Shekhar, M.R. Gunner, Leonid A Sazanov, Christophe Chipot, and Abhishek Singharoy. “Supporting Information.” American Chemical Society , 2020. https://doi.org/10.1021/jacs.9b13450.s001.","mla":"Gupta, Chitrak, et al. Supporting Information. American Chemical Society , 2020, doi:10.1021/jacs.9b13450.s001.","ista":"Gupta C, Khaniya U, Chan CK, Dehez F, Shekhar M, Gunner MR, Sazanov LA, Chipot C, Singharoy A. 2020. Supporting information, American Chemical Society , 10.1021/jacs.9b13450.s001."},"user_id":"6785fbc1-c503-11eb-8a32-93094b40e1cf","abstract":[{"lang":"eng","text":"Additional analyses of the trajectories"}],"related_material":{"record":[{"id":"8040","status":"public","relation":"used_in_publication"}]},"status":"public"},{"user_id":"6785fbc1-c503-11eb-8a32-93094b40e1cf","status":"public","related_material":{"record":[{"status":"public","relation":"used_in_publication","id":"8040"}]},"citation":{"ista":"Gupta C, Khaniya U, Chan CK, Dehez F, Shekhar M, Gunner MR, Sazanov LA, Chipot C, Singharoy A. 2020. Movies, American Chemical Society, 10.1021/jacs.9b13450.s002.","mla":"Gupta, Chitrak, et al. Movies. American Chemical Society, 2020, doi:10.1021/jacs.9b13450.s002.","chicago":"Gupta, Chitrak, Umesh Khaniya, Chun Kit Chan, Francois Dehez, Mrinal Shekhar, M.R. Gunner, Leonid A Sazanov, Christophe Chipot, and Abhishek Singharoy. “Movies.” American Chemical Society, 2020. https://doi.org/10.1021/jacs.9b13450.s002.","ama":"Gupta C, Khaniya U, Chan CK, et al. Movies. 2020. doi:10.1021/jacs.9b13450.s002","ieee":"C. Gupta et al., “Movies.” American Chemical Society, 2020.","apa":"Gupta, C., Khaniya, U., Chan, C. K., Dehez, F., Shekhar, M., Gunner, M. R., … Singharoy, A. (2020). Movies. American Chemical Society. https://doi.org/10.1021/jacs.9b13450.s002","short":"C. Gupta, U. Khaniya, C.K. Chan, F. Dehez, M. Shekhar, M.R. Gunner, L.A. Sazanov, C. Chipot, A. Singharoy, (2020)."},"type":"research_data_reference","year":"2020","article_processing_charge":"No","author":[{"first_name":"Chitrak","full_name":"Gupta, Chitrak","last_name":"Gupta"},{"full_name":"Khaniya, Umesh","last_name":"Khaniya","first_name":"Umesh"},{"first_name":"Chun Kit","full_name":"Chan, Chun Kit","last_name":"Chan"},{"first_name":"Francois","last_name":"Dehez","full_name":"Dehez, Francois"},{"full_name":"Shekhar, Mrinal","last_name":"Shekhar","first_name":"Mrinal"},{"full_name":"Gunner, M.R.","last_name":"Gunner","first_name":"M.R."},{"id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A","full_name":"Sazanov, Leonid A","orcid":"0000-0002-0977-7989","last_name":"Sazanov"},{"full_name":"Chipot, Christophe","last_name":"Chipot","first_name":"Christophe"},{"last_name":"Singharoy","full_name":"Singharoy, Abhishek","first_name":"Abhishek"}],"date_published":"2020-05-20T00:00:00Z","month":"05","department":[{"_id":"LeSa"}],"title":"Movies","date_updated":"2023-08-22T07:49:38Z","day":"20","date_created":"2021-08-11T09:18:54Z","publisher":"American Chemical Society","_id":"9878","oa_version":"Published Version","doi":"10.1021/jacs.9b13450.s002"},{"external_id":{"isi":["000491128800062"]},"date_created":"2019-09-29T22:00:45Z","_id":"6919","publication":"Science Advances","file_date_updated":"2020-07-14T12:47:44Z","article_processing_charge":"No","date_published":"2019-09-18T00:00:00Z","month":"09","date_updated":"2023-08-30T06:55:31Z","title":"Structural basis of sterol recognition by human hedgehog receptor PTCH1","scopus_import":"1","intvolume":" 5","oa":1,"issue":"9","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","article_number":"eaaw6490","volume":5,"day":"18","publisher":"American Association for the Advancement of Science","oa_version":"Published Version","doi":"10.1126/sciadv.aaw6490","year":"2019","isi":1,"author":[{"full_name":"Qi, Chao","last_name":"Qi","first_name":"Chao"},{"first_name":"Giulio Di","last_name":"Minin","full_name":"Minin, Giulio Di"},{"full_name":"Vercellino, Irene","orcid":"0000-0001-5618-3449","last_name":"Vercellino","id":"3ED6AF16-F248-11E8-B48F-1D18A9856A87","first_name":"Irene"},{"first_name":"Anton","full_name":"Wutz, Anton","last_name":"Wutz"},{"full_name":"Korkhov, Volodymyr M.","last_name":"Korkhov","first_name":"Volodymyr M."}],"tmp":{"image":"/images/cc_by_nc.png","name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode","short":"CC BY-NC (4.0)"},"publication_identifier":{"eissn":["23752548"]},"department":[{"_id":"LeSa"}],"ddc":["570"],"type":"journal_article","citation":{"ieee":"C. Qi, G. D. Minin, I. Vercellino, A. Wutz, and V. M. Korkhov, “Structural basis of sterol recognition by human hedgehog receptor PTCH1,” Science Advances, vol. 5, no. 9. American Association for the Advancement of Science, 2019.","short":"C. Qi, G.D. Minin, I. Vercellino, A. Wutz, V.M. Korkhov, Science Advances 5 (2019).","apa":"Qi, C., Minin, G. D., Vercellino, I., Wutz, A., & Korkhov, V. M. (2019). Structural basis of sterol recognition by human hedgehog receptor PTCH1. Science Advances. American Association for the Advancement of Science. https://doi.org/10.1126/sciadv.aaw6490","ista":"Qi C, Minin GD, Vercellino I, Wutz A, Korkhov VM. 2019. Structural basis of sterol recognition by human hedgehog receptor PTCH1. Science Advances. 5(9), eaaw6490.","mla":"Qi, Chao, et al. “Structural Basis of Sterol Recognition by Human Hedgehog Receptor PTCH1.” Science Advances, vol. 5, no. 9, eaaw6490, American Association for the Advancement of Science, 2019, doi:10.1126/sciadv.aaw6490.","ama":"Qi C, Minin GD, Vercellino I, Wutz A, Korkhov VM. Structural basis of sterol recognition by human hedgehog receptor PTCH1. Science Advances. 2019;5(9). doi:10.1126/sciadv.aaw6490","chicago":"Qi, Chao, Giulio Di Minin, Irene Vercellino, Anton Wutz, and Volodymyr M. Korkhov. “Structural Basis of Sterol Recognition by Human Hedgehog Receptor PTCH1.” Science Advances. American Association for the Advancement of Science, 2019. https://doi.org/10.1126/sciadv.aaw6490."},"file":[{"date_created":"2019-10-02T11:13:54Z","creator":"kschuh","file_id":"6928","access_level":"open_access","file_name":"2019_AAAS_Qi.pdf","file_size":1236101,"content_type":"application/pdf","date_updated":"2020-07-14T12:47:44Z","checksum":"b2256c9117655bc15f621ba0babf219f","relation":"main_file"}],"quality_controlled":"1","status":"public","has_accepted_license":"1","language":[{"iso":"eng"}],"publication_status":"published"},{"doi":"10.1016/j.molcel.2019.07.022","oa_version":"Published Version","publisher":"Cell Press","day":"19","publication_identifier":{"issn":["1097-2765"]},"department":[{"_id":"LeSa"}],"tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"isi":1,"author":[{"full_name":"Letts, James A","orcid":"0000-0002-9864-3586","last_name":"Letts","id":"322DA418-F248-11E8-B48F-1D18A9856A87","first_name":"James A"},{"id":"5BFF67CE-02D1-11E9-B11A-A5A4D7DFFFD0","first_name":"Karol","full_name":"Fiedorczuk, Karol","last_name":"Fiedorczuk"},{"last_name":"Degliesposti","full_name":"Degliesposti, Gianluca","first_name":"Gianluca"},{"first_name":"Mark","last_name":"Skehel","full_name":"Skehel, Mark"},{"id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A","full_name":"Sazanov, Leonid A","orcid":"0000-0002-0977-7989","last_name":"Sazanov"}],"year":"2019","file":[{"date_created":"2020-02-04T10:37:28Z","creator":"dernst","file_id":"7447","access_level":"open_access","file_name":"2019_MolecularCell_Letts.pdf","file_size":9654895,"date_updated":"2020-07-14T12:47:57Z","content_type":"application/pdf","relation":"main_file","checksum":"5202f53a237d6650ece038fbf13bdcea"}],"type":"journal_article","citation":{"apa":"Letts, J. A., Fiedorczuk, K., Degliesposti, G., Skehel, M., & Sazanov, L. A. (2019). Structures of respiratory supercomplex I+III2 reveal functional and conformational crosstalk. Molecular Cell. Cell Press. https://doi.org/10.1016/j.molcel.2019.07.022","short":"J.A. Letts, K. Fiedorczuk, G. Degliesposti, M. Skehel, L.A. Sazanov, Molecular Cell 75 (2019) 1131–1146.e6.","ieee":"J. A. Letts, K. Fiedorczuk, G. Degliesposti, M. Skehel, and L. A. Sazanov, “Structures of respiratory supercomplex I+III2 reveal functional and conformational crosstalk,” Molecular Cell, vol. 75, no. 6. Cell Press, p. 1131–1146.e6, 2019.","ama":"Letts JA, Fiedorczuk K, Degliesposti G, Skehel M, Sazanov LA. Structures of respiratory supercomplex I+III2 reveal functional and conformational crosstalk. Molecular Cell. 2019;75(6):1131-1146.e6. doi:10.1016/j.molcel.2019.07.022","chicago":"Letts, James A, Karol Fiedorczuk, Gianluca Degliesposti, Mark Skehel, and Leonid A Sazanov. “Structures of Respiratory Supercomplex I+III2 Reveal Functional and Conformational Crosstalk.” Molecular Cell. Cell Press, 2019. https://doi.org/10.1016/j.molcel.2019.07.022.","ista":"Letts JA, Fiedorczuk K, Degliesposti G, Skehel M, Sazanov LA. 2019. Structures of respiratory supercomplex I+III2 reveal functional and conformational crosstalk. Molecular Cell. 75(6), 1131–1146.e6.","mla":"Letts, James A., et al. “Structures of Respiratory Supercomplex I+III2 Reveal Functional and Conformational Crosstalk.” Molecular Cell, vol. 75, no. 6, Cell Press, 2019, p. 1131–1146.e6, doi:10.1016/j.molcel.2019.07.022."},"ddc":["570"],"article_type":"original","abstract":[{"lang":"eng","text":"The mitochondrial electron transport chain complexes are organized into supercomplexes (SCs) of defined stoichiometry, which have been proposed to regulate electron flux via substrate channeling. We demonstrate that CoQ trapping in the isolated SC I+III2 limits complex (C)I turnover, arguing against channeling. The SC structure, resolved at up to 3.8 Å in four distinct states, suggests that CoQ oxidation may be rate limiting because of unequal access of CoQ to the active sites of CIII2. CI shows a transition between “closed” and “open” conformations, accompanied by the striking rotation of a key transmembrane helix. Furthermore, the state of CI affects the conformational flexibility within CIII2, demonstrating crosstalk between the enzymes. CoQ was identified at only three of the four binding sites in CIII2, suggesting that interaction with CI disrupts CIII2 symmetry in a functionally relevant manner. Together, these observations indicate a more nuanced functional role for the SCs."}],"publication_status":"published","language":[{"iso":"eng"}],"has_accepted_license":"1","status":"public","pmid":1,"quality_controlled":"1","file_date_updated":"2020-07-14T12:47:57Z","publication":"Molecular Cell","page":"1131-1146.e6","project":[{"call_identifier":"H2020","_id":"2590DB08-B435-11E9-9278-68D0E5697425","grant_number":"701309","name":"Atomic-Resolution Structures of Mitochondrial Respiratory Chain Supercomplexes"}],"_id":"7395","date_created":"2020-01-29T16:02:33Z","external_id":{"isi":["000486614200006"],"pmid":["31492636"]},"title":"Structures of respiratory supercomplex I+III2 reveal functional and conformational crosstalk","date_updated":"2023-09-07T14:53:06Z","month":"09","date_published":"2019-09-19T00:00:00Z","article_processing_charge":"No","ec_funded":1,"scopus_import":"1","volume":75,"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","issue":"6","oa":1,"intvolume":" 75"},{"article_processing_charge":"Yes (via OA deal)","date_published":"2019-04-12T00:00:00Z","month":"04","date_updated":"2023-08-25T10:14:26Z","title":"Protective properties of the cultured stem cell proteome studied in an animal model of acetaminophen-induced acute liver failure","external_id":{"isi":["000470332600049"]},"date_created":"2019-04-28T21:59:14Z","_id":"6352","publication":"Molecular Biology Reports","file_date_updated":"2020-07-14T12:47:28Z","oa":1,"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","acknowledgement":"The studies were supported by the Austrian Federal Ministry of Economy, Family and Youth through the initiative “Laura Bassi Centres of Expertise” funding the Center of Optimized Structural Stud-ies, grant No. 253275","scopus_import":"1","year":"2019","isi":1,"author":[{"last_name":"Temnov","full_name":"Temnov, Andrey Alexandrovich","first_name":"Andrey Alexandrovich"},{"last_name":"Rogov","full_name":"Rogov, Konstantin Arkadevich","first_name":"Konstantin Arkadevich"},{"first_name":"Alla Nikolaevna","last_name":"Sklifas","full_name":"Sklifas, Alla Nikolaevna"},{"full_name":"Klychnikova, Elena Valerievna","last_name":"Klychnikova","first_name":"Elena Valerievna"},{"first_name":"Markus","last_name":"Hartl","full_name":"Hartl, Markus"},{"first_name":"Kristina","last_name":"Djinovic-Carugo","full_name":"Djinovic-Carugo, Kristina"},{"full_name":"Charnagalov, Alexej","last_name":"Charnagalov","first_name":"Alexej","id":"49F06DBA-F248-11E8-B48F-1D18A9856A87"}],"tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"department":[{"_id":"LeSa"}],"publication_identifier":{"eissn":["15734978"],"issn":["03014851"]},"day":"12","publisher":"Springer","oa_version":"Published Version","doi":"10.1007/s11033-019-04765-z","quality_controlled":"1","has_accepted_license":"1","status":"public","language":[{"iso":"eng"}],"abstract":[{"lang":"eng","text":"Chronic overuse of common pharmaceuticals, e.g. acetaminophen (paracetamol), often leads to the development of acute liver failure (ALF). This study aimed to elucidate the effect of cultured mesenchymal stem cells (MSCs) proteome on the onset of liver damage and regeneration dynamics in animals with ALF induced by acetaminophen, to test the liver protective efficacy of MSCs proteome depending on the oxygen tension in cell culture, and to blueprint protein components responsible for the effect. Protein compositions prepared from MSCs cultured in mild hypoxic (5% and 10% O2) and normal (21% O2) conditions were used to treat ALF induced in mice by injection of acetaminophen. To test the effect of reduced oxygen tension in cell culture on resulting MSCs proteome content we applied a combination of high performance liquid chromatography and mass-spectrometry (LC–MS/MS) for the identification of proteins in lysates of MSCs cultured at different O2 levels. The treatment of acetaminophen-administered animals with proteins released from cultured MSCs resulted in the inhibition of inflammatory reactions in damaged liver; the area of hepatocyte necrosis being reduced in the first 24 h. Compositions obtained from MSCs cultured at lower O2 level were shown to be more potent than a composition prepared from normoxic cells. A comparative characterization of protein pattern and identification of individual components done by a cytokine assay and proteomics analysis of protein compositions revealed that even moderate hypoxia produces discrete changes in the expression of various subsets of proteins responsible for intracellular respiration and cell signaling. The application of proteins prepared from MSCs grown in vitro at reduced oxygen tension significantly accelerates healing process in damaged liver tissue. The proteomics data obtained for different preparations offer new information about the potential candidates in the MSCs protein repertoire sensitive to oxygen tension in culture medium, which can be involved in the generalized mechanisms the cells use to respond to acute liver failure."}],"publication_status":"published","ddc":["570"],"citation":{"short":"A.A. Temnov, K.A. Rogov, A.N. Sklifas, E.V. Klychnikova, M. Hartl, K. Djinovic-Carugo, A. Charnagalov, Molecular Biology Reports (2019).","apa":"Temnov, A. A., Rogov, K. A., Sklifas, A. N., Klychnikova, E. V., Hartl, M., Djinovic-Carugo, K., & Charnagalov, A. (2019). Protective properties of the cultured stem cell proteome studied in an animal model of acetaminophen-induced acute liver failure. Molecular Biology Reports. Springer. https://doi.org/10.1007/s11033-019-04765-z","ieee":"A. A. Temnov et al., “Protective properties of the cultured stem cell proteome studied in an animal model of acetaminophen-induced acute liver failure,” Molecular Biology Reports. Springer, 2019.","ama":"Temnov AA, Rogov KA, Sklifas AN, et al. Protective properties of the cultured stem cell proteome studied in an animal model of acetaminophen-induced acute liver failure. Molecular Biology Reports. 2019. doi:10.1007/s11033-019-04765-z","chicago":"Temnov, Andrey Alexandrovich, Konstantin Arkadevich Rogov, Alla Nikolaevna Sklifas, Elena Valerievna Klychnikova, Markus Hartl, Kristina Djinovic-Carugo, and Alexej Charnagalov. “Protective Properties of the Cultured Stem Cell Proteome Studied in an Animal Model of Acetaminophen-Induced Acute Liver Failure.” Molecular Biology Reports. Springer, 2019. https://doi.org/10.1007/s11033-019-04765-z.","ista":"Temnov AA, Rogov KA, Sklifas AN, Klychnikova EV, Hartl M, Djinovic-Carugo K, Charnagalov A. 2019. Protective properties of the cultured stem cell proteome studied in an animal model of acetaminophen-induced acute liver failure. Molecular Biology Reports.","mla":"Temnov, Andrey Alexandrovich, et al. “Protective Properties of the Cultured Stem Cell Proteome Studied in an Animal Model of Acetaminophen-Induced Acute Liver Failure.” Molecular Biology Reports, Springer, 2019, doi:10.1007/s11033-019-04765-z."},"type":"journal_article","file":[{"date_updated":"2020-07-14T12:47:28Z","content_type":"application/pdf","file_size":1948014,"checksum":"45bf040bbce1cea274f6013fa18ba21b","relation":"main_file","access_level":"open_access","file_name":"2019_MolecularBioReport_Temnov.pdf","file_id":"6362","creator":"dernst","date_created":"2019-04-30T09:52:36Z"}]},{"date_published":"2019-09-12T00:00:00Z","article_processing_charge":"No","ec_funded":1,"date_updated":"2024-03-25T23:30:08Z","title":"Structure and mechanism of mitochondrial proton-translocating transhydrogenase","month":"09","_id":"6848","project":[{"name":"International IST Doctoral Program","call_identifier":"H2020","grant_number":"665385","_id":"2564DBCA-B435-11E9-9278-68D0E5697425"}],"date_created":"2019-09-04T06:21:41Z","external_id":{"pmid":["31462775"],"isi":["000485415400061"]},"file_date_updated":"2020-11-26T16:33:44Z","publication":"Nature","page":"291–295","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","acknowledgement":" We thank R. Thompson, G. Effantin and V.-V. Hodirnau for their assistance with collecting NADP+, NADPH and apo datasets, respectively. Data processing was performed at the IST high-performance computing cluster.\r\nThis project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement no. 665385.","issue":"7773","intvolume":" 573","oa":1,"volume":573,"related_material":{"record":[{"id":"8340","relation":"dissertation_contains","status":"public"}],"link":[{"relation":"press_release","url":"https://ist.ac.at/en/news/high-end-microscopy-reveals-structure-and-function-of-crucial-metabolic-enzyme/","description":"News on IST Website"}]},"scopus_import":"1","author":[{"last_name":"Kampjut","full_name":"Kampjut, Domen","first_name":"Domen","id":"37233050-F248-11E8-B48F-1D18A9856A87"},{"id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A","last_name":"Sazanov","orcid":"0000-0002-0977-7989","full_name":"Sazanov, Leonid A"}],"isi":1,"year":"2019","publication_identifier":{"eissn":["1476-4687"],"issn":["0028-0836"]},"department":[{"_id":"LeSa"}],"publisher":"Springer Nature","day":"12","doi":"10.1038/s41586-019-1519-2","oa_version":"Submitted Version","quality_controlled":"1","publication_status":"published","abstract":[{"text":"Proton-translocating transhydrogenase (also known as nicotinamide nucleotide transhydrogenase (NNT)) is found in the plasma membranes of bacteria and the inner mitochondrial membranes of eukaryotes. NNT catalyses the transfer of a hydride between NADH and NADP+, coupled to the translocation of one proton across the membrane. Its main physiological function is the generation of NADPH, which is a substrate in anabolic reactions and a regulator of oxidative status; however, NNT may also fine-tune the Krebs cycle1,2. NNT deficiency causes familial glucocorticoid deficiency in humans and metabolic abnormalities in mice, similar to those observed in type II diabetes3,4. The catalytic mechanism of NNT has been proposed to involve a rotation of around 180° of the entire NADP(H)-binding domain that alternately participates in hydride transfer and proton-channel gating. However, owing to the lack of high-resolution structures of intact NNT, the details of this process remain unclear5,6. Here we present the cryo-electron microscopy structure of intact mammalian NNT in different conformational states. We show how the NADP(H)-binding domain opens the proton channel to the opposite sides of the membrane, and we provide structures of these two states. We also describe the catalytically important interfaces and linkers between the membrane and the soluble domains and their roles in nucleotide exchange. These structures enable us to propose a revised mechanism for a coupling process in NNT that is consistent with a large body of previous biochemical work. Our results are relevant to the development of currently unavailable NNT inhibitors, which may have therapeutic potential in ischaemia reperfusion injury, metabolic syndrome and some cancers7,8,9.","lang":"eng"}],"language":[{"iso":"eng"}],"pmid":1,"status":"public","has_accepted_license":"1","acknowledged_ssus":[{"_id":"ScienComp"}],"ddc":["572"],"article_type":"letter_note","file":[{"file_id":"8821","creator":"lsazanov","date_created":"2020-11-26T16:33:44Z","file_size":3066206,"date_updated":"2020-11-26T16:33:44Z","content_type":"application/pdf","checksum":"52728cda5210a3e9b74cc204e8aed3d5","relation":"main_file","access_level":"open_access","success":1,"file_name":"Manuscript_final_acc_withFigs_SI_opt_red.pdf"}],"type":"journal_article","citation":{"ieee":"D. Kampjut and L. A. Sazanov, “Structure and mechanism of mitochondrial proton-translocating transhydrogenase,” Nature, vol. 573, no. 7773. Springer Nature, pp. 291–295, 2019.","apa":"Kampjut, D., & Sazanov, L. A. (2019). Structure and mechanism of mitochondrial proton-translocating transhydrogenase. Nature. Springer Nature. https://doi.org/10.1038/s41586-019-1519-2","short":"D. Kampjut, L.A. Sazanov, Nature 573 (2019) 291–295.","mla":"Kampjut, Domen, and Leonid A. Sazanov. “Structure and Mechanism of Mitochondrial Proton-Translocating Transhydrogenase.” Nature, vol. 573, no. 7773, Springer Nature, 2019, pp. 291–295, doi:10.1038/s41586-019-1519-2.","ista":"Kampjut D, Sazanov LA. 2019. Structure and mechanism of mitochondrial proton-translocating transhydrogenase. Nature. 573(7773), 291–295.","chicago":"Kampjut, Domen, and Leonid A Sazanov. “Structure and Mechanism of Mitochondrial Proton-Translocating Transhydrogenase.” Nature. Springer Nature, 2019. https://doi.org/10.1038/s41586-019-1519-2.","ama":"Kampjut D, Sazanov LA. Structure and mechanism of mitochondrial proton-translocating transhydrogenase. Nature. 2019;573(7773):291–295. doi:10.1038/s41586-019-1519-2"}},{"date_published":"2019-08-23T00:00:00Z","article_processing_charge":"No","title":"Structure and conformational plasticity of the intact Thermus thermophilus V/A-type ATPase","date_updated":"2023-08-29T07:52:02Z","month":"08","_id":"6859","date_created":"2019-09-07T19:04:45Z","external_id":{"isi":["000482464000043"],"pmid":["31439765"]},"publication":"Science","article_number":"eaaw9144","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","issue":"6455","intvolume":" 365","volume":365,"related_material":{"link":[{"url":"https://ist.ac.at/en/news/structure-of-protein-nano-turbine-revealed/","description":"News on IST Website","relation":"press_release"}]},"scopus_import":"1","isi":1,"author":[{"full_name":"Zhou, Long","orcid":"0000-0002-1864-8951","last_name":"Zhou","id":"3E751364-F248-11E8-B48F-1D18A9856A87","first_name":"Long"},{"id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A","last_name":"Sazanov","orcid":"0000-0002-0977-7989","full_name":"Sazanov, Leonid A"}],"year":"2019","publication_identifier":{"issn":["0036-8075"],"eissn":["1095-9203"]},"department":[{"_id":"LeSa"}],"publisher":"AAAS","day":"23","doi":"10.1126/science.aaw9144","oa_version":"None","quality_controlled":"1","abstract":[{"text":"V (vacuolar)/A (archaeal)-type adenosine triphosphatases (ATPases), found in archaeaand eubacteria, couple ATP hydrolysis or synthesis to proton translocation across theplasma membrane using the rotary-catalysis mechanism. They belong to the V-typeATPase family, which differs from the mitochondrial/chloroplast F-type ATP synthasesin overall architecture. We solved cryo–electron microscopy structures of the intactThermus thermophilusV/A-ATPase, reconstituted into lipid nanodiscs, in three rotationalstates and two substates. These structures indicate substantial flexibility betweenV1and Voin a working enzyme, which results from mechanical competition between centralshaft rotation and resistance from the peripheral stalks. We also describedetails of adenosine diphosphate inhibition release, V1-Votorque transmission, andproton translocation, which are relevant for the entire V-type ATPase family.","lang":"eng"}],"publication_status":"published","language":[{"iso":"eng"}],"status":"public","pmid":1,"acknowledged_ssus":[{"_id":"ScienComp"}],"citation":{"ista":"Zhou L, Sazanov LA. 2019. Structure and conformational plasticity of the intact Thermus thermophilus V/A-type ATPase. Science. 365(6455), eaaw9144.","mla":"Zhou, Long, and Leonid A. Sazanov. “Structure and Conformational Plasticity of the Intact Thermus Thermophilus V/A-Type ATPase.” Science, vol. 365, no. 6455, eaaw9144, AAAS, 2019, doi:10.1126/science.aaw9144.","chicago":"Zhou, Long, and Leonid A Sazanov. “Structure and Conformational Plasticity of the Intact Thermus Thermophilus V/A-Type ATPase.” Science. AAAS, 2019. https://doi.org/10.1126/science.aaw9144.","ama":"Zhou L, Sazanov LA. Structure and conformational plasticity of the intact Thermus thermophilus V/A-type ATPase. Science. 2019;365(6455). doi:10.1126/science.aaw9144","ieee":"L. Zhou and L. A. Sazanov, “Structure and conformational plasticity of the intact Thermus thermophilus V/A-type ATPase,” Science, vol. 365, no. 6455. AAAS, 2019.","short":"L. Zhou, L.A. Sazanov, Science 365 (2019).","apa":"Zhou, L., & Sazanov, L. A. (2019). Structure and conformational plasticity of the intact Thermus thermophilus V/A-type ATPase. Science. AAAS. https://doi.org/10.1126/science.aaw9144"},"type":"journal_article"},{"file":[{"file_id":"6994","date_created":"2019-11-07T12:55:20Z","creator":"lsazanov","file_size":2185385,"date_updated":"2020-07-14T12:45:00Z","content_type":"application/pdf","relation":"main_file","checksum":"ef6d2b4e1fd63948539639242610bfa6","access_level":"open_access","file_name":"SasanovFinalMS+EdComments_LS_allacc_withFigs.pdf"}],"type":"journal_article","citation":{"ieee":"K. Fiedorczuk and L. A. Sazanov, “Mammalian mitochondrial complex I structure and disease causing mutations,” Trends in Cell Biology, vol. 28, no. 10. Elsevier, pp. 835–867, 2018.","apa":"Fiedorczuk, K., & Sazanov, L. A. (2018). Mammalian mitochondrial complex I structure and disease causing mutations. Trends in Cell Biology. Elsevier. https://doi.org/10.1016/j.tcb.2018.06.006","short":"K. Fiedorczuk, L.A. Sazanov, Trends in Cell Biology 28 (2018) 835–867.","ista":"Fiedorczuk K, Sazanov LA. 2018. Mammalian mitochondrial complex I structure and disease causing mutations. Trends in Cell Biology. 28(10), 835–867.","mla":"Fiedorczuk, Karol, and Leonid A. Sazanov. “Mammalian Mitochondrial Complex I Structure and Disease Causing Mutations.” Trends in Cell Biology, vol. 28, no. 10, Elsevier, 2018, pp. 835–67, doi:10.1016/j.tcb.2018.06.006.","ama":"Fiedorczuk K, Sazanov LA. Mammalian mitochondrial complex I structure and disease causing mutations. Trends in Cell Biology. 2018;28(10):835-867. doi:10.1016/j.tcb.2018.06.006","chicago":"Fiedorczuk, Karol, and Leonid A Sazanov. “Mammalian Mitochondrial Complex I Structure and Disease Causing Mutations.” Trends in Cell Biology. Elsevier, 2018. https://doi.org/10.1016/j.tcb.2018.06.006."},"ddc":["572"],"article_type":"original","publist_id":"7769","publication_status":"published","abstract":[{"lang":"eng","text":"Complex I has an essential role in ATP production by coupling electron transfer from NADH to quinone with translocation of protons across the inner mitochondrial membrane. Isolated complex I deficiency is a frequent cause of mitochondrial inherited diseases. Complex I has also been implicated in cancer, ageing, and neurodegenerative conditions. Until recently, the understanding of complex I deficiency on the molecular level was limited due to the lack of high-resolution structures of the enzyme. However, due to developments in single particle cryo-electron microscopy (cryo-EM), recent studies have reported nearly atomic resolution maps and models of mitochondrial complex I. These structures significantly add to our understanding of complex I mechanism and assembly. The disease-causing mutations are discussed here in their structural context."}],"has_accepted_license":"1","status":"public","language":[{"iso":"eng"}],"quality_controlled":"1","doi":"10.1016/j.tcb.2018.06.006","oa_version":"Submitted Version","publisher":"Elsevier","day":"26","department":[{"_id":"LeSa"}],"tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","short":"CC BY-NC-ND (4.0)","image":"/images/cc_by_nc_nd.png"},"year":"2018","author":[{"last_name":"Fiedorczuk","full_name":"Fiedorczuk, Karol","first_name":"Karol","id":"5BFF67CE-02D1-11E9-B11A-A5A4D7DFFFD0"},{"full_name":"Sazanov, Leonid A","orcid":"0000-0002-0977-7989","last_name":"Sazanov","first_name":"Leonid A","id":"338D39FE-F248-11E8-B48F-1D18A9856A87"}],"isi":1,"scopus_import":"1","volume":28,"intvolume":" 28","oa":1,"issue":"10","user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","publication":"Trends in Cell Biology","file_date_updated":"2020-07-14T12:45:00Z","page":"835 - 867","_id":"152","external_id":{"isi":["000445118200007"]},"date_created":"2018-12-11T11:44:54Z","date_updated":"2023-09-13T08:51:56Z","title":"Mammalian mitochondrial complex I structure and disease causing mutations","month":"07","article_processing_charge":"No","date_published":"2018-07-26T00:00:00Z"},{"type":"book_chapter","citation":{"chicago":"Sazanov, Leonid A. “Structure of Respiratory Complex I: ‘Minimal’ Bacterial and ‘de Luxe’ Mammalian Versions.” In Mechanisms of Primary Energy Transduction in Biology , edited by Mårten Wikström, 25–59. Mechanisms of Primary Energy Transduction in Biology . Royal Society of Chemistry, 2017. https://doi.org/10.1039/9781788010405-00025.","ama":"Sazanov LA. Structure of respiratory complex I: “Minimal” bacterial and “de luxe” mammalian versions. In: Wikström M, ed. Mechanisms of Primary Energy Transduction in Biology . Mechanisms of Primary Energy Transduction in Biology . Royal Society of Chemistry; 2017:25-59. doi:10.1039/9781788010405-00025","mla":"Sazanov, Leonid A. “Structure of Respiratory Complex I: ‘Minimal’ Bacterial and ‘de Luxe’ Mammalian Versions.” Mechanisms of Primary Energy Transduction in Biology , edited by Mårten Wikström, Royal Society of Chemistry, 2017, pp. 25–59, doi:10.1039/9781788010405-00025.","ista":"Sazanov LA. 2017.Structure of respiratory complex I: “Minimal” bacterial and “de luxe” mammalian versions. In: Mechanisms of primary energy transduction in biology . , 25–59.","apa":"Sazanov, L. A. (2017). Structure of respiratory complex I: “Minimal” bacterial and “de luxe” mammalian versions. In M. Wikström (Ed.), Mechanisms of primary energy transduction in biology (pp. 25–59). Royal Society of Chemistry. https://doi.org/10.1039/9781788010405-00025","short":"L.A. Sazanov, in:, M. Wikström (Ed.), Mechanisms of Primary Energy Transduction in Biology , Royal Society of Chemistry, 2017, pp. 25–59.","ieee":"L. A. Sazanov, “Structure of respiratory complex I: ‘Minimal’ bacterial and ‘de luxe’ mammalian versions,” in Mechanisms of primary energy transduction in biology , M. Wikström, Ed. Royal Society of Chemistry, 2017, pp. 25–59."},"quality_controlled":"1","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","publist_id":"7379","abstract":[{"lang":"eng","text":"Complex I (NADH:ubiquinone oxidoreductase) plays a central role in cellular energy generation, contributing to the proton motive force used to produce ATP. It couples the transfer of two electrons between NADH and quinone to translocation of four protons across the membrane. It is the largest protein assembly of bacterial and mitochondrial respiratory chains, composed, in mammals, of up to 45 subunits with a total molecular weight of ∼1 MDa. Bacterial enzyme is about half the size, providing the important “minimal” model of complex I. The l-shaped complex consists of a hydrophilic arm, where electron transfer occurs, and a membrane arm, where proton translocation takes place. Previously, we have solved the crystal structures of the hydrophilic domain of complex I from Thermus thermophilus and of the membrane domain from Escherichia coli, followed by the atomic structure of intact, entire complex I from T. thermophilus. Recently, we have solved by cryo-EM a first complete atomic structure of mammalian (ovine) mitochondrial complex I. Core subunits are well conserved from the bacterial version, whilst supernumerary subunits form an interlinked, stabilizing shell around the core. Subunits containing additional cofactors, including Zn ion, NADPH and phosphopantetheine, probably have regulatory roles. Dysfunction of mitochondrial complex I is implicated in many human neurodegenerative diseases. The structure of mammalian enzyme provides many insights into complex I mechanism, assembly, maturation and dysfunction, allowing detailed molecular analysis of disease-causing mutations."}],"publication_status":"published","status":"public","language":[{"iso":"eng"}],"series_title":"Mechanisms of Primary Energy Transduction in Biology ","_id":"444","publisher":"Royal Society of Chemistry","day":"29","date_created":"2018-12-11T11:46:30Z","doi":"10.1039/9781788010405-00025","publication":"Mechanisms of primary energy transduction in biology ","oa_version":"None","page":"25 - 59","year":"2017","date_published":"2017-11-29T00:00:00Z","author":[{"first_name":"Leonid A","id":"338D39FE-F248-11E8-B48F-1D18A9856A87","last_name":"Sazanov","full_name":"Sazanov, Leonid A","orcid":"0000-0002-0977-7989"}],"editor":[{"full_name":"Wikström, Mårten","last_name":"Wikström","first_name":"Mårten"}],"publication_identifier":{"isbn":["978-1-78262-865-1"]},"department":[{"_id":"LeSa"}],"date_updated":"2021-01-12T07:56:59Z","title":"Structure of respiratory complex I: “Minimal” bacterial and “de luxe” mammalian versions","month":"11"},{"oa":1,"intvolume":" 24","issue":"10","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","volume":24,"scopus_import":1,"ec_funded":1,"date_published":"2017-10-05T00:00:00Z","month":"10","date_updated":"2021-01-12T08:01:17Z","title":"Clarifying the supercomplex: The higher-order organization of the mitochondrial electron transport chain","date_created":"2018-12-11T11:46:54Z","_id":"515","project":[{"name":"Atomic-Resolution Structures of Mitochondrial Respiratory Chain Supercomplexes (H2020)","grant_number":"701309","_id":"2590DB08-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"}],"page":"800 - 808","publication":"Nature Structural and Molecular Biology","file_date_updated":"2020-07-14T12:46:36Z","quality_controlled":"1","has_accepted_license":"1","status":"public","language":[{"iso":"eng"}],"publist_id":"7304","abstract":[{"text":"The oxidative phosphorylation electron transport chain (OXPHOS-ETC) of the inner mitochondrial membrane is composed of five large protein complexes, named CI-CV. These complexes convert energy from the food we eat into ATP, a small molecule used to power a multitude of essential reactions throughout the cell. OXPHOS-ETC complexes are organized into supercomplexes (SCs) of defined stoichiometry: CI forms a supercomplex with CIII2 and CIV (SC I+III2+IV, known as the respirasome), as well as with CIII2 alone (SC I+III2). CIII2 forms a supercomplex with CIV (SC III2+IV) and CV forms dimers (CV2). Recent cryo-EM studies have revealed the structures of SC I+III2+IV and SC I+III2. Furthermore, recent work has shed light on the assembly and function of the SCs. Here we review and compare these recent studies and discuss how they have advanced our understanding of mitochondrial electron transport.","lang":"eng"}],"publication_status":"published","article_type":"original","ddc":["572"],"citation":{"ieee":"J. A. Letts and L. A. Sazanov, “Clarifying the supercomplex: The higher-order organization of the mitochondrial electron transport chain,” Nature Structural and Molecular Biology, vol. 24, no. 10. Nature Publishing Group, pp. 800–808, 2017.","short":"J.A. Letts, L.A. Sazanov, Nature Structural and Molecular Biology 24 (2017) 800–808.","apa":"Letts, J. A., & Sazanov, L. A. (2017). Clarifying the supercomplex: The higher-order organization of the mitochondrial electron transport chain. Nature Structural and Molecular Biology. Nature Publishing Group. https://doi.org/10.1038/nsmb.3460","ista":"Letts JA, Sazanov LA. 2017. Clarifying the supercomplex: The higher-order organization of the mitochondrial electron transport chain. Nature Structural and Molecular Biology. 24(10), 800–808.","mla":"Letts, James A., and Leonid A. Sazanov. “Clarifying the Supercomplex: The Higher-Order Organization of the Mitochondrial Electron Transport Chain.” Nature Structural and Molecular Biology, vol. 24, no. 10, Nature Publishing Group, 2017, pp. 800–08, doi:10.1038/nsmb.3460.","chicago":"Letts, James A, and Leonid A Sazanov. “Clarifying the Supercomplex: The Higher-Order Organization of the Mitochondrial Electron Transport Chain.” Nature Structural and Molecular Biology. Nature Publishing Group, 2017. https://doi.org/10.1038/nsmb.3460.","ama":"Letts JA, Sazanov LA. Clarifying the supercomplex: The higher-order organization of the mitochondrial electron transport chain. Nature Structural and Molecular Biology. 2017;24(10):800-808. doi:10.1038/nsmb.3460"},"type":"journal_article","file":[{"access_level":"open_access","file_name":"29893_2_merged_1501257589_red.pdf","date_updated":"2020-07-14T12:46:36Z","content_type":"application/pdf","file_size":4118385,"checksum":"9bc7e8c41b43636dd7566289e511f096","relation":"main_file","date_created":"2019-11-07T12:51:07Z","creator":"lsazanov","file_id":"6993"}],"year":"2017","author":[{"id":"322DA418-F248-11E8-B48F-1D18A9856A87","first_name":"James A","orcid":"0000-0002-9864-3586","full_name":"Letts, James A","last_name":"Letts"},{"last_name":"Sazanov","full_name":"Sazanov, Leonid A","orcid":"0000-0002-0977-7989","id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A"}],"publication_identifier":{"issn":["15459993"]},"department":[{"_id":"LeSa"}],"day":"05","publisher":"Nature Publishing Group","oa_version":"Submitted Version","doi":"10.1038/nsmb.3460"},{"year":"2016","author":[{"id":"5BFF67CE-02D1-11E9-B11A-A5A4D7DFFFD0","first_name":"Karol","last_name":"Fiedorczuk","full_name":"Fiedorczuk, Karol"},{"last_name":"Letts","orcid":"0000-0002-9864-3586","full_name":"Letts, James A","id":"322DA418-F248-11E8-B48F-1D18A9856A87","first_name":"James A"},{"full_name":"Degliesposti, Gianluca","last_name":"Degliesposti","first_name":"Gianluca"},{"full_name":"Kaszuba, Karol","last_name":"Kaszuba","first_name":"Karol","id":"3FDF9472-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Mark","last_name":"Skehel","full_name":"Skehel, Mark"},{"id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A","last_name":"Sazanov","orcid":"0000-0002-0977-7989","full_name":"Sazanov, Leonid A"}],"department":[{"_id":"LeSa"}],"publisher":"Nature Publishing Group","day":"20","doi":"10.1038/nature19794","oa_version":"Submitted Version","quality_controlled":"1","publist_id":"6108","abstract":[{"lang":"eng","text":"Mitochondrial complex I (also known as NADH:ubiquinone oxidoreductase) contributes to cellular energy production by transferring electrons from NADH to ubiquinone coupled to proton translocation across the membrane. It is the largest protein assembly of the respiratory chain with a total mass of 970 kilodaltons. Here we present a nearly complete atomic structure of ovine (Ovis aries) mitochondrial complex I at 3.9 Å resolution, solved by cryo-electron microscopy with cross-linking and mass-spectrometry mapping experiments. All 14 conserved core subunits and 31 mitochondria-specific supernumerary subunits are resolved within the L-shaped molecule. The hydrophilic matrix arm comprises flavin mononucleotide and 8 iron-sulfur clusters involved in electron transfer, and the membrane arm contains 78 transmembrane helices, mostly contributed by antiporter-like subunits involved in proton translocation. Supernumerary subunits form an interlinked, stabilizing shell around the conserved core. Tightly bound lipids (including cardiolipins) further stabilize interactions between the hydrophobic subunits. Subunits with possible regulatory roles contain additional cofactors, NADPH and two phosphopantetheine molecules, which are shown to be involved in inter-subunit interactions. We observe two different conformations of the complex, which may be related to the conformationally driven coupling mechanism and to the active-deactive transition of the enzyme. Our structure provides insight into the mechanism, assembly, maturation and dysfunction of mitochondrial complex I, and allows detailed molecular analysis of disease-causing mutations."}],"publication_status":"published","pmid":1,"status":"public","language":[{"iso":"eng"}],"article_type":"original","type":"journal_article","citation":{"ama":"Fiedorczuk K, Letts JA, Degliesposti G, Kaszuba K, Skehel M, Sazanov LA. Atomic structure of the entire mammalian mitochondrial complex i. Nature. 2016;538(7625):406-410. doi:10.1038/nature19794","chicago":"Fiedorczuk, Karol, James A Letts, Gianluca Degliesposti, Karol Kaszuba, Mark Skehel, and Leonid A Sazanov. “Atomic Structure of the Entire Mammalian Mitochondrial Complex I.” Nature. Nature Publishing Group, 2016. https://doi.org/10.1038/nature19794.","ista":"Fiedorczuk K, Letts JA, Degliesposti G, Kaszuba K, Skehel M, Sazanov LA. 2016. Atomic structure of the entire mammalian mitochondrial complex i. Nature. 538(7625), 406–410.","mla":"Fiedorczuk, Karol, et al. “Atomic Structure of the Entire Mammalian Mitochondrial Complex I.” Nature, vol. 538, no. 7625, Nature Publishing Group, 2016, pp. 406–10, doi:10.1038/nature19794.","short":"K. Fiedorczuk, J.A. Letts, G. Degliesposti, K. Kaszuba, M. Skehel, L.A. Sazanov, Nature 538 (2016) 406–410.","apa":"Fiedorczuk, K., Letts, J. A., Degliesposti, G., Kaszuba, K., Skehel, M., & Sazanov, L. A. (2016). Atomic structure of the entire mammalian mitochondrial complex i. Nature. Nature Publishing Group. https://doi.org/10.1038/nature19794","ieee":"K. Fiedorczuk, J. A. Letts, G. Degliesposti, K. Kaszuba, M. Skehel, and L. A. Sazanov, “Atomic structure of the entire mammalian mitochondrial complex i,” Nature, vol. 538, no. 7625. Nature Publishing Group, pp. 406–410, 2016."},"article_processing_charge":"No","date_published":"2016-10-20T00:00:00Z","ec_funded":1,"date_updated":"2021-01-12T06:49:13Z","title":"Atomic structure of the entire mammalian mitochondrial complex i","month":"10","_id":"1226","project":[{"name":"Atomic-Resolution Structures of Mitochondrial Respiratory Chain Supercomplexes (FEBS)","_id":"2593EBD6-B435-11E9-9278-68D0E5697425"},{"name":"Atomic-Resolution Structures of Mitochondrial Respiratory Chain Supercomplexes (H2020)","_id":"2590DB08-B435-11E9-9278-68D0E5697425","grant_number":"701309","call_identifier":"H2020"}],"external_id":{"pmid":["27595392"]},"date_created":"2018-12-11T11:50:49Z","publication":"Nature","page":"406 - 410","intvolume":" 538","oa":1,"issue":"7625","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","main_file_link":[{"open_access":"1","url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164932/"}],"volume":538,"scopus_import":1},{"type":"journal_article","citation":{"ista":"Letts JA, Fiedorczuk K, Sazanov LA. 2016. The architecture of respiratory supercomplexes. Nature. 537(7622), 644–648.","mla":"Letts, James A., et al. “The Architecture of Respiratory Supercomplexes.” Nature, vol. 537, no. 7622, Nature Publishing Group, 2016, pp. 644–48, doi:10.1038/nature19774.","ama":"Letts JA, Fiedorczuk K, Sazanov LA. The architecture of respiratory supercomplexes. Nature. 2016;537(7622):644-648. doi:10.1038/nature19774","chicago":"Letts, James A, Karol Fiedorczuk, and Leonid A Sazanov. “The Architecture of Respiratory Supercomplexes.” Nature. Nature Publishing Group, 2016. https://doi.org/10.1038/nature19774.","ieee":"J. A. Letts, K. Fiedorczuk, and L. A. Sazanov, “The architecture of respiratory supercomplexes,” Nature, vol. 537, no. 7622. Nature Publishing Group, pp. 644–648, 2016.","apa":"Letts, J. A., Fiedorczuk, K., & Sazanov, L. A. (2016). The architecture of respiratory supercomplexes. Nature. Nature Publishing Group. https://doi.org/10.1038/nature19774","short":"J.A. Letts, K. Fiedorczuk, L.A. Sazanov, Nature 537 (2016) 644–648."},"scopus_import":1,"issue":"7622","user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","acknowledgement":"We thank the MRC LMB Cambridge for the use of the Titan Krios microscope. Data processing was performed using the IST high-performance computer cluster. J.A.L. holds a long-term fellowship from FEBS. K.F. is partially funded by a MRC UK PhD fellowship.","intvolume":" 537","quality_controlled":"1","language":[{"iso":"eng"}],"status":"public","abstract":[{"text":"Mitochondrial electron transport chain complexes are organized into supercomplexes responsible for carrying out cellular respiration. Here we present three architectures of mammalian (ovine) supercomplexes determined by cryo-electron microscopy. We identify two distinct arrangements of supercomplex CICIII 2 CIV (the respirasome) - a major 'tight' form and a minor 'loose' form (resolved at the resolution of 5.8 Å and 6.7 Å, respectively), which may represent different stages in supercomplex assembly or disassembly. We have also determined an architecture of supercomplex CICIII 2 at 7.8 Å resolution. All observed density can be attributed to the known 80 subunits of the individual complexes, including 132 transmembrane helices. The individual complexes form tight interactions that vary between the architectures, with complex IV subunit COX7a switching contact from complex III to complex I. The arrangement of active sites within the supercomplex may help control reactive oxygen species production. To our knowledge, these are the first complete architectures of the dominant, physiologically relevant state of the electron transport chain.","lang":"eng"}],"publication_status":"published","volume":537,"publist_id":"6102","date_created":"2018-12-11T11:50:51Z","day":"29","_id":"1232","project":[{"name":"Atomic-Resolution Structures of Mitochondrial Respiratory Chain Supercomplexes (FEBS)","_id":"2593EBD6-B435-11E9-9278-68D0E5697425"}],"publisher":"Nature Publishing Group","oa_version":"None","page":"644 - 648","doi":"10.1038/nature19774","publication":"Nature","date_published":"2016-09-29T00:00:00Z","author":[{"first_name":"James A","id":"322DA418-F248-11E8-B48F-1D18A9856A87","last_name":"Letts","full_name":"Letts, James A","orcid":"0000-0002-9864-3586"},{"last_name":"Fiedorczuk","full_name":"Fiedorczuk, Karol","id":"5BFF67CE-02D1-11E9-B11A-A5A4D7DFFFD0","first_name":"Karol"},{"last_name":"Sazanov","orcid":"0000-0002-0977-7989","full_name":"Sazanov, Leonid A","id":"338D39FE-F248-11E8-B48F-1D18A9856A87","first_name":"Leonid A"}],"year":"2016","month":"09","title":"The architecture of respiratory supercomplexes","date_updated":"2021-01-12T06:49:16Z","department":[{"_id":"LeSa"}]},{"date_created":"2018-12-11T11:51:05Z","_id":"1276","pubrep_id":"691","file_date_updated":"2020-07-14T12:44:42Z","publication":"Scientific Reports","date_published":"2016-09-26T00:00:00Z","month":"09","title":"Atomistic determinants of co-enzyme Q reduction at the Qi-site of the cytochrome bc1 complex","date_updated":"2021-01-12T06:49:34Z","scopus_import":1,"acknowledgement":"We wish to thank CSC – IT Centre for Science (Espoo, Finland) for computational resources. For financial support, we wish to thank the Academy of Finland (TR, IV and PAP; Center of Excellence in Biomembrane Research (IV, TR)), the Finnish Doctoral Programme in Computational Sciences (KK), the Sigrid Juselius Foundation (IV), the Paulo Foundation (PAP), and the European Research Council (IV, TR; Advanced Grant project CROWDED-PRO-LIPIDS). AO acknowledges The Wellcome Trust International Senior Research Fellowship.","user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","oa":1,"intvolume":" 6","article_number":"33607","volume":6,"day":"26","publisher":"Nature Publishing Group","oa_version":"Published Version","doi":"10.1038/srep33607","author":[{"last_name":"Postila","full_name":"Postila, Pekka","first_name":"Pekka"},{"last_name":"Kaszuba","full_name":"Kaszuba, Karol","id":"3FDF9472-F248-11E8-B48F-1D18A9856A87","first_name":"Karol"},{"first_name":"Patryk","last_name":"Kuleta","full_name":"Kuleta, Patryk"},{"full_name":"Vattulainen, Ilpo","last_name":"Vattulainen","first_name":"Ilpo"},{"first_name":"Marcin","last_name":"Sarewicz","full_name":"Sarewicz, Marcin"},{"first_name":"Artur","last_name":"Osyczka","full_name":"Osyczka, Artur"},{"first_name":"Tomasz","full_name":"Róg, Tomasz","last_name":"Róg"}],"year":"2016","tmp":{"image":"/images/cc_by.png","short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"department":[{"_id":"LeSa"}],"ddc":["576"],"citation":{"short":"P. Postila, K. Kaszuba, P. Kuleta, I. Vattulainen, M. Sarewicz, A. Osyczka, T. Róg, Scientific Reports 6 (2016).","apa":"Postila, P., Kaszuba, K., Kuleta, P., Vattulainen, I., Sarewicz, M., Osyczka, A., & Róg, T. (2016). Atomistic determinants of co-enzyme Q reduction at the Qi-site of the cytochrome bc1 complex. Scientific Reports. Nature Publishing Group. https://doi.org/10.1038/srep33607","ieee":"P. Postila et al., “Atomistic determinants of co-enzyme Q reduction at the Qi-site of the cytochrome bc1 complex,” Scientific Reports, vol. 6. Nature Publishing Group, 2016.","ama":"Postila P, Kaszuba K, Kuleta P, et al. Atomistic determinants of co-enzyme Q reduction at the Qi-site of the cytochrome bc1 complex. Scientific Reports. 2016;6. doi:10.1038/srep33607","chicago":"Postila, Pekka, Karol Kaszuba, Patryk Kuleta, Ilpo Vattulainen, Marcin Sarewicz, Artur Osyczka, and Tomasz Róg. “Atomistic Determinants of Co-Enzyme Q Reduction at the Qi-Site of the Cytochrome Bc1 Complex.” Scientific Reports. Nature Publishing Group, 2016. https://doi.org/10.1038/srep33607.","ista":"Postila P, Kaszuba K, Kuleta P, Vattulainen I, Sarewicz M, Osyczka A, Róg T. 2016. Atomistic determinants of co-enzyme Q reduction at the Qi-site of the cytochrome bc1 complex. Scientific Reports. 6, 33607.","mla":"Postila, Pekka, et al. “Atomistic Determinants of Co-Enzyme Q Reduction at the Qi-Site of the Cytochrome Bc1 Complex.” Scientific Reports, vol. 6, 33607, Nature Publishing Group, 2016, doi:10.1038/srep33607."},"type":"journal_article","file":[{"file_id":"5261","date_created":"2018-12-12T10:17:09Z","creator":"system","date_updated":"2020-07-14T12:44:42Z","content_type":"application/pdf","file_size":1960563,"relation":"main_file","checksum":"07c591c1250ebef266333cbc3228b4dd","access_level":"open_access","file_name":"IST-2016-691-v1+1_srep33607.pdf"}],"quality_controlled":"1","language":[{"iso":"eng"}],"status":"public","has_accepted_license":"1","abstract":[{"text":"The cytochrome (cyt) bc 1 complex is an integral component of the respiratory electron transfer chain sustaining the energy needs of organisms ranging from humans to bacteria. Due to its ubiquitous role in the energy metabolism, both the oxidation and reduction of the enzyme's substrate co-enzyme Q has been studied vigorously. Here, this vast amount of data is reassessed after probing the substrate reduction steps at the Q i-site of the cyt bc 1 complex of Rhodobacter capsulatus using atomistic molecular dynamics simulations. The simulations suggest that the Lys251 side chain could rotate into the Q i-site to facilitate binding of half-protonated semiquinone-a reaction intermediate that is potentially formed during substrate reduction. At this bent pose, the Lys251 forms a salt bridge with the Asp252, thus making direct proton transfer possible. In the neutral state, the lysine side chain stays close to the conserved binding location of cardiolipin (CL). This back-and-forth motion between the CL and Asp252 indicates that Lys251 functions as a proton shuttle controlled by pH-dependent negative feedback. The CL/K/D switching, which represents a refinement to the previously described CL/K pathway, fine-tunes the proton transfer process. Lastly, the simulation data was used to formulate a mechanism for reducing the substrate at the Q i-site.","lang":"eng"}],"publication_status":"published","publist_id":"6040"}]