{"day":"08","article_processing_charge":"No","oa":1,"publisher":"Proceedings of the National Academy of Sciences","doi":"10.1073/pnas.1917269117","main_file_link":[{"open_access":"1","url":"https://doi.org/10.1073/pnas.191726911"}],"acknowledged_ssus":[{"_id":"LifeSc"}],"abstract":[{"lang":"eng","text":"The actin cytoskeleton, a dynamic network of actin filaments and associated F-actin–binding proteins, is fundamentally important in eukaryotes. α-Actinins are major F-actin bundlers that are inhibited by Ca2+ in nonmuscle cells. Here we report the mechanism of Ca2+-mediated regulation of Entamoeba histolytica α-actinin-2 (EhActn2) with features expected for the common ancestor of Entamoeba and higher eukaryotic α-actinins. Crystal structures of Ca2+-free and Ca2+-bound EhActn2 reveal a calmodulin-like domain (CaMD) uniquely inserted within the rod domain. Integrative studies reveal an exceptionally high affinity of the EhActn2 CaMD for Ca2+, binding of which can only be regulated in the presence of physiological concentrations of Mg2+. Ca2+ binding triggers an increase in protein multidomain rigidity, reducing conformational flexibility of F-actin–binding domains via interdomain cross-talk and consequently inhibiting F-actin bundling. In vivo studies uncover that EhActn2 plays an important role in phagocytic cup formation and might constitute a new drug target for amoebic dysentery."}],"acknowledgement":"We thank the staff of the macromolecular crystallography (MX) and SAXS beamlines at the European Synchrotron Radiation facility, Diamond, and Swiss Light Source for excellent support, and the Life Sciences Facility of the Institute of Science and Technology Austria for usage of the rheometer. We thank Life Sciences editors for editing assistance. EM data were\r\nrecorded at the EM Facility of the Vienna BioCenter Core Facilities (Austria). Confocal microscopy was carried out at the Advanced Instrument Research Facility, Jawaharlal Nehru University. K.D.-C.’s research was supported by the Initial Training Network MUZIC (ITN-MUZIC) (N°238423), Austrian Science Fund (FWF) Projects I525, I1593, P22276, P19060, and W1221, Laura Bassi Centre of Optimized Structural Studies (N°253275), a Wellcome Trust Collaborative Award (201543/Z/16/Z), COST Action BM1405, Vienna Science and Technology Fund (WWTF) Chemical Biology Project LS17-008, and Christian Doppler Laboratory for High-Content Structural Biology and Biotechnology. K.Z., J.L.A., C.S., E.A.G., and A.S. were supported by the University of Vienna, J.K. by a Wellcome Trust Collaborative Award and by the Centre of Optimized Structural Studies, M.P. by FWF Project I1593, E.d.A.R. ITN-MUZIC, and FWF Projects I525 and I1593, and T.C.M. and L.C. by FWF Project I 2408-B22. E.A.G. acknowledges the PhD program Structure and Interaction of Biological Macromolecules. M.B. acknowledges the University Grant Commission, India, for a senior research fellowship. A.B. acknowledges a JC Bose Fellowship from the Science Engineering Research Council. ","date_created":"2024-03-04T10:03:52Z","pmid":1,"language":[{"iso":"eng"}],"publication_identifier":{"eissn":["1091-6490"],"issn":["0027-8424"]},"intvolume":"       117","author":[{"full_name":"Pinotsis, Nikos","last_name":"Pinotsis","first_name":"Nikos"},{"last_name":"Zielinska","first_name":"Karolina","full_name":"Zielinska, Karolina"},{"first_name":"Mrigya","last_name":"Babuta","full_name":"Babuta, Mrigya"},{"last_name":"Arolas","first_name":"Joan L.","full_name":"Arolas, Joan L."},{"full_name":"Kostan, Julius","last_name":"Kostan","first_name":"Julius"},{"full_name":"Khan, Muhammad Bashir","first_name":"Muhammad Bashir","last_name":"Khan"},{"first_name":"Claudia","last_name":"Schreiner","full_name":"Schreiner, Claudia"},{"first_name":"Anita P","id":"41F1F098-F248-11E8-B48F-1D18A9856A87","last_name":"Testa Salmazo","full_name":"Testa Salmazo, Anita P"},{"last_name":"Ciccarelli","first_name":"Luciano","full_name":"Ciccarelli, Luciano"},{"full_name":"Puchinger, Martin","last_name":"Puchinger","first_name":"Martin"},{"last_name":"Gkougkoulia","first_name":"Eirini A.","full_name":"Gkougkoulia, Eirini A."},{"last_name":"Ribeiro","first_name":"Euripedes de Almeida","full_name":"Ribeiro, Euripedes de Almeida"},{"full_name":"Marlovits, Thomas C.","last_name":"Marlovits","first_name":"Thomas C."},{"full_name":"Bhattacharya, Alok","first_name":"Alok","last_name":"Bhattacharya"},{"last_name":"Djinovic-Carugo","first_name":"Kristina","full_name":"Djinovic-Carugo, Kristina"}],"type":"journal_article","publication_status":"published","quality_controlled":"1","date_updated":"2024-03-04T10:14:44Z","date_published":"2020-09-08T00:00:00Z","volume":117,"article_type":"original","year":"2020","oa_version":"Published Version","status":"public","publication":"Proceedings of the National Academy of Sciences","issue":"36","department":[{"_id":"CaBe"}],"external_id":{"pmid":["32848067"]},"title":"Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","citation":{"ista":"Pinotsis N, Zielinska K, Babuta M, Arolas JL, Kostan J, Khan MB, Schreiner C, Testa Salmazo AP, Ciccarelli L, Puchinger M, Gkougkoulia EA, Ribeiro E de A, Marlovits TC, Bhattacharya A, Djinovic-Carugo K. 2020. Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin. Proceedings of the National Academy of Sciences. 117(36), 22101–22112.","ama":"Pinotsis N, Zielinska K, Babuta M, et al. Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin. <i>Proceedings of the National Academy of Sciences</i>. 2020;117(36):22101-22112. doi:<a href=\"https://doi.org/10.1073/pnas.1917269117\">10.1073/pnas.1917269117</a>","ieee":"N. Pinotsis <i>et al.</i>, “Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin,” <i>Proceedings of the National Academy of Sciences</i>, vol. 117, no. 36. Proceedings of the National Academy of Sciences, pp. 22101–22112, 2020.","short":"N. Pinotsis, K. Zielinska, M. Babuta, J.L. Arolas, J. Kostan, M.B. Khan, C. Schreiner, A.P. Testa Salmazo, L. Ciccarelli, M. Puchinger, E.A. Gkougkoulia, E. de A. Ribeiro, T.C. Marlovits, A. Bhattacharya, K. Djinovic-Carugo, Proceedings of the National Academy of Sciences 117 (2020) 22101–22112.","chicago":"Pinotsis, Nikos, Karolina Zielinska, Mrigya Babuta, Joan L. Arolas, Julius Kostan, Muhammad Bashir Khan, Claudia Schreiner, et al. “Calcium Modulates the Domain Flexibility and Function of an α-Actinin Similar to the Ancestral α-Actinin.” <i>Proceedings of the National Academy of Sciences</i>. Proceedings of the National Academy of Sciences, 2020. <a href=\"https://doi.org/10.1073/pnas.1917269117\">https://doi.org/10.1073/pnas.1917269117</a>.","apa":"Pinotsis, N., Zielinska, K., Babuta, M., Arolas, J. L., Kostan, J., Khan, M. B., … Djinovic-Carugo, K. (2020). Calcium modulates the domain flexibility and function of an α-actinin similar to the ancestral α-actinin. <i>Proceedings of the National Academy of Sciences</i>. Proceedings of the National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.1917269117\">https://doi.org/10.1073/pnas.1917269117</a>","mla":"Pinotsis, Nikos, et al. “Calcium Modulates the Domain Flexibility and Function of an α-Actinin Similar to the Ancestral α-Actinin.” <i>Proceedings of the National Academy of Sciences</i>, vol. 117, no. 36, Proceedings of the National Academy of Sciences, 2020, pp. 22101–12, doi:<a href=\"https://doi.org/10.1073/pnas.1917269117\">10.1073/pnas.1917269117</a>."},"_id":"15061","month":"09","page":"22101-22112"}