---
_id: '8318'
abstract:
- lang: eng
text: Complex I is the first and the largest enzyme of respiratory chains in bacteria
and mitochondria. The mechanism which couples spatially separated transfer of
electrons to proton translocation in complex I is not known. Here we report five
crystal structures of T. thermophilus enzyme in complex with NADH or quinone-like
compounds. We also determined cryo-EM structures of major and minor native states
of the complex, differing in the position of the peripheral arm. Crystal structures
show that binding of quinone-like compounds (but not of NADH) leads to a related
global conformational change, accompanied by local re-arrangements propagating
from the quinone site to the nearest proton channel. Normal mode and molecular
dynamics analyses indicate that these are likely to represent the first steps
in the proton translocation mechanism. Our results suggest that quinone binding
and chemistry play a key role in the coupling mechanism of complex I.
acknowledgement: This work was funded by the Medical Research Council, UK and IST
Austria. We thank the European Synchrotron Radiation Facility and the Diamond Light
Source for provision of synchrotron radiation facilities. We are grateful to the
staff of beamlines ID29, ID23-2 (ESRF, Grenoble, France) and I03 (Diamond Light
Source, Didcot, UK) for assistance. Data processing was performed at the IST high-performance
computing cluster.
article_number: '4135'
article_processing_charge: No
article_type: original
author:
- first_name: Javier
full_name: Gutierrez-Fernandez, Javier
id: 3D9511BA-F248-11E8-B48F-1D18A9856A87
last_name: Gutierrez-Fernandez
- first_name: Karol
full_name: Kaszuba, Karol
id: 3FDF9472-F248-11E8-B48F-1D18A9856A87
last_name: Kaszuba
- first_name: Gurdeep S.
full_name: Minhas, Gurdeep S.
last_name: Minhas
- first_name: Rozbeh
full_name: Baradaran, Rozbeh
last_name: Baradaran
- first_name: Margherita
full_name: Tambalo, Margherita
id: 4187dfe4-ec23-11ea-ae46-f08ab378313a
last_name: Tambalo
- first_name: David T.
full_name: Gallagher, David T.
last_name: Gallagher
- first_name: Leonid A
full_name: Sazanov, Leonid A
id: 338D39FE-F248-11E8-B48F-1D18A9856A87
last_name: Sazanov
orcid: 0000-0002-0977-7989
citation:
ama: Gutierrez-Fernandez J, Kaszuba K, Minhas GS, et al. Key role of quinone in
the mechanism of respiratory complex I. Nature Communications. 2020;11(1).
doi:10.1038/s41467-020-17957-0
apa: Gutierrez-Fernandez, J., Kaszuba, K., Minhas, G. S., Baradaran, R., Tambalo,
M., Gallagher, D. T., & Sazanov, L. A. (2020). Key role of quinone in the
mechanism of respiratory complex I. Nature Communications. Springer Nature.
https://doi.org/10.1038/s41467-020-17957-0
chicago: Gutierrez-Fernandez, Javier, Karol Kaszuba, Gurdeep S. Minhas, Rozbeh Baradaran,
Margherita Tambalo, David T. Gallagher, and Leonid A Sazanov. “Key Role of Quinone
in the Mechanism of Respiratory Complex I.” Nature Communications. Springer
Nature, 2020. https://doi.org/10.1038/s41467-020-17957-0.
ieee: J. Gutierrez-Fernandez et al., “Key role of quinone in the mechanism
of respiratory complex I,” Nature Communications, vol. 11, no. 1. Springer
Nature, 2020.
ista: Gutierrez-Fernandez J, Kaszuba K, Minhas GS, Baradaran R, Tambalo M, Gallagher
DT, Sazanov LA. 2020. Key role of quinone in the mechanism of respiratory complex
I. Nature Communications. 11(1), 4135.
mla: Gutierrez-Fernandez, Javier, et al. “Key Role of Quinone in the Mechanism of
Respiratory Complex I.” Nature Communications, vol. 11, no. 1, 4135, Springer
Nature, 2020, doi:10.1038/s41467-020-17957-0.
short: J. Gutierrez-Fernandez, K. Kaszuba, G.S. Minhas, R. Baradaran, M. Tambalo,
D.T. Gallagher, L.A. Sazanov, Nature Communications 11 (2020).
date_created: 2020-08-30T22:01:10Z
date_published: 2020-08-18T00:00:00Z
date_updated: 2023-08-22T09:03:00Z
day: '18'
ddc:
- '570'
department:
- _id: LeSa
doi: 10.1038/s41467-020-17957-0
external_id:
isi:
- '000607072900001'
pmid:
- '32811817'
file:
- access_level: open_access
checksum: 52b96f41d7d0db9728064c08da00d030
content_type: application/pdf
creator: cziletti
date_created: 2020-08-31T13:40:00Z
date_updated: 2020-08-31T13:40:00Z
file_id: '8326'
file_name: 2020_NatComm_Gutierrez-Fernandez.pdf
file_size: 7527373
relation: main_file
success: 1
file_date_updated: 2020-08-31T13:40:00Z
has_accepted_license: '1'
intvolume: ' 11'
isi: 1
issue: '1'
language:
- iso: eng
month: '08'
oa: 1
oa_version: Published Version
pmid: 1
publication: Nature Communications
publication_identifier:
eissn:
- '20411723'
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
related_material:
link:
- description: News on IST Homepage
relation: press_release
url: https://ist.ac.at/en/news/mystery-of-giant-proton-pump-solved/
scopus_import: '1'
status: public
title: Key role of quinone in the mechanism of respiratory complex I
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 11
year: '2020'
...
---
_id: '1226'
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.
article_processing_charge: No
article_type: original
author:
- first_name: Karol
full_name: Fiedorczuk, Karol
id: 5BFF67CE-02D1-11E9-B11A-A5A4D7DFFFD0
last_name: Fiedorczuk
- first_name: James A
full_name: Letts, James A
id: 322DA418-F248-11E8-B48F-1D18A9856A87
last_name: Letts
orcid: 0000-0002-9864-3586
- first_name: Gianluca
full_name: Degliesposti, Gianluca
last_name: Degliesposti
- first_name: Karol
full_name: Kaszuba, Karol
id: 3FDF9472-F248-11E8-B48F-1D18A9856A87
last_name: Kaszuba
- first_name: Mark
full_name: Skehel, Mark
last_name: Skehel
- first_name: Leonid A
full_name: Sazanov, Leonid A
id: 338D39FE-F248-11E8-B48F-1D18A9856A87
last_name: Sazanov
orcid: 0000-0002-0977-7989
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
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
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.
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.
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.
date_created: 2018-12-11T11:50:49Z
date_published: 2016-10-20T00:00:00Z
date_updated: 2021-01-12T06:49:13Z
day: '20'
department:
- _id: LeSa
doi: 10.1038/nature19794
ec_funded: 1
external_id:
pmid:
- '27595392'
intvolume: ' 538'
issue: '7625'
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164932/
month: '10'
oa: 1
oa_version: Submitted Version
page: 406 - 410
pmid: 1
project:
- _id: 2593EBD6-B435-11E9-9278-68D0E5697425
name: Atomic-Resolution Structures of Mitochondrial Respiratory Chain Supercomplexes
(FEBS)
- _id: 2590DB08-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '701309'
name: Atomic-Resolution Structures of Mitochondrial Respiratory Chain Supercomplexes
(H2020)
publication: Nature
publication_status: published
publisher: Nature Publishing Group
publist_id: '6108'
quality_controlled: '1'
scopus_import: 1
status: public
title: Atomic structure of the entire mammalian mitochondrial complex i
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 538
year: '2016'
...
---
_id: '1276'
abstract:
- lang: eng
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.
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.
article_number: '33607'
author:
- first_name: Pekka
full_name: Postila, Pekka
last_name: Postila
- first_name: Karol
full_name: Kaszuba, Karol
id: 3FDF9472-F248-11E8-B48F-1D18A9856A87
last_name: Kaszuba
- first_name: Patryk
full_name: Kuleta, Patryk
last_name: Kuleta
- first_name: Ilpo
full_name: Vattulainen, Ilpo
last_name: Vattulainen
- first_name: Marcin
full_name: Sarewicz, Marcin
last_name: Sarewicz
- first_name: Artur
full_name: Osyczka, Artur
last_name: Osyczka
- first_name: Tomasz
full_name: Róg, Tomasz
last_name: Róg
citation:
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
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
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.
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.
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.
short: P. Postila, K. Kaszuba, P. Kuleta, I. Vattulainen, M. Sarewicz, A. Osyczka,
T. Róg, Scientific Reports 6 (2016).
date_created: 2018-12-11T11:51:05Z
date_published: 2016-09-26T00:00:00Z
date_updated: 2021-01-12T06:49:34Z
day: '26'
ddc:
- '576'
department:
- _id: LeSa
doi: 10.1038/srep33607
file:
- access_level: open_access
checksum: 07c591c1250ebef266333cbc3228b4dd
content_type: application/pdf
creator: system
date_created: 2018-12-12T10:17:09Z
date_updated: 2020-07-14T12:44:42Z
file_id: '5261'
file_name: IST-2016-691-v1+1_srep33607.pdf
file_size: 1960563
relation: main_file
file_date_updated: 2020-07-14T12:44:42Z
has_accepted_license: '1'
intvolume: ' 6'
language:
- iso: eng
month: '09'
oa: 1
oa_version: Published Version
publication: Scientific Reports
publication_status: published
publisher: Nature Publishing Group
publist_id: '6040'
pubrep_id: '691'
quality_controlled: '1'
scopus_import: 1
status: public
title: Atomistic determinants of co-enzyme Q reduction at the Qi-site of the cytochrome
bc1 complex
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87
volume: 6
year: '2016'
...