--- _id: '10146' abstract: - lang: eng text: The enzymes of the mitochondrial electron transport chain are key players of cell metabolism. Despite being active when isolated, in vivo they associate into supercomplexes1, whose precise role is debated. Supercomplexes CIII2CIV1-2 (refs. 2,3), CICIII2 (ref. 4) and CICIII2CIV (respirasome)5,6,7,8,9,10 exist in mammals, but in contrast to CICIII2 and the respirasome, to date the only known eukaryotic structures of CIII2CIV1-2 come from Saccharomyces cerevisiae11,12 and plants13, which have different organization. Here we present the first, to our knowledge, structures of mammalian (mouse and ovine) CIII2CIV and its assembly intermediates, in different conformations. We describe the assembly of CIII2CIV from the CIII2 precursor to the final CIII2CIV conformation, driven by the insertion of the N terminus of the assembly factor SCAF1 (ref. 14) deep into CIII2, while its C terminus is integrated into CIV. Our structures (which include CICIII2 and the respirasome) also confirm that SCAF1 is exclusively required for the assembly of CIII2CIV and has no role in the assembly of the respirasome. We show that CIII2 is asymmetric due to the presence of only one copy of subunit 9, which straddles both monomers and prevents the attachment of a second copy of SCAF1 to CIII2, explaining the presence of one copy of CIV in CIII2CIV in mammals. Finally, we show that CIII2 and CIV gain catalytic advantage when assembled into the supercomplex and propose a role for CIII2CIV in fine tuning the efficiency of electron transfer in the electron transport chain. acknowledged_ssus: - _id: PreCl - _id: EM-Fac - _id: ScienComp acknowledgement: We thank the pre-clinical facility of the IST Austria and A. Venturino for assistance with the animals; and V.-V. Hodirnau for assistance during the Titan Krios data collection, performed at the IST Austria. The data processing was performed at the IST high-performance computing cluster. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 754411. article_processing_charge: No article_type: original author: - first_name: Irene full_name: Vercellino, Irene id: 3ED6AF16-F248-11E8-B48F-1D18A9856A87 last_name: Vercellino orcid: 0000-0001-5618-3449 - 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: Vercellino I, Sazanov LA. Structure and assembly of the mammalian mitochondrial supercomplex CIII2CIV. Nature. 2021;598(7880):364-367. doi:10.1038/s41586-021-03927-z apa: Vercellino, I., & Sazanov, L. A. (2021). Structure and assembly of the mammalian mitochondrial supercomplex CIII2CIV. Nature. Springer Nature. https://doi.org/10.1038/s41586-021-03927-z chicago: Vercellino, Irene, and Leonid A Sazanov. “Structure and Assembly of the Mammalian Mitochondrial Supercomplex CIII2CIV.” Nature. Springer Nature, 2021. https://doi.org/10.1038/s41586-021-03927-z. ieee: I. Vercellino and L. A. Sazanov, “Structure and assembly of the mammalian mitochondrial supercomplex CIII2CIV,” Nature, vol. 598, no. 7880. Springer Nature, pp. 364–367, 2021. ista: Vercellino I, Sazanov LA. 2021. Structure and assembly of the mammalian mitochondrial supercomplex CIII2CIV. Nature. 598(7880), 364–367. mla: Vercellino, Irene, and Leonid A. Sazanov. “Structure and Assembly of the Mammalian Mitochondrial Supercomplex CIII2CIV.” Nature, vol. 598, no. 7880, Springer Nature, 2021, pp. 364–67, doi:10.1038/s41586-021-03927-z. short: I. Vercellino, L.A. Sazanov, Nature 598 (2021) 364–367. date_created: 2021-10-17T22:01:17Z date_published: 2021-10-14T00:00:00Z date_updated: 2023-08-14T08:01:21Z day: '14' department: - _id: LeSa doi: 10.1038/s41586-021-03927-z ec_funded: 1 external_id: isi: - '000704581600001' pmid: - '34616041' intvolume: ' 598' isi: 1 issue: '7880' language: - iso: eng month: '10' oa_version: None page: 364-367 pmid: 1 project: - _id: 260C2330-B435-11E9-9278-68D0E5697425 call_identifier: H2020 grant_number: '754411' name: ISTplus - Postdoctoral Fellowships publication: Nature publication_identifier: eissn: - 1476-4687 issn: - 0028-0836 publication_status: published publisher: Springer Nature quality_controlled: '1' related_material: link: - description: News on IST Webpage relation: press_release url: https://ist.ac.at/en/news/boosting-the-cells-power-house/ scopus_import: '1' status: public title: Structure and assembly of the mammalian mitochondrial supercomplex CIII2CIV type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 598 year: '2021' ... --- _id: '10310' abstract: - lang: eng text: A high-resolution structure of trimeric cyanobacterial Photosystem I (PSI) from Thermosynechococcus elongatus was reported as the first atomic model of PSI almost 20 years ago. However, the monomeric PSI structure has not yet been reported despite long-standing interest in its structure and extensive spectroscopic characterization of the loss of red chlorophylls upon monomerization. Here, we describe the structure of monomeric PSI from Thermosynechococcus elongatus BP-1. Comparison with the trimer structure gave detailed insights into monomerization-induced changes in both the central trimerization domain and the peripheral regions of the complex. Monomerization-induced loss of red chlorophylls is assigned to a cluster of chlorophylls adjacent to PsaX. Based on our findings, we propose a role of PsaX in the stabilization of red chlorophylls and that lipids of the surrounding membrane present a major source of thermal energy for uphill excitation energy transfer from red chlorophylls to P700. acknowledgement: We are grateful for additional support and valuable scientific input for this project by Yuko Misumi, Jiannan Li, Hisako Kubota-Kawai, Takeshi Kawabata, Mian Wu, Eiki Yamashita, Atsushi Nakagawa, Volker Hartmann, Melanie Völkel and Matthias Rögner. Parts of this research were funded by the German Research Council (DFG) within the framework of GRK 2341 (Microbial Substrate Conversion) to M.M.N., the Platform Project for Supporting Drug Discovery and Life Science Research [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] from AMED under grant number JP20am0101117 (K.N.), JP16K07266 to Atsunori Oshima and C.G., a Grants-in-Aid for Scientific Research under grant number JP 25000013 (K.N.), 17H03647 (C.G.) and 16H06560 (G.K.) from MEXT-KAKENHI, the International Joint Research Promotion Program from Osaka University to M.M.N., C.G. and G.K., and the Cyclic Innovation for Clinical Empowerment (CiCLE) Grant Number JP17pc0101020 from AMED to K.N. and G.K. article_number: '304' article_processing_charge: No article_type: original author: - first_name: Mehmet Orkun full_name: Çoruh, Mehmet Orkun id: d25163e5-8d53-11eb-a251-e6dd8ea1b8ef last_name: Çoruh orcid: 0000-0002-3219-2022 - first_name: Anna full_name: Frank, Anna last_name: Frank - first_name: Hideaki full_name: Tanaka, Hideaki last_name: Tanaka - first_name: Akihiro full_name: Kawamoto, Akihiro last_name: Kawamoto - first_name: Eithar full_name: El-Mohsnawy, Eithar last_name: El-Mohsnawy - first_name: Takayuki full_name: Kato, Takayuki last_name: Kato - first_name: Keiichi full_name: Namba, Keiichi last_name: Namba - first_name: Christoph full_name: Gerle, Christoph last_name: Gerle - first_name: Marc M. full_name: Nowaczyk, Marc M. last_name: Nowaczyk - first_name: Genji full_name: Kurisu, Genji last_name: Kurisu citation: ama: Çoruh MO, Frank A, Tanaka H, et al. Cryo-EM structure of a functional monomeric Photosystem I from Thermosynechococcus elongatus reveals red chlorophyll cluster. Communications Biology. 2021;4(1). doi:10.1038/s42003-021-01808-9 apa: Çoruh, M. O., Frank, A., Tanaka, H., Kawamoto, A., El-Mohsnawy, E., Kato, T., … Kurisu, G. (2021). Cryo-EM structure of a functional monomeric Photosystem I from Thermosynechococcus elongatus reveals red chlorophyll cluster. Communications Biology. Springer . https://doi.org/10.1038/s42003-021-01808-9 chicago: Çoruh, Mehmet Orkun, Anna Frank, Hideaki Tanaka, Akihiro Kawamoto, Eithar El-Mohsnawy, Takayuki Kato, Keiichi Namba, Christoph Gerle, Marc M. Nowaczyk, and Genji Kurisu. “Cryo-EM Structure of a Functional Monomeric Photosystem I from Thermosynechococcus Elongatus Reveals Red Chlorophyll Cluster.” Communications Biology. Springer , 2021. https://doi.org/10.1038/s42003-021-01808-9. ieee: M. O. Çoruh et al., “Cryo-EM structure of a functional monomeric Photosystem I from Thermosynechococcus elongatus reveals red chlorophyll cluster,” Communications Biology, vol. 4, no. 1. Springer , 2021. ista: Çoruh MO, Frank A, Tanaka H, Kawamoto A, El-Mohsnawy E, Kato T, Namba K, Gerle C, Nowaczyk MM, Kurisu G. 2021. Cryo-EM structure of a functional monomeric Photosystem I from Thermosynechococcus elongatus reveals red chlorophyll cluster. Communications Biology. 4(1), 304. mla: Çoruh, Mehmet Orkun, et al. “Cryo-EM Structure of a Functional Monomeric Photosystem I from Thermosynechococcus Elongatus Reveals Red Chlorophyll Cluster.” Communications Biology, vol. 4, no. 1, 304, Springer , 2021, doi:10.1038/s42003-021-01808-9. short: M.O. Çoruh, A. Frank, H. Tanaka, A. Kawamoto, E. El-Mohsnawy, T. Kato, K. Namba, C. Gerle, M.M. Nowaczyk, G. Kurisu, Communications Biology 4 (2021). date_created: 2021-11-19T11:37:29Z date_published: 2021-03-08T00:00:00Z date_updated: 2023-08-14T11:51:19Z day: '08' ddc: - '570' department: - _id: LeSa doi: 10.1038/s42003-021-01808-9 external_id: isi: - '000627440700001' pmid: - '33686186' file: - access_level: open_access checksum: 8ffd39f2bba7152a2441802ff313bf0b content_type: application/pdf creator: cchlebak date_created: 2021-11-19T15:09:18Z date_updated: 2021-11-19T15:09:18Z file_id: '10318' file_name: 2021_CommBio_Çoruh.pdf file_size: 6030261 relation: main_file success: 1 file_date_updated: 2021-11-19T15:09:18Z has_accepted_license: '1' intvolume: ' 4' isi: 1 issue: '1' keyword: - general agricultural and biological Sciences - general biochemistry - genetics and molecular biology - medicine (miscellaneous) language: - iso: eng license: https://creativecommons.org/licenses/by/4.0/ month: '03' oa: 1 oa_version: Published Version pmid: 1 publication: Communications Biology publication_identifier: issn: - 2399-3642 publication_status: published publisher: 'Springer ' quality_controlled: '1' scopus_import: '1' status: public title: Cryo-EM structure of a functional monomeric Photosystem I from Thermosynechococcus elongatus reveals red chlorophyll cluster 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: 4 year: '2021' ... --- _id: '7788' abstract: - lang: eng 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. article_number: '148213' article_processing_charge: No article_type: original author: - first_name: Merel J.W. full_name: Adjobo-Hermans, Merel J.W. last_name: Adjobo-Hermans - first_name: Ria full_name: De Haas, Ria last_name: De Haas - first_name: Peter H.G.M. full_name: Willems, Peter H.G.M. last_name: Willems - first_name: Aleksandra full_name: Wojtala, Aleksandra last_name: Wojtala - first_name: Sjenet E. full_name: Van Emst-De Vries, Sjenet E. last_name: Van Emst-De Vries - first_name: Jori A. full_name: Wagenaars, Jori A. last_name: Wagenaars - first_name: Mariel full_name: Van Den Brand, Mariel last_name: Van Den Brand - first_name: Richard J. full_name: Rodenburg, Richard J. last_name: Rodenburg - first_name: Jan A.M. full_name: Smeitink, Jan A.M. last_name: Smeitink - first_name: Leo G. full_name: Nijtmans, Leo G. last_name: Nijtmans - first_name: Leonid A full_name: Sazanov, Leonid A id: 338D39FE-F248-11E8-B48F-1D18A9856A87 last_name: Sazanov orcid: 0000-0002-0977-7989 - first_name: Mariusz R. full_name: Wieckowski, Mariusz R. last_name: Wieckowski - first_name: Werner J.H. full_name: Koopman, Werner J.H. last_name: Koopman citation: 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' 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' 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.' 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.' 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.' 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). date_created: 2020-05-03T22:00:47Z date_published: 2020-08-01T00:00:00Z date_updated: 2023-08-21T06:19:18Z day: '01' ddc: - '570' department: - _id: LeSa doi: 10.1016/j.bbabio.2020.148213 external_id: isi: - '000540842000012' pmid: - '32335026' file: - access_level: open_access checksum: a9b152381307cf45fe266a8dc5640388 content_type: application/pdf creator: dernst date_created: 2020-05-04T12:25:19Z date_updated: 2020-07-14T12:48:03Z file_id: '7798' file_name: 2020_BBA_Adjobo_Hermans.pdf file_size: 3826792 relation: main_file file_date_updated: 2020-07-14T12:48:03Z has_accepted_license: '1' intvolume: ' 1861' isi: 1 issue: '8' language: - iso: eng month: '08' oa: 1 oa_version: Published Version pmid: 1 publication: Biochimica et Biophysica Acta - Bioenergetics publication_identifier: eissn: - '18792650' issn: - '00052728' publication_status: published publisher: Elsevier quality_controlled: '1' scopus_import: '1' status: public title: 'NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2' 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: 1861 year: '2020' ... --- _id: '8040' 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_processing_charge: No article_type: original author: - first_name: Chitrak full_name: Gupta, Chitrak last_name: Gupta - first_name: Umesh full_name: Khaniya, Umesh last_name: Khaniya - first_name: Chun Kit full_name: Chan, Chun Kit last_name: Chan - first_name: Francois full_name: Dehez, Francois last_name: Dehez - first_name: Mrinal full_name: Shekhar, Mrinal last_name: Shekhar - first_name: M. R. full_name: Gunner, M. R. last_name: Gunner - first_name: Leonid A full_name: Sazanov, Leonid A id: 338D39FE-F248-11E8-B48F-1D18A9856A87 last_name: Sazanov orcid: 0000-0002-0977-7989 - first_name: Christophe full_name: Chipot, Christophe last_name: Chipot - first_name: Abhishek full_name: Singharoy, Abhishek last_name: Singharoy citation: 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 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 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. 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. 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. 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. 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. date_created: 2020-06-29T07:59:35Z date_published: 2020-05-20T00:00:00Z date_updated: 2023-08-22T07:49:38Z day: '20' department: - _id: LeSa doi: 10.1021/jacs.9b13450 external_id: isi: - '000537415600020' pmid: - '32347721' intvolume: ' 142' isi: 1 issue: '20' language: - iso: eng month: '05' oa_version: None page: 9220-9230 pmid: 1 publication: Journal of the American Chemical Society publication_identifier: eissn: - '15205126' issn: - '00027863' publication_status: published publisher: American Chemical Society quality_controlled: '1' related_material: record: - id: '9326' relation: research_data status: public - id: '9713' relation: research_data status: public - id: '9878' relation: research_data status: public scopus_import: '1' status: public title: Charge transfer and chemo-mechanical coupling in respiratory complex I type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 142 year: '2020' ... --- _id: '9326' 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_processing_charge: No author: - first_name: Chitrak full_name: Gupta, Chitrak last_name: Gupta - first_name: Umesh full_name: Khaniya, Umesh last_name: Khaniya - first_name: Chun full_name: Chan, Chun last_name: Chan - first_name: Francois full_name: Dehez, Francois last_name: Dehez - first_name: Mrinal full_name: Shekhar, Mrinal last_name: Shekhar - first_name: M. R. full_name: Gunner, M. R. last_name: Gunner - first_name: Leonid A full_name: Sazanov, Leonid A id: 338D39FE-F248-11E8-B48F-1D18A9856A87 last_name: Sazanov orcid: 0000-0002-0977-7989 - first_name: Christophe full_name: Chipot, Christophe last_name: Chipot - first_name: Abhishek full_name: Singharoy, Abhishek last_name: Singharoy citation: 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 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 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. ieee: C. Gupta et al., “Charge transfer and chemo-mechanical coupling in respiratory complex I.” American Chemical Society, 2020. 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. 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. short: C. Gupta, U. Khaniya, C. Chan, F. Dehez, M. Shekhar, M.R. Gunner, L.A. Sazanov, C. Chipot, A. Singharoy, (2020). date_created: 2021-04-14T12:05:20Z date_published: 2020-05-20T00:00:00Z date_updated: 2023-08-22T07:49:37Z day: '20' department: - _id: LeSa doi: 10.1021/jacs.9b13450.s002 license: https://creativecommons.org/licenses/by-nc/4.0/ main_file_link: - open_access: '1' month: '05' oa: 1 oa_version: Published Version publisher: American Chemical Society related_material: record: - id: '8040' relation: used_in_publication status: public status: public title: Charge transfer and chemo-mechanical coupling in respiratory complex I tmp: image: /images/cc_by_nc.png legal_code_url: https://creativecommons.org/licenses/by-nc/4.0/legalcode name: Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) short: CC BY-NC (4.0) type: research_data_reference user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 year: '2020' ...