[{"pmid":1,"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.","year":"2021","publisher":"Springer Nature","department":[{"_id":"LeSa"}],"publication_status":"published","related_material":{"link":[{"url":"https://ist.ac.at/en/news/boosting-the-cells-power-house/","description":"News on IST Webpage","relation":"press_release"}]},"author":[{"full_name":"Vercellino, Irene","first_name":"Irene","last_name":"Vercellino","id":"3ED6AF16-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0001-5618-3449"},{"id":"338D39FE-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-0977-7989","first_name":"Leonid A","last_name":"Sazanov","full_name":"Sazanov, Leonid A"}],"volume":598,"date_updated":"2023-08-14T08:01:21Z","date_created":"2021-10-17T22:01:17Z","ec_funded":1,"external_id":{"isi":["000704581600001"],"pmid":["34616041"]},"project":[{"call_identifier":"H2020","name":"ISTplus - Postdoctoral Fellowships","_id":"260C2330-B435-11E9-9278-68D0E5697425","grant_number":"754411"}],"isi":1,"quality_controlled":"1","doi":"10.1038/s41586-021-03927-z","language":[{"iso":"eng"}],"acknowledged_ssus":[{"_id":"PreCl"},{"_id":"EM-Fac"},{"_id":"ScienComp"}],"publication_identifier":{"eissn":["1476-4687"],"issn":["0028-0836"]},"month":"10","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","_id":"10146","intvolume":" 598","title":"Structure and assembly of the mammalian mitochondrial supercomplex CIII2CIV","status":"public","oa_version":"None","type":"journal_article","issue":"7880","abstract":[{"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.","lang":"eng"}],"citation":{"ista":"Vercellino I, Sazanov LA. 2021. Structure and assembly of the mammalian mitochondrial supercomplex CIII2CIV. Nature. 598(7880), 364–367.","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.","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","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","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.","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."},"publication":"Nature","page":"364-367","article_type":"original","date_published":"2021-10-14T00:00:00Z","scopus_import":"1","article_processing_charge":"No","day":"14"},{"publication_identifier":{"issn":["2399-3642"]},"month":"03","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"oa":1,"external_id":{"isi":["000627440700001"],"pmid":["33686186"]},"isi":1,"quality_controlled":"1","doi":"10.1038/s42003-021-01808-9","language":[{"iso":"eng"}],"article_number":"304","file_date_updated":"2021-11-19T15:09:18Z","pmid":1,"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.","year":"2021","department":[{"_id":"LeSa"}],"publisher":"Springer ","publication_status":"published","author":[{"full_name":"Çoruh, Mehmet Orkun","last_name":"Çoruh","first_name":"Mehmet Orkun","orcid":"0000-0002-3219-2022","id":"d25163e5-8d53-11eb-a251-e6dd8ea1b8ef"},{"first_name":"Anna","last_name":"Frank","full_name":"Frank, Anna"},{"first_name":"Hideaki","last_name":"Tanaka","full_name":"Tanaka, Hideaki"},{"last_name":"Kawamoto","first_name":"Akihiro","full_name":"Kawamoto, Akihiro"},{"full_name":"El-Mohsnawy, Eithar","last_name":"El-Mohsnawy","first_name":"Eithar"},{"full_name":"Kato, Takayuki","last_name":"Kato","first_name":"Takayuki"},{"first_name":"Keiichi","last_name":"Namba","full_name":"Namba, Keiichi"},{"first_name":"Christoph","last_name":"Gerle","full_name":"Gerle, Christoph"},{"full_name":"Nowaczyk, Marc M.","last_name":"Nowaczyk","first_name":"Marc M."},{"full_name":"Kurisu, Genji","last_name":"Kurisu","first_name":"Genji"}],"volume":4,"date_updated":"2023-08-14T11:51:19Z","date_created":"2021-11-19T11:37:29Z","scopus_import":"1","keyword":["general agricultural and biological Sciences","general biochemistry","genetics and molecular biology","medicine (miscellaneous)"],"article_processing_charge":"No","has_accepted_license":"1","day":"08","citation":{"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).","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.","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.","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","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."},"publication":"Communications Biology","article_type":"original","date_published":"2021-03-08T00:00:00Z","type":"journal_article","issue":"1","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."}],"_id":"10310","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","intvolume":" 4","title":"Cryo-EM structure of a functional monomeric Photosystem I from Thermosynechococcus elongatus reveals red chlorophyll cluster","ddc":["570"],"status":"public","file":[{"file_id":"10318","relation":"main_file","success":1,"checksum":"8ffd39f2bba7152a2441802ff313bf0b","date_created":"2021-11-19T15:09:18Z","date_updated":"2021-11-19T15:09:18Z","access_level":"open_access","file_name":"2021_CommBio_Çoruh.pdf","creator":"cchlebak","content_type":"application/pdf","file_size":6030261}],"oa_version":"Published Version"},{"file":[{"file_name":"2020_BBA_Adjobo_Hermans.pdf","access_level":"open_access","creator":"dernst","file_size":3826792,"content_type":"application/pdf","file_id":"7798","relation":"main_file","date_updated":"2020-07-14T12:48:03Z","date_created":"2020-05-04T12:25:19Z","checksum":"a9b152381307cf45fe266a8dc5640388"}],"oa_version":"Published Version","_id":"7788","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","intvolume":" 1861","title":"NDUFS4 deletion triggers loss of NDUFA12 in Ndufs4−/− mice and Leigh syndrome patients: A stabilizing role for NDUFAF2","ddc":["570"],"status":"public","issue":"8","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"}],"type":"journal_article","date_published":"2020-08-01T00:00:00Z","citation":{"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.","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.","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","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","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.","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)."},"publication":"Biochimica et Biophysica Acta - Bioenergetics","article_type":"original","article_processing_charge":"No","has_accepted_license":"1","day":"01","scopus_import":"1","author":[{"full_name":"Adjobo-Hermans, Merel J.W.","last_name":"Adjobo-Hermans","first_name":"Merel J.W."},{"first_name":"Ria","last_name":"De Haas","full_name":"De Haas, Ria"},{"full_name":"Willems, Peter H.G.M.","last_name":"Willems","first_name":"Peter H.G.M."},{"full_name":"Wojtala, Aleksandra","last_name":"Wojtala","first_name":"Aleksandra"},{"full_name":"Van Emst-De Vries, Sjenet E.","first_name":"Sjenet E.","last_name":"Van Emst-De Vries"},{"last_name":"Wagenaars","first_name":"Jori A.","full_name":"Wagenaars, Jori A."},{"full_name":"Van Den Brand, Mariel","last_name":"Van Den Brand","first_name":"Mariel"},{"full_name":"Rodenburg, Richard J.","last_name":"Rodenburg","first_name":"Richard J."},{"full_name":"Smeitink, Jan A.M.","first_name":"Jan A.M.","last_name":"Smeitink"},{"full_name":"Nijtmans, Leo G.","last_name":"Nijtmans","first_name":"Leo G."},{"full_name":"Sazanov, Leonid A","first_name":"Leonid A","last_name":"Sazanov","id":"338D39FE-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-0977-7989"},{"first_name":"Mariusz R.","last_name":"Wieckowski","full_name":"Wieckowski, Mariusz R."},{"first_name":"Werner J.H.","last_name":"Koopman","full_name":"Koopman, Werner J.H."}],"volume":1861,"date_created":"2020-05-03T22:00:47Z","date_updated":"2023-08-21T06:19:18Z","pmid":1,"year":"2020","publisher":"Elsevier","department":[{"_id":"LeSa"}],"publication_status":"published","file_date_updated":"2020-07-14T12:48:03Z","article_number":"148213","doi":"10.1016/j.bbabio.2020.148213","language":[{"iso":"eng"}],"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"oa":1,"external_id":{"pmid":["32335026"],"isi":["000540842000012"]},"isi":1,"quality_controlled":"1","publication_identifier":{"eissn":["18792650"],"issn":["00052728"]},"month":"08"},{"oa_version":"None","_id":"8040","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","intvolume":" 142","title":"Charge transfer and chemo-mechanical coupling in respiratory complex I","status":"public","issue":"20","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."}],"type":"journal_article","date_published":"2020-05-20T00:00:00Z","citation":{"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.","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.","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.","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.","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","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"},"publication":"Journal of the American Chemical Society","page":"9220-9230","article_type":"original","article_processing_charge":"No","day":"20","scopus_import":"1","related_material":{"record":[{"relation":"research_data","status":"public","id":"9326"},{"relation":"research_data","status":"public","id":"9713"},{"id":"9878","relation":"research_data","status":"public"}]},"author":[{"full_name":"Gupta, Chitrak","first_name":"Chitrak","last_name":"Gupta"},{"full_name":"Khaniya, Umesh","first_name":"Umesh","last_name":"Khaniya"},{"first_name":"Chun Kit","last_name":"Chan","full_name":"Chan, Chun Kit"},{"first_name":"Francois","last_name":"Dehez","full_name":"Dehez, Francois"},{"first_name":"Mrinal","last_name":"Shekhar","full_name":"Shekhar, Mrinal"},{"last_name":"Gunner","first_name":"M. R.","full_name":"Gunner, M. R."},{"orcid":"0000-0002-0977-7989","id":"338D39FE-F248-11E8-B48F-1D18A9856A87","last_name":"Sazanov","first_name":"Leonid A","full_name":"Sazanov, Leonid A"},{"full_name":"Chipot, Christophe","first_name":"Christophe","last_name":"Chipot"},{"full_name":"Singharoy, Abhishek","first_name":"Abhishek","last_name":"Singharoy"}],"volume":142,"date_updated":"2023-08-22T07:49:38Z","date_created":"2020-06-29T07:59:35Z","pmid":1,"year":"2020","publisher":"American Chemical Society","department":[{"_id":"LeSa"}],"publication_status":"published","doi":"10.1021/jacs.9b13450","language":[{"iso":"eng"}],"external_id":{"pmid":["32347721"],"isi":["000537415600020"]},"quality_controlled":"1","isi":1,"publication_identifier":{"eissn":["15205126"],"issn":["00027863"]},"month":"05"},{"date_updated":"2023-08-22T07:49:37Z","date_created":"2021-04-14T12:05:20Z","oa_version":"Published Version","author":[{"first_name":"Chitrak","last_name":"Gupta","full_name":"Gupta, Chitrak"},{"first_name":"Umesh","last_name":"Khaniya","full_name":"Khaniya, Umesh"},{"last_name":"Chan","first_name":"Chun","full_name":"Chan, Chun"},{"full_name":"Dehez, Francois","first_name":"Francois","last_name":"Dehez"},{"full_name":"Shekhar, Mrinal","last_name":"Shekhar","first_name":"Mrinal"},{"full_name":"Gunner, M. R.","first_name":"M. R.","last_name":"Gunner"},{"full_name":"Sazanov, Leonid A","id":"338D39FE-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-0977-7989","first_name":"Leonid A","last_name":"Sazanov"},{"last_name":"Chipot","first_name":"Christophe","full_name":"Chipot, Christophe"},{"full_name":"Singharoy, Abhishek","first_name":"Abhishek","last_name":"Singharoy"}],"related_material":{"record":[{"relation":"used_in_publication","status":"public","id":"8040"}]},"title":"Charge transfer and chemo-mechanical coupling in respiratory complex I","status":"public","department":[{"_id":"LeSa"}],"publisher":"American Chemical Society","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","_id":"9326","year":"2020","license":"https://creativecommons.org/licenses/by-nc/4.0/","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 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."}],"type":"research_data_reference","doi":"10.1021/jacs.9b13450.s002","date_published":"2020-05-20T00:00:00Z","tmp":{"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","image":"/images/cc_by_nc.png","short":"CC BY-NC (4.0)"},"oa":1,"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","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.","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.","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).","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."},"main_file_link":[{"open_access":"1"}],"month":"05","day":"20","article_processing_charge":"No"}]