An atlas of protein homo-oligomerization across domains of life

Hugo Schweke; Martin Pacesa; Tal Levin; Casper A. Goverde; Prasun Kumar; Yoan Duhoo; Lars J. Dornfeld; Benjamin Dubreuil; Sandrine Georgeon; Sergey Ovchinnikov; Derek N. Woolfson; Bruno E. Correia; Sucharita Dey; Emmanuel D. Levy

doi:10.1016/j.cell.2024.01.022

An atlas of protein homo-oligomerization across domains of life

Hugo Schweke, Martin Pacesa, Tal Levin, Casper A. Goverde, Prasun Kumar, Yoan Duhoo, Lars J. Dornfeld, Benjamin Dubreuil, Sandrine Georgeon, Sergey Ovchinnikov, Derek N. Woolfson^*, Bruno E. Correia^*, Sucharita Dey^*, Emmanuel D. Levy^*

^*Corresponding author for this work

Department of Chemical and Structural Biology

Research output: Contribution to journal › Article › peer-review

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Abstract

Protein structures are essential to understanding cellular processes in molecular detail. While advances in artificial intelligence revealed the tertiary structure of proteins at scale, their quaternary structure remains mostly unknown. We devise a scalable strategy based on AlphaFold2 to predict homo-oligomeric assemblies across four proteomes spanning the tree of life. Our results suggest that approximately 45% of an archaeal proteome and a bacterial proteome and 20% of two eukaryotic proteomes form homomers. Our predictions accurately capture protein homo-oligomerization, recapitulate megadalton complexes, and unveil hundreds of homo-oligomer types, including three confirmed experimentally by structure determination. Integrating these datasets with omics information suggests that a majority of known protein complexes are symmetric. Finally, these datasets provide a structural context for interpreting disease mutations and reveal coiled-coil regions as major enablers of quaternary structure evolution in human. Our strategy is applicable to any organism and provides a comprehensive view of homo-oligomerization in proteomes.

Original language	English
Pages (from-to)	999-1010.e15
Number of pages	12
Journal	Cell
Volume	187
Issue number	4
Early online date	6 Feb 2024
DOIs	https://doi.org/10.1016/j.cell.2024.01.022
Publication status	Published - 15 Feb 2024

Bibliographical note

We thank Sergei Grudinin for help with AnAnaS as well as Harry Greenblatt and the HPC Weizmann team for help with the computer infrastructure. We thank the Protein Production and Structure Characterization Core Facility, EPFL, Switzerland for help with protein purification. We thank the Dubochet Center for Imaging (DCI), EPFL-UNIL-UNIGE, Switzerland, for cryo-EM data collection. We thank Sreenath Nair, Mihaly Varadi, and Sameer Velankar for help with integration of our data into 3DBeacon. We thank Anil Pasupulati, John Jumper, Moran Shalev Benami, Patrick Barth, Pierre Gönczy, Robert Jefferson, Sven Dahms, and the members of E.D.L. and B.E.C. laboratories for helpful discussions. We thank the anonymous reviewers for helpful and constructive feedback. M.P. was supported by the Peter und Traudl Engelhorn Stiftung. P.K. was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) grant to D.N.W. (BB/R00661X/1). D.N.W. was also supported by the BrisSynBio, a BBSRC/Engineering and Physical Sciences Research Council-funded Synthetic Biology Research Centre (BB/L01386X/1). B.E.C. was supported by the Swiss National Science Foundation, the NCCR in Chemical Biology, the NCCR in Molecular Systems Engineering, and the Swiss Cancer League (grant number KFS-5032-02-2020). E.D.L. acknowledges support by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 819318), by a research grant from HFSP (ref.-no: RGP0016/2022), by the Israel Science Foundation (grant no. 1452/18), and by the Abisch-Frenkel Foundation. S.O. and C.A.G. were supported by Amgen for this project. S.D. acknowledges the Ramalingaswami research grant from the Department of Biotechnology, Govt. India (RLS: BT/RLF/Re-entry/10/2020, sanction order serial number 145).Publisher Copyright:
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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Cite this

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title = "An atlas of protein homo-oligomerization across domains of life",

abstract = "Protein structures are essential to understanding cellular processes in molecular detail. While advances in artificial intelligence revealed the tertiary structure of proteins at scale, their quaternary structure remains mostly unknown. We devise a scalable strategy based on AlphaFold2 to predict homo-oligomeric assemblies across four proteomes spanning the tree of life. Our results suggest that approximately 45% of an archaeal proteome and a bacterial proteome and 20% of two eukaryotic proteomes form homomers. Our predictions accurately capture protein homo-oligomerization, recapitulate megadalton complexes, and unveil hundreds of homo-oligomer types, including three confirmed experimentally by structure determination. Integrating these datasets with omics information suggests that a majority of known protein complexes are symmetric. Finally, these datasets provide a structural context for interpreting disease mutations and reveal coiled-coil regions as major enablers of quaternary structure evolution in human. Our strategy is applicable to any organism and provides a comprehensive view of homo-oligomerization in proteomes.",

author = "Hugo Schweke and Martin Pacesa and Tal Levin and Goverde, {Casper A.} and Prasun Kumar and Yoan Duhoo and Dornfeld, {Lars J.} and Benjamin Dubreuil and Sandrine Georgeon and Sergey Ovchinnikov and Woolfson, {Derek N.} and Correia, {Bruno E.} and Sucharita Dey and Levy, {Emmanuel D.}",

note = "We thank Sergei Grudinin for help with AnAnaS as well as Harry Greenblatt and the HPC Weizmann team for help with the computer infrastructure. We thank the Protein Production and Structure Characterization Core Facility, EPFL, Switzerland for help with protein purification. We thank the Dubochet Center for Imaging (DCI), EPFL-UNIL-UNIGE, Switzerland, for cryo-EM data collection. We thank Sreenath Nair, Mihaly Varadi, and Sameer Velankar for help with integration of our data into 3DBeacon. We thank Anil Pasupulati, John Jumper, Moran Shalev Benami, Patrick Barth, Pierre G{\"o}nczy, Robert Jefferson, Sven Dahms, and the members of E.D.L. and B.E.C. laboratories for helpful discussions. We thank the anonymous reviewers for helpful and constructive feedback. M.P. was supported by the Peter und Traudl Engelhorn Stiftung. P.K. was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) grant to D.N.W. (BB/R00661X/1). D.N.W. was also supported by the BrisSynBio, a BBSRC/Engineering and Physical Sciences Research Council-funded Synthetic Biology Research Centre (BB/L01386X/1). B.E.C. was supported by the Swiss National Science Foundation, the NCCR in Chemical Biology, the NCCR in Molecular Systems Engineering, and the Swiss Cancer League (grant number KFS-5032-02-2020). E.D.L. acknowledges support by the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant agreement no. 819318), by a research grant from HFSP (ref.-no: RGP0016/2022), by the Israel Science Foundation (grant no. 1452/18), and by the Abisch-Frenkel Foundation. S.O. and C.A.G. were supported by Amgen for this project. S.D. acknowledges the Ramalingaswami research grant from the Department of Biotechnology, Govt. India (RLS: BT/RLF/Re-entry/10/2020, sanction order serial number 145).Publisher Copyright: Copyright {\textcopyright} 2024 The Author(s). Published by Elsevier Inc. All rights reserved.",

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AU - Schweke, Hugo

AU - Pacesa, Martin

AU - Levin, Tal

AU - Goverde, Casper A.

AU - Kumar, Prasun

AU - Duhoo, Yoan

AU - Dornfeld, Lars J.

AU - Dubreuil, Benjamin

AU - Georgeon, Sandrine

AU - Ovchinnikov, Sergey

AU - Woolfson, Derek N.

AU - Correia, Bruno E.

AU - Dey, Sucharita

AU - Levy, Emmanuel D.

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PY - 2024/2/15

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N2 - Protein structures are essential to understanding cellular processes in molecular detail. While advances in artificial intelligence revealed the tertiary structure of proteins at scale, their quaternary structure remains mostly unknown. We devise a scalable strategy based on AlphaFold2 to predict homo-oligomeric assemblies across four proteomes spanning the tree of life. Our results suggest that approximately 45% of an archaeal proteome and a bacterial proteome and 20% of two eukaryotic proteomes form homomers. Our predictions accurately capture protein homo-oligomerization, recapitulate megadalton complexes, and unveil hundreds of homo-oligomer types, including three confirmed experimentally by structure determination. Integrating these datasets with omics information suggests that a majority of known protein complexes are symmetric. Finally, these datasets provide a structural context for interpreting disease mutations and reveal coiled-coil regions as major enablers of quaternary structure evolution in human. Our strategy is applicable to any organism and provides a comprehensive view of homo-oligomerization in proteomes.

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An atlas of protein homo-oligomerization across domains of life

Abstract

Bibliographical note

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