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PreprintCited by 42RNA and protein synthesis mechanismsRNA Research and SplicingProtein Structure and Dynamics

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Structural determinants of co-translational protein complex assembly

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Mallik, Saurav, Venezian, Johannes, Lobov, Arseniy, Heidenreich, Meta, Garcia-Seisdedos, Hector, Yeates, Todd O., Shiber, Ayala, Levy, Emmanuel D.·2024·Cell
DOI 10.1101/2024.01.20.576408

Preprint — published as 10.1016/j.cell.2024.11.013 · Paper page

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Abstract

The assembly of proteins into functional complexes is critical to life’s processes. While textbooks depict complex assembly as occurring between fully synthesized proteins, we know today that thousands of proteins in the human proteome assemble co-translationally during their synthesis. Why this process takes place, however, remains unknown. We show that co-translational assembly is governed by biophysical and structural characteristics of the protein complex, and involves mutually stabilized, intertwined subunits. Consequently, these subunits are also co-regulated across the central dogma, from transcription to protein degradation. Leveraging structural signatures with AlphaFold2-based predictions enables us to accurately predict co-translational assembly on a proteome-wide scale, which we validated by ribosome profiling, genetic perturbations, and smFISH experiments. Notably, the latter showed that co-translationally assembling subunits exhibit co-localized mRNAs. This work unveils a fundamental connection between protein structure and the translation process, highlighting the overarching impact of three-dimensional structure on gene expression, mRNA localization, and proteostasis. One Sentence Summary: Protein complexes with topologically intertwined subunits require co-translational assembly and synchronized proteostasis of subunits, with implications in protein stability, mRNA localization, and evolution. Graphical Abstract:

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Metadata

Authors
Mallik, S., Venezian, J., Lobov, A., Heidenreich, M., Garcia-Seisdedos, H., Yeates, T. O., Shiber, A., & Levy, E. D.
Affiliations
  • Weizmann Institute of Science (IL)
  • Technion – Israel Institute of Technology (IL)
  • Institut de Biologia Molecular de Barcelona (ES)
  • University of California, Los Angeles (US)
  • University of Geneva (CH)
ORCID
Venue
Cell
Publisher
openRxiv
Published
2024-01-23
Volume
188
Issue
3
Pages
764-777.e22
ISSN
0092-8674 (ISSN-L)
DOI
10.1101/2024.01.20.576408
OpenAlex
W4405632896
Cited by
42
References
1
Citations by year
2026: 26 · 2025: 13 · 2024: 3
FWCI
5.72
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Cell (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion)
Funders
  • European Commission
  • Weizmann Institute of Science
  • Ministry of Aliyah and Immigrant Absorption
  • Israel Science Foundation (1452/18, 2106/20)
  • Abisch-Frenkel-Stiftung (2031817)
  • European Research Council
  • Horizon 2020
  • H2020 European Research Council (819318)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
protein complex structure, protein stability, proteostasis, mRNA localization, ribosome profiling, single-molecule RNA FISH, AlphaFold2, protein-protein interaction, gene expression regulation
MeSH terms
Proteostasis, Animals, Humans, Ribosomes, RNA, Messenger, Protein Biosynthesis, In Situ Hybridization, Fluorescence, Proteome, Multiprotein Complexes, HEK293 Cells

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