Visualization of translation and protein biogenesis at the ER membrane

Max Gemmer, Marten L. Chaillet, Joyce Loenhout, Rodrigo Cuevas Arenas, Dimitrios Vismpas, Mariska Gröllers-Mulderij, Fujiet A. Koh, Pascal Albanese, Richard A. Scheltema, Stuart C. Howes, Abhay Kotecha, Juliette Fedry () and Friedrich Förster ()
Additional contact information
Max Gemmer: Utrecht University
Marten L. Chaillet: Utrecht University
Joyce Loenhout: Utrecht University
Rodrigo Cuevas Arenas: Utrecht University
Dimitrios Vismpas: Utrecht University
Mariska Gröllers-Mulderij: Utrecht University
Fujiet A. Koh: Thermo Fisher Scientific
Pascal Albanese: Utrecht Institute for Pharmaceutical Sciences, Utrecht University
Richard A. Scheltema: Utrecht Institute for Pharmaceutical Sciences, Utrecht University
Stuart C. Howes: Utrecht University
Abhay Kotecha: Thermo Fisher Scientific
Juliette Fedry: Utrecht University
Friedrich Förster: Utrecht University

Nature, 2023, vol. 614, issue 7946, 160-167

Abstract: Abstract The dynamic ribosome–translocon complex, which resides at the endoplasmic reticulum (ER) membrane, produces a major fraction of the human proteome1,2. It governs the synthesis, translocation, membrane insertion, N-glycosylation, folding and disulfide-bond formation of nascent proteins. Although individual components of this machinery have been studied at high resolution in isolation3–7, insights into their interplay in the native membrane remain limited. Here we use cryo-electron tomography, extensive classification and molecular modelling to capture snapshots of mRNA translation and protein maturation at the ER membrane at molecular resolution. We identify a highly abundant classical pre-translocation intermediate with eukaryotic elongation factor 1a (eEF1a) in an extended conformation, suggesting that eEF1a may remain associated with the ribosome after GTP hydrolysis during proofreading. At the ER membrane, distinct polysomes bind to different ER translocons specialized in the synthesis of proteins with signal peptides or multipass transmembrane proteins with the translocon-associated protein complex (TRAP) present in both. The near-complete atomic model of the most abundant ER translocon variant comprising the protein-conducting channel SEC61, TRAP and the oligosaccharyltransferase complex A (OSTA) reveals specific interactions of TRAP with other translocon components. We observe stoichiometric and sub-stoichiometric cofactors associated with OSTA, which are likely to include protein isomerases. In sum, we visualize ER-bound polysomes with their coordinated downstream machinery.

Date: 2023
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DOI: 10.1038/s41586-022-05638-5

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