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PreprintCited by 43Endoplasmic Reticulum Stress and DiseaseCellular transport and secretionRNA and protein synthesis mechanisms

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Molecular basis of the TRAP complex function in ER protein biogenesis

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Jaskolowski, Mateusz, Jomaa, Ahmad, Gamerdinger, Martin, Shrestha, Sandeep, Leibundgut, Marc, Deuerling, Elke, Ban, Nenad·2022·Nature Structural & Molecular Biology
DOI 10.1101/2022.10.04.510795PMC PMC10279528

Preprint — published as 10.1038/s41594-023-00990-0 · Paper page

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Abstract

The Translocon Associated Protein (TRAP) complex resides in the endoplasmic reticulum (ER) membrane and interacts with the Sec translocon and the translating ribosome to facilitate biogenesis of secretory and membrane proteins 1–4 . TRAP is essential for the secretion of many hormones, and its key role in the production of the hormone peptide insulin has been particularly well established 5,6 . The mechanism by which TRAP engages ribosomes and the translocon to facilitate translocation of protein clients in the secretory pathway is not clear. Here, we reveal the molecular architecture of the mammalian TRAP complex and how it engages the translating ribosome associated with Sec61 translocon on the ER membrane. The TRAP complex is anchored to the ribosome via a long tether and its position relative to the ribosome and the translocon is further stabilized by a finger-like loop. This spatial arrangement positions a cradle-like lumenal domain of TRAP below the protein conducting pore of the translocon for interactions with translocated nascent chains. The biological importance of these key interactions is evident by structure-guided TRAP mutations in C. elegans that lead to growth deficits associated with increased ER stress and defects in insulin secretion. Our findings elucidate the molecular basis of the TRAP complex in the biogenesis and translocation of proteins at the ER.

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Metadata

Authors
Jaskolowski, M., Jomaa, A., Gamerdinger, M., Shrestha, S., Leibundgut, M., Deuerling, E., & Ban, N.
Affiliations
  • ETH Zurich (CH)
  • University of Konstanz (DE)
Corresponding author
  • Jomaa, Ahmad
  • Deuerling, Elke
  • Ban, Nenad
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
openRxiv
Published
2022-10-04
Volume
30
Issue
6
Pages
770-777
ISSN
1545-9985 (ISSN-L)
DOI
10.1101/2022.10.04.510795
PMC
PMC10279528
OpenAlex
W4376134764
Cited by
43
References
1
Citations by year
2026: 9 · 2025: 13 · 2024: 12 · 2023: 8 · 2022: 1
FWCI
6.05
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Structural & Molecular Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KOPS (University of Konstanz) (submittedVersion, cc-by)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
  • ETH Zürich Research Collection
Funders
  • National Science Foundation
  • University of Virginia
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (212308, 141735, 205601, 163478, 310030)
  • Eidgenössische Technische Hochschule Zürich
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
TRAP complex, endoplasmic reticulum, Sec61 translocon, protein translocation, nascent polypeptide chains, insulin secretion, endoplasmic reticulum stress, Caenorhabditis elegans, protein secretion, membrane protein biogenesis
MeSH terms
SEC Translocation Channels, Animals, Calcium-Binding Proteins, Endoplasmic Reticulum, Mammals, Membrane Glycoproteins, Membrane Proteins, Receptors, Peptide, Receptors, Cytoplasmic and Nuclear, Protein Transport

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