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Cited by 39Cellular transport and secretionRNA and protein synthesis mechanismsEndoplasmic Reticulum Stress and Disease

Mechanism of signal-anchor triage during early steps of membrane protein insertion

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Wu, Haoxi, Hegde, Ramanujan S.·2023·Molecular Cell
DOI 10.1016/j.molcel.2023.01.018PMC PMC10155758
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Abstract

Most membrane proteins use their first transmembrane domain, known as a signal anchor (SA), for co-translational targeting to the endoplasmic reticulum (ER) via the signal recognition particle (SRP). The SA then inserts into the membrane using either the Sec61 translocation channel or the ER membrane protein complex (EMC) insertase. How EMC and Sec61 collaborate to ensure SA insertion in the correct topology is not understood. Using site-specific crosslinking, we detect a pre-insertion SA intermediate adjacent to EMC. This intermediate forms after SA release from SRP but before ribosome transfer to Sec61. The polypeptide's N-terminal tail samples a cytosolic vestibule bordered by EMC3, from where it can translocate across the membrane concomitant with SA insertion. The ribosome then docks on Sec61, which has an opportunity to insert those SAs skipped by EMC. These results suggest that EMC acts between SRP and Sec61 to triage SAs for insertion during membrane protein biogenesis.

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  • Proteins with uncleaved signal anchors can adopt orientations in which their N-terminus faces the cytoplasm or the ER lumen, a process regulated by EMC.

    “Proteins with uncleaved signal anchors can adopt orientations in which their N-terminus faces the cytoplasm or the ER lumen, a process regulated by EMC (Wu and Hegde 2023).”

    From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Wu and Hegde 2023

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Cited by

Sorted by citations

Authors
Wu, H., & Hegde, R. S.
Affiliations
MRC Laboratory of Molecular Biology (GB)
Corresponding author
Hegde, Ramanujan S.
ORCID
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2023-03
Volume
83
Issue
6
Pages
961-973.e7
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/j.molcel.2023.01.018
PMC
PMC10155758
OpenAlex
W4319727176
Cited by
39
References
2
Citations by year
2026: 12 · 2025: 9 · 2024: 13 · 2023: 5
FWCI
5.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Medical Research Council (MC_UP_A022_1007)
  • European Molecular Biology Organization
Topics
  • 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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
signal recognition particle, membrane protein biogenesis
MeSH terms
SEC Translocation Channels, Endoplasmic Reticulum, Membrane Proteins, Triage, Signal Recognition Particle, Protein Transport

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