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Related Concept Videos

Insertion of Multi-pass Transmembrane Proteins in the RER01:29

Insertion of Multi-pass Transmembrane Proteins in the RER

The rough ER membrane synthesizes, assembles, and embeds transmembrane proteins in diverse topologies. These proteins function as transporters or channels and can remain in the ER membrane or are sent to the Golgi complex, lysosome, and cell membrane.
The multipass transmembrane proteins are the type IV integral membrane proteins with multiple topogenic sequences determining their spatial arrangement in the ER membrane. Nearly all multipass proteins lack a cleavable signal sequence and use...
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Integral membrane proteins are proteins adhered to the lipid bilayer of a cell organelle or membrane. They can be of two types: transmembrane integral proteins that span the lipid bilayer and monotopic proteins that are attached to either side of the membrane but do not pass through it.
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Protein Transport into the Inner Mitochondrial Membrane

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Multi-pass Transmembrane Proteins and β-barrels

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α-Helix containing multi-pass transmembrane proteins
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Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

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Updated: Jun 26, 2026

Reconstitution of Msp1 Extraction Activity with Fully Purified Components
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Published on: August 10, 2021

Pairwise transmembrane domain insertion during multipass protein biogenesis.

Luka Smalinskaitė1, Haoxi Wu1, Ramanujan S Hegde1

  • 1Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.

Molecular Cell
|June 24, 2026
PubMed
Summary

Most multipass membrane proteins use Oxa1-family insertases, not the Sec61 channel, for their transmembrane domain (TMD) pairs. This challenges long-held models of membrane protein biogenesis.

Keywords:
endoplasmic reticulummembrane proteinprotein translocationproteostasis

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Last Updated: Jun 26, 2026

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Published on: August 10, 2021

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Transmembrane Domain Oligomerization Propensity determined by ToxR Assay
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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Multipass membrane proteins are crucial cellular components.
  • They are typically composed of transmembrane domain (TMD) pairs.
  • Previously, Sec61 was thought to be the sole insertion pathway for TMD pairs.

Purpose of the Study:

  • To investigate the insertion pathways of transmembrane domain (TMD) pairs.
  • To challenge the established Sec61-centric model of membrane protein biogenesis.
  • To identify alternative insertion routes for TMD pairs.

Main Methods:

  • Analysis of TMD pair insertion routes.
  • Testing small-molecule blockade of the Sec61 lateral gate.
  • Investigating the role of EMC and GEL insertase complexes.

Main Results:

  • TMD pairs utilize multiple insertion pathways, not exclusively Sec61.
  • Most TMD pairs are unaffected by Sec61 lateral gate blockade.
  • Shorter loop TMD pairs predominantly use EMC or GEL insertases from the Oxa1 superfamily.

Conclusions:

  • The Oxa1 superfamily, via EMC and GEL, is the primary insertion machinery for most TMD pairs.
  • The Sec61 pathway is only obligately used for TMD pairs with long translocated loops (>60 amino acids).
  • This study reframes the fundamental understanding of multipass membrane protein biogenesis.