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Updated: Jun 26, 2026
05:52
Reconstitution of Msp1 Extraction Activity with Fully Purified Components
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
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.
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.
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