2. Academic Validation
  3. The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins

The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins

  • Elife. 2018 May 29;7:e37018. doi: 10.7554/eLife.37018.
Matthew J Shurtleff # 1,  Daniel N Itzhak # 2,  Jeffrey A Hussmann 1,  Nicole T Schirle Oakdale 1 3,  Elizabeth A Costa 1,  Martin Jonikas 1,  Jimena Weibezahn 1,  Katerina D Popova 1,  Calvin H Jan 1,  Pavel Sinitcyn 2,  Shruthi S Vembar 4,  Hilda Hernandez 5,  Jürgen Cox 2,  Alma L Burlingame 5,  Jeffrey L Brodsky 4,  Adam Frost 3 6,  Georg Hh Borner 2,  Jonathan S Weissman 1 7
Affiliations

Affiliations

  • 1 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
  • 2 Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 3 Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
  • 4 Department of Biological Sciences, University of Pittsburgh, Pittsburgh, United States.
  • 5 Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.
  • 6 Chan Zuckerberg Biohub, San Francisco, United States.
  • 7 Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
  • # Contributed equally.
PMID: 29809151 DOI: 10.7554/eLife.37018
Abstract

The endoplasmic reticulum (ER) supports biosynthesis of proteins with diverse transmembrane domain (TMD) lengths and hydrophobicity. Features in transmembrane domains such as charged residues in ion channels are often functionally important, but could pose a challenge during cotranslational membrane insertion and folding. Our systematic proteomic approaches in both yeast and human cells revealed that the ER membrane protein complex (EMC) binds to and promotes the biogenesis of a range of multipass transmembrane proteins, with a particular enrichment for transporters. Proximity-specific ribosome profiling demonstrates that the EMC engages clients cotranslationally and immediately following clusters of TMDs enriched for charged residues. The EMC can remain associated after completion of translation, which both protects clients from premature degradation and allows recruitment of substrate-specific and general chaperones. Thus, the EMC broadly enables the biogenesis of multipass transmembrane proteins containing destabilizing features, thereby mitigating the trade-off between function and stability.

Keywords

EMC; cell biology; endoplasmic reticulum; human; ion channel; transmembrane; transporter.

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