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

Matthew J. Shurtleff, Daniel N. Itzhak, Jeffrey A. Hussmann, Nicole T. Schirle Oakdale, Elizabeth A. Costa, Martin Jonikas, Jimena Weibezahn, Katerina D. Popova, Calvin H. Jan, Pavel Sinitcyn, Shruthi S. Vembar, Hilda Hernandez, Jürgen Cox, Alma L. Burlingame, Jeffrey L. Brodsky, Adam Frost, Georg H.H. Borner, Jonathan S. Weissman

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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.

Original languageEnglish (US)
Article numbere37018
JournaleLife
Volume7
DOIs
StatePublished - May 29 2018

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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