Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Daniel N Itzhak
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
Jeffrey A Hussmann
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
Nicole T Schirle Oakdale
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Chan Zuckerberg Biohub, San Francisco, United States
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
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.
