@article{5fef6745d5714dfea6d8efaf09f226aa,
title = "The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins",
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.",
author = "Shurtleff, {Matthew J.} and Itzhak, {Daniel N.} and Hussmann, {Jeffrey A.} and {Schirle Oakdale}, {Nicole T.} and Costa, {Elizabeth A.} and Martin Jonikas and Jimena Weibezahn and Popova, {Katerina D.} and Jan, {Calvin H.} and Pavel Sinitcyn and Vembar, {Shruthi S.} and Hilda Hernandez and J{\"u}rgen Cox and Burlingame, {Alma L.} and Brodsky, {Jeffrey L.} and Adam Frost and Borner, {Georg H.H.} and Weissman, {Jonathan S.}",
note = "Funding Information: We gratefully acknowledge funding and support from the following institutions and foundations: MJS is a Howard Hughes Medical Institute Fellow of the Helen Hay Whitney Foundation, JSW is an Investigator of the Howard Hughes Medical Institute and, AF is a Searle Scholar and Chan-Zucker-berg Biohub investigator. This work was further supported by the Jane Coffin Childs Memorial Foundation (NTSO), the Howard Hughes Medical Institute (ALB), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (ALB,) a Faculty Scholar grant from the Howard Hughes Medical Institute (AF), the Sandler Family Foundation through the UCSF Program for Breakthrough Biomedical Research (AF), the American Asthma Foundation (AF), the Max Planck Society for the Advancement of Science (GHHB, DNI), the German Research Foundation (Gottfried Wilhelm Leibniz Prize MA 1764/2-1 (GHHB), the louis-Jeantet Foundation (DNI), the European Research Council Synergy Grant {\textquoteleft}ToPAG – Toxic Protein Aggregation in neurodegeneration{\textquoteright} (ERC2012-SyG_318987-ToPAG (DNI), and the National Institutes of Health (NIH) (GM075061 - JLB, AG041826 - JSW, 1DP2GM110772-01 -AF, 8P41GM103481 and 1S10OD16229 –ALB). We thank Kendra Swain, Christopher Williams and Maya Schuldiner for their experimental and intellectual contributions. We also thank Lakshmi Miller-Vedam, Marco Jost and Marco Hein for critical reading of the manuscript, Jeffrey Quinn for producing model figures, and the rest of the Weissman lab for helpful discussions and various contributions. Funding Information: We gratefully acknowledge funding and support from the following institutions and foundations: MJS is a Howard Hughes Medical Institute Fellow of the Helen Hay Whitney Foundation, JSW is an Investigator of the Howard Hughes Medical Institute and, AF is a Searle Scholar and Chan-Zucker-berg Biohub investigator. This work was further supported by the Jane Coffin Childs Memorial Foundation (NTSO), the Howard Hughes Medical Institute (ALB), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (ALB,) a Faculty Scholar grant from the Howard Hughes Medical Institute (AF), the Sandler Family Foundation through the UCSF Program for Breakthrough Biomedical Research (AF), the American Asthma Foundation (AF), the Max Planck Society for the Advancement of Science (GHHB, DNI), the German Research Foundation (Gottfried Wilhelm Leibniz Prize MA 1764/2-1 (GHHB), the louis-Jeantet Foundation (DNI), the European Research Council Synergy Grant {\textquoteleft}ToPAG – Toxic Protein Aggregation in neurodegeneration{\textquoteright} (ERC2012-SyG_318987-ToPAG (DNI), and the National Institutes of Health (NIH) (GM075061-JLB, AG041826-JSW, 1DP2GM110772-01-AF, 8P41GM103481 and 1S10OD16229 –ALB). We thank Kendra Swain, Christopher Williams and Maya Schuldiner for their experimental and intellectual contributions. We also thank Lakshmi Miller-Vedam, Marco Jost and Marco Hein for critical reading of the manuscript, Jeffrey Quinn for producing model figures, and the rest of the Weissman lab for helpful discussions and various contributions. Howard Hughes Medical Institute Investigator Program Jonathan S Weissman National Institutes of Health GM075061 Jeffrey Brodsky Helen Hay Whitney Foundation Postdoctoral Fellowship Matthew J Shurtleff Jane Coffin Childs Memorial Fund for Medical Research Postdoctoral Fellowship Nicole T Schirle Oakdale Sandler Foundation Program for Breakthrough Biomedical Research Adam Frost American Asthma Foundation Adam Frost Louis-Jeantet Foundation Daniel N Itzhak Dr. Miriam and Sheldon G. Adelson Medical Research Foundation Alma L Burlingame Max-Planck-Gesellschaft Daniel N Itzhak Deutsche Forschungsge- meinschaft Gottfried Wilhelm Leibniz Prize MA 1764/2-1 Georg HH Borner European Research Council ERC2012-SyG_318987- ToPAG Daniel N Itzhak Howard Hughes Medical Insti- tute Faculty Scholar Grant Adam Frost National Institutes of Health AG041826 Jonathan S Weissman National Institutes of Health 1DP2GM110772-01 Adam Frost National Institutes of Health 8P41GM103481 Alma L Burlingame National Institutes of Health 1S10OD16229 Alma L Burlingame.",
year = "2018",
month = may,
day = "29",
doi = "10.7554/eLife.37018",
language = "English (US)",
volume = "7",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}