期刊
MOLECULAR CELL
卷 80, 期 1, 页码 72-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2020.08.012
关键词
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资金
- Ministry of Science, Research and the Arts Baden-Wurttemberg
- Deutsche Forschungsgemeinschaft (DFG) [INST 35/1314-1 FUGG, INST 35/1134-1 FUGG]
- EMBO Long Term Fellowship [ALTF 1230-2013]
- DFG through the Leibniz Programme [SI 586/6-1, TRR83]
- Medical Research Council program grant [MR/N020413/1]
- ERC Advanced Grant ENABLE [695511]
- Wellcome Trust Investigator Award [104633/Z/14/Z]
- SABS CDT Scholarship - Engineering and Physical Sciences Research Council
- Medical Research Council [EP/L016044/1]
- DFG [SFB 1190, EXC 2067/1-390729940]
- MRC [MR/N020413/1] Funding Source: UKRI
Membrane protein biogenesis faces the challenge of chaperoning hydrophobic transmembrane helices for faithful membrane insertion. The guided entry of tail-anchored proteins (GET) pathway targets and inserts tail-anchored (TA) proteins into the endoplasmic reticulum (ER) membrane with an insertase (yeast Get1/Get2 or mammalian WRB/CAML) that captures the TA from a cytoplasmic chaperone (Get3 or TRC40, respectively). Here, we present cryo-electron microscopy reconstructions, native mass spectrometry, and structure-based mutagenesis of human WRB/CAML/TRC40 and yeast Get1/Get2/Get3 complexes. Get3 binding to the membrane insertase supports heterotetramer formation, and phosphatidylinositol binding at the heterotetramer interface stabilizes the insertase for efficient TA insertion in vivo. We identify a Get2/CAML cytoplasmic helix that forms a gating interaction with Get3/TRC40 important for TA insertion. Structural homology with YidC and the ER membrane protein complex (EMC) implicates an evolutionarily conserved insertion mechanism for divergent substrates utilizing a hydrophilic groove. Thus, we provide a detailed structural and mechanistic framework to understand TA membrane insertion.
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