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Structural basis of tail-anchored membrane protein biogenesis by the GET insertase complex

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 (y...

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Main Authors: McDowell, Melanie (Author) , Heimes, Michael (Author) , Fiorentino, Francesco (Author) , Mehmood, Shahid (Author) , Farkas, Ákos (Author) , Coy-Vergara, Javier (Author) , Wu, Di (Author) , Bolla, Jani Reddy (Author) , Schmid, Volker (Author) , Heinze, Roger J. (Author) , Wild, Klemens (Author) , Flemming, Dirk (Author) , Pfeffer, Stefan (Author) , Schwappach, Blanche (Author) , Robinson, Carol V. (Author) , Sinning, Irmgard (Author)
Format: Article (Journal)
Language:English
Published: 9 September 2020
In: Molecular cell
Year: 2020, Volume: 80, Issue: 1, Pages: 72-86.e7
ISSN:1097-4164
DOI:10.1016/j.molcel.2020.08.012
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.molcel.2020.08.012
Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S109727652030575X
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Author Notes:Melanie A. McDowell, Michael Heimes, Francesco Fiorentino, Shahid Mehmood, Ákos Farkas, Javier Coy-Vergara, Di Wu, Jani Reddy Bolla, Volker Schmid, Roger Heinze, Klemens Wild, Dirk Flemming, Stefan Pfeffer, Blanche Schwappach, Carol V. Robinson, and Irmgard Sinning
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Summary: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.
Item Description:Gesehen am 10.11.2020
Physical Description:Online Resource
ISSN:1097-4164
DOI:10.1016/j.molcel.2020.08.012

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