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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| Hauptverfasser: | , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
9 September 2020
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| In: |
Molecular cell
Year: 2020, Jahrgang: 80, Heft: 1, Pages: 72-86.e7 |
| ISSN: | 1097-4164 |
| DOI: | 10.1016/j.molcel.2020.08.012 |
| Online-Zugang: | 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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| Verfasserangaben: | 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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| 245 | 1 | 0 | |a Structural basis of tail-anchored membrane protein biogenesis by the GET insertase complex |c 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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| 520 | |a 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. | ||
| 650 | 4 | |a cryo-EM | |
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| 650 | 4 | |a GET/TRC pathway | |
| 650 | 4 | |a lipid binding | |
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| 650 | 4 | |a protein transport | |
| 650 | 4 | |a tail anchor | |
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