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Journal Article

Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex

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McDowell, M. A., Heimes, M., Fiorentino, F., Mehmood, S., Farkas, Á., Coy-Vergara, J., et al. (2020). Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex. Molecular Cell, 80(1), 72-86. doi:10.1016/j.molcel.2020.08.012.

Cite as: https://hdl.handle.net/21.11116/0000-0009-598E-4
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.