6SO5

Homo sapiens WRB/CAML heterotetramer in complex with a TRC40 dimer

Summary for 6SO5

• Entry DOI: 10.2210/pdb6so5/pdb
• EMDB information: 10266
• Descriptor: ATPase ASNA1, Tail-anchored protein insertion receptor WRB, Calcium signal-modulating cyclophilin ligand, ... (4 entities in total)
• Functional Keywords: er, insertase, complex, tail-anchor, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 150560.23

Authors

McDowell, M.A.,Heimes, M.,Wild, K.,Flemming, D.,Sinning, I. (deposition date: 2019-08-29, release date: 2020-09-09, Last modification date: 2024-11-20)

Primary citation

McDowell, M.A.,Heimes, M.,Fiorentino, F.,Mehmood, S.,Farkas, A.,Coy-Vergara, J.,Wu, D.,Bolla, J.R.,Schmid, V.,Heinze, R.,Wild, K.,Flemming, D.,Pfeffer, S.,Schwappach, B.,Robinson, C.V.,Sinning, I.
Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex.
Mol.Cell, 80:72-, 2020

PubMed Abstract: 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.

PubMed: 32910895
DOI: 10.1016/j.molcel.2020.08.012

Experimental method

ELECTRON MICROSCOPY (4.2 Å)