3), where the oligosaccharyl transferase complex (OST) ordinarily resides 14. Using cryogenic electron microscopy, these factors were visualized behind Sec61 (ref. This ‘multipass translocon’ also contains CCDC47 and a three-protein complex comprising TMEM147, nicalin and NOMO 13 (hereafter termed the BOS complex). We recently discovered that affinity purification of TMCO1 strongly enriches for ribosome–Sec61 complexes that are translating multipass membrane proteins 3. The ER also contains members of the Oxa1 superfamily of TMD insertases 9, including the guided entry of tail anchored protein (GET) complex 10, the ER membrane protein complex (EMC) 11 and TMCO1 (ref. This essential factor binds ribosomes, houses a membrane-spanning channel for polypeptide translocation, and a contains a lateral gate that opens towards the lipid bilayer for transmembrane domain (TMD) insertion 5– 8. The ER translocon is built around the Sec61 complex 4. More broadly, they define the ER translocon as a dynamic assembly whose subunit composition adjusts co-translationally to accommodate the biosynthetic needs of its diverse range of substrates. These results establish the mechanism by which nascent multipass proteins selectively recruit the multipass translocon to facilitate their biogenesis. Reconstitution studies demonstrate a role for multipass translocon components in protein topogenesis, and cells lacking these components show reduced multipass protein stability. Analysis of insertion intermediates reveals how features of the nascent chain trigger multipass translocon assembly. This ‘multipass translocon’ is distinguished by three components that selectively bind the ribosome–Sec61 complex during multipass protein synthesis: the GET- and EMC-like (GEL), protein associated with translocon (PAT) and back of Sec61 (BOS) complexes. Here we define the composition, function and assembly of a translocon specialized for multipass membrane protein biogenesis 3. How the translocon coordinates the actions of these factors to accommodate its different substrates is not well understood. Most membrane proteins are synthesized on endoplasmic reticulum (ER)-bound ribosomes docked at the translocon, a heterogeneous ensemble of transmembrane factors operating on the nascent chain 1, 2.
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