Journal Article

Substrate-driven assembly of a translocon for multipass membrane proteins

Yamsek, Melvin, Hegde, Ramanujan S., Sundaram, Arunkumar, Keenan, Robert J., Hooda, Yogesh, Zhong, Frank

2022

Overview

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 . How the translocon coordinates the actions of these factors to accommodate its different substrates is not well understood. Here we define the composition, function and assembly of a translocon specialized for multipass membrane protein biogenesis 3 . 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. Analysis of insertion intermediates reveals how features of the nascent chain trigger multipass translocon assembly. Reconstitution studies demonstrate a role for multipass translocon components in protein topogenesis, and cells lacking these components show reduced multipass protein stability. These results establish the mechanism by which nascent multipass proteins selectively recruit the multipass translocon to facilitate their biogenesis. 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. Biochemical reconstitution and functional analysis reveal how newly synthesized multipass membrane proteins dynamically remodel the translocon to facilitate their successful biogenesis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/31 / 631/45/470/1981 / 631/80/2023/2022 / 631/80/470/1463 / 82/1 / 82/29 / Assembly / Biosynthesis / Composition / Endoplasmic reticulum / Endoplasmic Reticulum - metabolism / Humanities and Social Sciences / Intermediates / Membrane proteins / Membrane Proteins - metabolism / Membranes / multidisciplinary / Protein biosynthesis / Protein Stability / Protein synthesis / Protein Transport / Proteins / Recruitment / Ribosomes / Ribosomes - metabolism / Science / Science (multidisciplinary) / SEC Translocation Channels - metabolism / Substrate Specificity / Substrates / Subunit structure