Membrane protein folding and quality control

Abstract

Membrane proteins account for a quarter of cellular proteins, and most are synthesised at the endoplasmic reticulum (ER). Insertion and folding of polypeptides in the membrane environment is prone to error, necessitating diverse quality control systems. Recent discoveries have demonstrated how forces act on the nascent chain during insertion, and revealed new translocon components and accessories that facilitate the correct biogenesis of substrates. Our understanding of one of the best studied quality control systems-ER-associated degradation-has been advanced through new structural and functional studies of the core Hrd1 complex, and through the discovery of a new branch of this degradative pathway. New data also reveal how cells resolve clogged translocons, which would otherwise be unable to function. Finally, new work elucidates how mitochondrial tail-anchored proteins that have been mistargeted to the ER are identified and destroyed. Overall, we describe an emerging picture of an increasingly complex quality control network.

Figure 1

Cellular machineries that drive quality control at the ER. Recent work has revealed new pathways in degradative quality control pathways, and in the pro-biogenesis machinery required for substrate insertion and folding. Degradative processes include the ATP13A1 dislocase that removes mislocalised mitochondrial substrates from the ER; the RNF185/MBRL complex that drives ERAD of integral membrane proteins; the ERAD component Hrd1, for which a new structure reveals a membrane thinning channel produced by two V-shaped cavities in Hrd1/Der1, and the capacity for Hrd1 to resolve clogging of the Sec61 translocon. New pro-biogenesis events include force generating events that contribute to polytopic membrane protein insertion; cis-acting elements that contribute to lumenal domain folding; the TMEM147/Nicalin/NOMO translocon associated complex and the PAT10 complex, both of which promote polytopic membrane protein biogenesis.