Mechanisms of membrane protein sorting

Abstract

Producing diverse membrane proteins requires multi‐step biosynthetic pathways with tightly integrated quality control mechanisms. Two biosynthetic challenges common to all membrane proteins are the need to localize to the appropriate cellular membrane and the need to insert each transmembrane segment (TM) in the correct topology. Using approaches that integrate cell biology, structural biology, and biochemistry, we examine mechanisms that ensure the fidelity of single‐spanning membrane protein localization and topogenesis at the endoplasmic reticulum (ER). We recently discovered that the ER‐resident P5A‐ATPase ATP13A1 (yeast Spf1) dislocates mislocalized mitochondrial tail‐anchored (TA) proteins. We leverage ATP13A1 as an experimental handle to investigate how mitochondrial membrane proteins misinsert into the ER. We also identify a role for ATP13A1 in the topogenesis of type II membrane proteins that should insert into the ER membrane with their N‐terminus in the cytosol. Without corrective protein quality control by ATP13A1, mislocalized TA proteins and misinserted type II proteins engage distinct ER‐associated degradation (ERAD) mechanisms. Our findings reveal­ how cells integrate counteracting ER activities with different specificities to fine tune membrane protein biogenesis.