Cotranslational membrane protein biogenesis at the endoplasmic reticulum.

In eukaryotic cells, most polypeptides destined to become membrane proteins are initially integrated into the membrane of the endoplasmic reticulum (ER) before being sorted to the location at which they function. Integration occurs at sites in the ER membrane termed translocons that are comprised of a specific set of membrane proteins (1, 2). In most cases, proteins are integrated into the bilayer cotranslationally, i.e. at the same time that they are being synthesized by ribosomes. During this process, the biosynthetic machinery mediates the integration of transmembrane sequences (TMSs) into the nonpolar core of the bilayer and delivers aqueous cytoplasmic and luminal domains to the appropriate compartments. Simultaneously, a nascent protein may undergo covalent modification (e.g. signal sequence cleavage, disulfide bond formation, and N-glycosylation), folding, and interactions with other proteins (e.g. chaperones) that ultimately lead to the assembly of the polypeptide into a functional monomeric or multimeric complex (1–3). Membrane protein biogenesis is therefore exceedingly complex, especially because the mechanisms involved are further constrained by the need to maintain the permeability barrier of the membrane. Here we highlight the most recent advances in our understanding of cotranslational integration at the ER membrane, focusing on four overlapping areas: translocon structural and functional states; nascent chain topogenesis; insertion of TMSs into the bilayer; and nascent chain regulation of integration. Other processes coupled with integration (e.g. covalent modification, folding, assembly, and quality control) and protein integration at other membranes are beyond the scope of this minireview.