Protein biosynthesis at the ER: finding the right accessories

Abstract

More than 30% of eukaryotic proteins contain domains that must translocate across or integrate into the endoplasmic reticulum (ER) membrane. With few exceptions, protein translocation and transmembrane domain integration at the ER require the conserved Sec61 translocon. Decades of studies have established a clear mechanistic model for how the Sec61 translocon functions. The biosynthesis of distinct subsets of proteins at the ER also involves accessory factors that interact with the Sec61 translocon and translocating nascent proteins. However, assigning specific functions to many translocon accessory factors has been a persistent challenge in the field. This Perspective discusses recent insights into mechanisms that promote protein biosynthesis at the ER through accessory factors that directly regulate the Sec61 translocon or chaperone nascent proteins within the ER membrane. These translocon accessory factor functions, and more still to be discovered, are essential for producing a diverse and high-fidelity proteome at the ER.

FIGURE 1:

Accessory factors modulate translocon conformations. (A) The isolated Sec translocon (Protein Data Bank [PDB] 1RH5). Lateral gate helices (purple) and the N-terminal (dark gray) and the C-terminal (light gray) halves of the Sec61α homologue are indicated along with the Sec61β and Sec61γ homologues. (B) The yeast posttranslational translocon (PDB 6N3Q). Sec63 (teal) acts as a brace holding the Sec61α lateral gate open; Sec62 and the yeast-specific Sec72 and Sec73 subunits are not shown. (C) The mammalian translocon associated with the PAT complex (PDB 7TM3) comprising Asterix (yellow) and CCDC47 (teal). The translocon-bound ribosome and the GEL and BOS complexes are not shown.