A clearer picture of the ER translocon complex

The endoplasmic reticulum (ER) translocon complex is the main gate into the secretory pathway, facilitating the translocation of nascent peptides into the ER lumen or their integration into the lipid membrane. Protein biogenesis in the ER involves additional processes, many of them occurring co-translationally while the nascent protein resides at the translocon complex, including recruitment of ER-targeted ribosome–nascent-chain complexes, glycosylation, signal peptide cleavage, membrane protein topogenesis and folding. To perform such varied functions on a broad range of substrates, the ER translocon complex has different accessory components that associate with it either stably or transiently. Here, we review recent structural and functional insights into this dynamically constituted central hub in the ER and its components. Recent cryo-electron microscopy (EM) studies have dissected the molecular organization of the co-translational ER translocon complex, comprising the Sec61 protein-conducting channel, the translocon-associated protein complex and the oligosaccharyl transferase complex. Complemented by structural characterization of the post-translational import machinery, key molecular principles emerge that distinguish co- and post-translational protein import and biogenesis. Further cryo-EM structures promise to expand our mechanistic understanding of the various biochemical functions involving protein biogenesis and quality control in the ER.