![]() In higher eukaryotes, the translocon-associated protein (TRAP) complex binds constitutively to Sec61 and a ribosome ( Menetret et al., 2008 Pfeffer et al., 2014, 2017), possibly to support the recruitment of specific SPs ( Nguyen et al., 2018) and membrane topogenesis of some substrates ( Sommer et al., 2013). In the co-translational mode, the ribosome binds to the Sec61 complex, enabling the nascent unfolded peptide to enter the Sec61 channel. Sec61 is a trimeric membrane protein complex that is structurally and functionally highly conserved throughout all domains of life, known as SecYEG in bacteria and SecYEβ in archaea ( Rapoport et al., 2017). This post-translational pathway is widespread in yeast ( Panzner et al., 1995), whereas higher eukaryotes primarily use it for relatively short peptides ( Schlenstedt and Zimmermann, 1987 Shao and Hegde, 2011).ĮR translocon complexes are dynamic entities, organized around an invariant core, the Sec61 protein-conducting channel. In addition to co-translational protein import and translocation, distinct ER translocon complexes enable post-translational translocation and membrane integration. These membrane protein complexes translocate nascent soluble proteins into the ER, integrate nascent membrane proteins into the ER membrane, mediate protein folding and membrane protein topogenesis, and modify them chemically. In this SRP-dependent co-translational ER-targeting mode, ribosomes associate with the ER membrane via ER translocon complexes. SP-equivalent N-terminal transmembrane helices that are not cleaved off can also target proteins to the ER through the same mechanism. The ER-resident signal peptidase complex (SPC) eventually cleaves off the SP from the nascent peptide ( Evans et al., 1986). As the nascent SP emerges from the ribosome, it binds the soluble signal recognition particle (SRP), which mediates recruitment of the ribosome–nascent-chain (RNC) complex to the ER via the ER-membrane residing SRP receptor (SR) ( Egea et al., 2005). Many secretory pathway proteins are targeted to the ER via a hydrophobic N-terminal signal peptide (SP) ( Blobel and Dobberstein, 1975). Further cryo-EM structures promise to expand our mechanistic understanding of the various biochemical functions involving protein biogenesis and quality control in the ER. Complemented by structural characterization of the post-translational import machinery, key molecular principles emerge that distinguish co- and post-translational protein import and biogenesis. 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. Here, we review recent structural and functional insights into this dynamically constituted central hub in the ER and its components. 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. 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. 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. ![]()
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