3.A.5.9.1
Sec-SRP translocase complex. The BAP29 and BAP31 (also called BCAP31) proteins interact directly with the Sec translocon (Wilson & Barlowe et al., 2010).  SRP68 and SRP72 form a complex with SRP RNA and SRP19.  The SRP68 binding site for the RNA is a tetratricopeptide-like module that bends the RNA and inserts an arginine-rich helix into the major groove to open the conserved 5f RNA loop and remodel the RNA for protein translocation (Grotwinkel et al. 2014).  Sec31 (Sec 31L1; HSPC334; HSPC275) is an outer cage component of the coat protein complex II (COPII) machinery which is recruited to specialized regions of the ER, called ER exit sites (ERES), where it plays a central role in the early secretory pathway. Sec31 also interacts with ALG-2 (Programed cell death protein 6 (PDCD6)) and annexin A11 (AnxA11) (Shibata et al. 2015). The Sec61 translocon mediates poorly efficient membrane insertion of Arg-containing TMSs, but a combination of arginine snorkeling, bilayer deformation, and peptide tilting is sufficient to lower the penalty of Arg insertion to an extent that a hydrophobic TMS with a central Arg residue readily inserts into a membrane (Ulmschneider et al. 2017). Mycolactone is a bacterium-derived macrolide that blocks the biogenesis of a large array of secretory and integral transmembrane proteins through potent inhibition of the Sec61 translocon (Morel et al. 2018). The Sec61α subunit possesses an opening between TMS2b and TMS7, the lateral gate, that is the exit for signal sequences and TMSs of translocating polypeptides to the lipid bilayer (Kida and Sakaguchi 2018). BCAP31 (BAP31; 246 aas and 3 N-terminal TMSs) is an ER chaparone that plays a role in the export of secreted proteins in the ER as well as the recognition of abnormally folded protein for targeting to the ER associated-degradation (ERAD) pathway (Wakana et al. 2008). It also serves as a cargo receptor for the export of transmembrane proteins (Annaert et al. 1997). Sec61 is the target of the cytotoxic plant-derived compound, ipomoeassin F (see TC family 8.C.10).Two accessory proteins of the Sec system are TRAP1 (of humans) and TRAM1 (of mice) (Shao 2023). The endoplasmic reticulum (ER) is a major site for protein synthesis, folding, and maturation in eukaryotic cells, responsible for production of secretory proteins and most integral membrane proteins. The universally conserved protein-conducting channel Sec61 complex mediates core steps in these processes by translocating hydrophilic polypeptide segments of client proteins across the ER membrane and integrating hydrophobic transmembrane segments into the membrane. The Sec61 complex associates with several other molecular machines and enzymes to enable substrate engagement with the channel and coordination of protein translocation with translation, protein folding, and/or post-translational modifications. Cryo-EM and functional studies have advanced our mechanistic understanding of Sec61-dependent protein biogenesis at the ER. Itskanov and Park 2022 reviewed current models for how Sec61 performs its functions in coordination with partner complexes. The SEC62 gene plays a role in dermato-oncology (Linxweiler and Müller 2022). The dynamic ribosome-translocon complex, which resides at the ER membrane, produces most of the human proteome. It governs the synthesis, translocation, membrane insertion, N-glycosylation, folding and disulfide-bond formation of nascent proteins. Gemmer et al. 2023  identified a pre-translocation intermediate with eukaryotic elongation factor 1a (eEF1a) in an extended conformation, suggesting that eEF1a may remain associated with the ribosome after GTP hydrolysis during proofreading. At the ER membrane, distinct polysomes bind to different ER translocons specialized in the synthesis of proteins with signal peptides or multipass TMSs with the translocon-associated protein complex (TRAP) present in both. The near-complete atomic model of the most abundant ER translocon variant, comprising the protein-conducting channel SEC61, TRAP and the oligosaccharyltransferase complex A (OSTA) revealed specific interactions of TRAP with other translocon components. Stoichiometric and sub-stoichiometric cofactors associated with OSTA were determined (Gemmer et al. 2023). Mycolactone B (not A) is an exotoxin produced by Mycobacterium ulcerans that causes the tropical skin disease, Buruli ulcer (Nguyen et al. 2023). This toxin inhibits the Sec61 translocon in the endoplasmic reticulum (ER), preventing the host cell from producing many secretory and transmembrane proteins. This results in cytotoxic and immunomodulatory effects. Isomer B's unique cytotoxicity is a consequence of both increased localization to the ER membrane and direct channel-locking association with the Sec61 translocon (Nguyen et al. 2023).