![]() ![]() It is poorly understood how these accessory factors are recruited to the Sec61 translocon to promote protein translocation. Earlier studies have shown that translocon-associated factors TRAM, TRAP, Sec62/Sec63, and the luminal chaperone BiP assist in the translocation of selected substrates ( Fons et al., 2003 Lang et al., 2012 Nguyen et al., 2018 Schorr et al., 2020 Tyedmers et al., 2003 Voigt et al., 1996). However, many SSs inefficiently engage the Sec61 translocon in a non-looped orientation, thus requiring accessory factors to promote protein translocation into the ER ( Hegde and Kang, 2008). The looped engagement of the SS to the Sec61 translocon drives forward translocation of the nascent chain into the ER lumen upon further translation elongation. Strong SSs, such as the one from prolactin (Prl), efficiently engage the Sec61 translocon in a looped orientation in which the h-region of SS is intercalated into the lateral gate of the Sec61 translocon with its N-terminus facing the cytosol, and the following nascent chain is inserted into the aqueous pore of the Sec61 channel ( Jungnickel and Rapoport, 1995 Li et al., 2016 Voorhees and Hegde, 2016). However, the interaction between the Sec61 translocon and SSs significantly varies. In mammals, SRP can efficiently recognize a broad range of hydrophobic SSs in RNCs and target them to the ER ( Hegde and Kang, 2008 Jungnickel and Rapoport, 1995 Kim et al., 2002 Voorhees and Hegde, 2015). SSs are diverse and significantly differ in length, hydrophobicity, charge, and flanking sequences but contain a hydrophobic core (h-region) of at least seven non-hydrophilic amino acids ( von Heijne, 1985). Thus, the signal sequence–guided protein folding may explain why signal sequences are diverse and use multiple protein translocation pathways. Increasing hydrophobicity of signal sequences bypasses Sec63/BiP-dependent translocation, but translocated proteins are prone to misfold and aggregate in the ER under limited BiP availability. BiP binding not only releases translocationally paused nascent chains but also ensures protein folding in the ER. Sec63 is co-translationally recruited to the translocation site and mediates BiP binding to incoming polypeptides. Using a substrate-trapping proteomic approach, we identify that nascent proteins bearing marginally hydrophobic signal sequences accumulate on the cytosolic side of the Sec61 translocon. We find that marginally hydrophobic signal sequences and transmembrane domains cause transient retention at the Sec61 translocon and require the luminal BiP chaperone for efficient protein translocation. How protein translocation coordinates with chaperone availability in the ER to promote protein folding remains unclear. One-third of newly synthesized proteins in mammals are translocated into the endoplasmic reticulum (ER) through the Sec61 translocon. ![]()
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