Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-06188-z
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Funding
- DFG [ZI234/13-1, FO716/4-1, IRTG1830]
- Rocket Fund
- [R01DK99551]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK099551] Funding Source: NIH RePORTER
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In mammalian cells, one-third of all polypeptides are transported into or across the ER membrane via the Sec61 channel. While the Sec61 complex facilitates translocation of all polypeptides with amino-terminal signal peptides (SP) or transmembrane helices, the Sec61auxiliary translocon-associated protein (TRAP) complex supports translocation of only a subset of precursors. To characterize determinants of TRAP substrate specificity, we here systematically identify TRAP-dependent precursors by analyzing cellular protein abundance changes upon TRAP depletion using quantitative label-free proteomics. The results are validated in independent experiments by western blotting, quantitative RT-PCR, and complementation analysis. The SPs of TRAP clients exhibit above-average glycine-plus-proline content and below-average hydrophobicity as distinguishing features. Thus, TRAP may act as SP receptor on the ER membrane's cytosolic face, recognizing precursor polypeptides with SPs of high glycine-plus-proline content and/or low hydrophobicity, and triggering substratespecific opening of the Sec61 channel through interactions with the ER-lumenal hinge of Sec61 alpha.
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