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Proteomics reveals signal peptide features determining the client specificity in human TRAP-dependent ER protein import.


ABSTRACT: 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 Sec61-auxiliary 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 substrate-specific opening of the Sec61 channel through interactions with the ER-lumenal hinge of Sec61?.

SUBMITTER: Nguyen D 

PROVIDER: S-EPMC6138672 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Proteomics reveals signal peptide features determining the client specificity in human TRAP-dependent ER protein import.

Nguyen Duy D   Stutz Regine R   Schorr Stefan S   Lang Sven S   Pfeffer Stefan S   Freeze Hudson H HH   Förster Friedrich F   Helms Volkhard V   Dudek Johanna J   Zimmermann Richard R  

Nature communications 20180914 1


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 Sec61-auxiliary 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 an  ...[more]

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