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

Duy Nguyen, Regine Stutz, Stefan Schorr, Sven Lang, Stefan Pfeffer, Hudson H. Freeze, Friedrich Förster, Volkhard Helms (), Johanna Dudek () and Richard Zimmermann ()
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Duy Nguyen: Saarland University
Regine Stutz: Saarland University
Stefan Schorr: Saarland University
Sven Lang: Saarland University
Stefan Pfeffer: Max-Planck Institute of Biochemistry, Department of Molecular Structural Biology
Hudson H. Freeze: Sanford-Burnham-Prebys Medical Discovery Institute
Friedrich Förster: Utrecht University
Volkhard Helms: Saarland University
Johanna Dudek: Saarland University
Richard Zimmermann: Saarland University

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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 Sec61α.

Date: 2018
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DOI: 10.1038/s41467-018-06188-z

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