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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Duy Nguyen & Regine Stutz & Stefan Schorr & Sven Lang & Stefan Pfeffer & Hudson H. Freeze & Friedrich Förster & Volkhard Helms & Johanna Dudek & Richard Zimmermann, 2018. "Proteomics reveals signal peptide features determining the client specificity in human TRAP-dependent ER protein import," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06188-z
    DOI: 10.1038/s41467-018-06188-z
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