Identification of signal peptide features for substrate specificity in human Sec62/Sec63-dependent ER protein import.

The FEBS Journal
Stefan SchorrRichard Zimmermann

Abstract

In mammalian cells, one-third of all polypeptides are integrated into the membrane or translocated into the lumen of the endoplasmic reticulum (ER) via the Sec61 channel. While the Sec61 complex facilitates ER import of most precursor polypeptides, the Sec61-associated Sec62/Sec63 complex supports ER import in a substrate-specific manner. So far, mainly posttranslationally imported precursors and the two cotranslationally imported precursors of ERj3 and prion protein were found to depend on the Sec62/Sec63 complex in vitro. Therefore, we determined the rules for engagement of Sec62/Sec63 in ER import in intact human cells using a recently established unbiased proteomics approach. In addition to confirming ERj3, we identified 22 novel Sec62/Sec63 substrates under these in vivo-like conditions. As a common feature, those previously unknown substrates share signal peptides (SP) with comparatively longer but less hydrophobic hydrophobic region of SP and lower carboxy-terminal region of SP (C-region) polarity. Further analyses with four substrates, and ERj3 in particular, revealed the combination of a slowly gating SP and a downstream translocation-disruptive positively charged cluster of amino acid residues as decisive for the Sec6...Continue Reading

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Citations

Apr 18, 2020·The FEBS Journal·Sarah O'Keefe, Stephen High
Jun 4, 2021·Scientific Reports·Peristera RobotiStephen High
May 8, 2021·The FEBS Journal·Sarah O'KeefeStephen High
Aug 7, 2021·Cell Death Discovery·Lea Daverkausen-Fischer, Felicitas Pröls
Sep 25, 2021·Nature Reviews. Molecular Cell Biology·Ramanujan S Hegde, Robert J Keenan
Oct 13, 2021·ChemPlusChem·Ziqi Lyu, Joseph C Genereux

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