The Signal Peptide Plus a Cluster of Positive Charges in Prion Protein Dictate Chaperone-mediated Sec61 Channel Gating

Overview

Journal Biol Open

Specialty Biology

Date 2019 Feb 13

PMID 30745438

Citations 18

Authors

Anke Ziska

Jorg Tatzelt

Johanna Dudek

Adrienne W Paton

James C Paton

Richard Zimmermann

Sarah Hassdenteufel

Affiliations

Soon will be listed here.

Abstract

The Sec61-complex as a dynamic polypeptide-conducting channel mediates protein transport into the human endoplasmic reticulum (ER) with the help of additional components. ER membrane resident Hsp40-type co-chaperone Sec63 as well as the ER lumenal Hsp70-type chaperone BiP were proposed to facilitate channel opening in a precursor-specific fashion. Here, we report on their rules of engagement in ER import of the prion protein (PrP) by addressing sixteen PrP-related variants which differ in their signal peptides and mature parts, respectively. Transport into the ER of semi-permeabilized human cells was analyzed upon depletion of the components by siRNA- or toxin-treatment. The results are consistent with the view of separate functions of BiP and Sec63 and strongly suggest that the co-chaperone/chaperone-pair facilitates Sec61 channel gating to the open state when precursor polypeptides with weak signal peptides in combination with detrimental features in the adjacent mature part were targeted. Thus, we expand the view of chaperone-mediated Sec61 channel gating by providing a novel example of a polybasic motif that interferes with signal peptide-mediated Sec61 channel gating. This article has an associated First Person interview with the first author of the paper.

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