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A prion-like domain in Hsp42 drives chaperone-facilitated aggregation of misfolded proteins.

Authors
  • Grousl, Tomas1, 2
  • Ungelenk, Sophia1, 2
  • Miller, Stephanie1, 2
  • Ho, Chi-Ting1, 2
  • Khokhrina, Maria1, 2
  • Mayer, Matthias P1
  • Bukau, Bernd3, 2
  • Mogk, Axel4, 2
  • 1 Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany. , (Germany)
  • 2 Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany. , (Germany)
  • 3 Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany [email protected] , (Germany)
  • 4 Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany [email protected] , (Germany)
Type
Published Article
Journal
The Journal of Cell Biology
Publisher
The Rockefeller University Press
Publication Date
Apr 02, 2018
Volume
217
Issue
4
Pages
1269–1285
Identifiers
DOI: 10.1083/jcb.201708116
PMID: 29362223
Source
Medline
License
Unknown

Abstract

Chaperones with aggregase activity promote and organize the aggregation of misfolded proteins and their deposition at specific intracellular sites. This activity represents a novel cytoprotective strategy of protein quality control systems; however, little is known about its mechanism. In yeast, the small heat shock protein Hsp42 orchestrates the stress-induced sequestration of misfolded proteins into cytosolic aggregates (CytoQ). In this study, we show that Hsp42 harbors a prion-like domain (PrLD) and a canonical intrinsically disordered domain (IDD) that act coordinately to promote and control protein aggregation. Hsp42 PrLD is essential for CytoQ formation and is bifunctional, mediating self-association as well as binding to misfolded proteins. Hsp42 IDD confines chaperone and aggregase activity and affects CytoQ numbers and stability in vivo. Hsp42 PrLD and IDD are both crucial for cellular fitness during heat stress, demonstrating the need for sequestering misfolded proteins in a regulated manner.

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