Proteome-wide identification of HSP70/HSC70 chaperone clients in human cells

PLoS Biology
Seung Woo RyuTanya Paull

Abstract

The 70 kDa heat shock protein (HSP70) family of chaperones are the front line of protection from stress-induced misfolding and aggregation of polypeptides in most organisms and are responsible for promoting the stability, folding, and degradation of clients to maintain cellular protein homeostasis. Here, we demonstrate quantitative identification of HSP70 and 71 kDa heat shock cognate (HSC70) clients using a ubiquitin-mediated proximity tagging strategy and show that, despite their high degree of similarity, these enzymes have largely nonoverlapping specificities. Both proteins show a preference for association with newly synthesized polypeptides, but each responds differently to changes in the stoichiometry of proteins in obligate multi-subunit complexes. In addition, expression of an amyotrophic lateral sclerosis (ALS)-associated superoxide dismutase 1 (SOD1) mutant protein induces changes in HSP70 and HSC70 client association and aggregation toward polypeptides with predicted disorder, indicating that there are global effects from a single misfolded protein that extend to many clients within chaperone networks. Together these findings show that the ubiquitin-activated interaction trap (UBAIT) fusion system can efficiently is...Continue Reading

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Citations

Aug 8, 2020·Biomolecules·Amanda B AbildgaardRasmus Hartmann-Petersen
May 5, 2021·Disease Models & Mechanisms·Charlotte M Fare, James Shorter
May 20, 2021·Journal of Medicinal Chemistry·Andrew J Ambrose, Eli Chapman
Jul 3, 2021·International Journal of Molecular Sciences·Alina D NikotinaIrina V Guzhova
Aug 15, 2021·Neurobiology of Disease·Bin HuangStefan Kochanek
Sep 28, 2021·Biochimica Et Biophysica Acta. Proteins and Proteomics·Noeli Soares Melo SilvaJúlio César Borges

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Methods Mentioned

BETA
affinity purification
ubiquitination
nucleotide exchange
immunoprecipitation
transfection

Key Resources (RRID) Mentioned

Addgene_19514
Addgene_19510
Addgene_52961
Addgene_92308

Software Mentioned

BioID
Proteome Discover
Proteome Discoverer

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