A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways

Mikko Taipale, George Tucker, Jian Peng, Irina Krykbaeva, Zhen Yuan Lin, Brett Larsen, Hyungwon Choi, Bonnie Berger, Anne Claude Gingras, Susan Lindquist

Research output: Contribution to journalArticlepeer-review

Abstract

Chaperones are abundant cellular proteins that promote the folding and function of their substrate proteins (clients). In vivo, chaperones also associate with a large and diverse set of cofactors (cochaperones) that regulate their specificity and function. However, how these cochaperones regulate protein folding and whether they have chaperone-independent biological functions is largely unknown. We combined mass spectrometry and quantitative high-throughput LUMIER assays to systematically characterize the chaperone-cochaperone-client interaction network in human cells. We uncover hundreds of chaperone clients, delineate their participation in specific cochaperone complexes, and establish a surprisingly distinct network of protein-protein interactions for cochaperones. As a salient example of the power of such analysis, we establish that NUDC family cochaperones specifically associate with structurally related but evolutionarily distinct β-propeller folds. We provide a framework for deciphering the proteostasis network and its regulation in development and disease and expand the use of chaperones as sensors for drug-target engagement.

Original languageEnglish (US)
Pages (from-to)434-448
Number of pages15
JournalCell
Volume158
Issue number2
DOIs
StatePublished - Jul 17 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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