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Cell. 2014 Jul 17;158(2):434-448. doi: 10.1016/j.cell.2014.05.039.

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

Author information

1
Whitehead Institute for Biomedical Research, Cambridge, MA 02114, USA.
2
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
3
Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada.
4
National University of Singapore and National University Health System, Singapore 117597, Singapore.
5
Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: gingras@lunenfeld.ca.
6
Whitehead Institute for Biomedical Research, Cambridge, MA 02114, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA. Electronic address: lindquist_admin@wi.mit.edu.

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.

PMID:
25036637
PMCID:
PMC4104544
DOI:
10.1016/j.cell.2014.05.039
[Indexed for MEDLINE]
Free PMC Article

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