A Quantitative Chaperone Interaction Network Reveals the Architecture of Cellular Protein Homeostasis Pathways
Author(s)
Taipale, Mikko; Krykbaeva, Irina; Lin, Zhen-Yuan; Larsen, Brett; Choi, Hyungwon; Gingras, Anne-Claude; Tucker, George Jay; Peng, Jian; Berger, Bonnie A.; Lindquist, Susan; ... Show more Show less![Thumbnail](/bitstream/handle/1721.1/105723/Lindquist_A%20quantitative.pdf.jpg?sequence=4&isAllowed=y)
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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.
Date issued
2014-07Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory; Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Department of Mathematics; Whitehead Institute for Biomedical ResearchJournal
Cell
Publisher
Elsevier
Citation
Taipale, Mikko et al. “A Quantitative Chaperone Interaction Network Reveals the Architecture of Cellular Protein Homeostasis Pathways.” Cell 158.2 (2014): 434–448.
Version: Author's final manuscript
ISSN
00928674
1097-4172