2. Academic Validation
  3. A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways

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

  • Cell. 2014 Jul 17;158(2):434-448. doi: 10.1016/j.cell.2014.05.039.
Mikko Taipale 1,  George Tucker 2,  Jian Peng 2,  Irina Krykbaeva 1,  Zhen-Yuan Lin 3,  Brett Larsen 3,  Hyungwon Choi 4,  Bonnie Berger 2,  Anne-Claude Gingras 5,  Susan Lindquist 6
Affiliations

Affiliations

  • 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.
PMID: 25036637 DOI: 10.1016/j.cell.2014.05.039
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.

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