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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • HSP70 Heat-Shock Proteins / metabolism*
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Protein Folding
  • Protein Interaction Maps*
  • Tacrolimus Binding Proteins / metabolism

Substances

  • FKBP6 protein, human
  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Tacrolimus Binding Proteins