title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02114, USA.
authors.forename: Mikko
authors.initials: M
authors.lastname: Taipale
authors.affiliation: 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.
authors.forename: George
authors.initials: G
authors.lastname: Tucker
authors.affiliation: 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Peng
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02114, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Krykbaeva
authors.affiliation: Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada.
authors.forename: Zhen-Yuan
authors.initials: ZY
authors.lastname: Lin
authors.affiliation: Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada.
authors.forename: Brett
authors.initials: B
authors.lastname: Larsen
authors.affiliation: National University of Singapore and National University Health System, Singapore 117597, Singapore.
authors.forename: Hyungwon
authors.initials: H
authors.lastname: Choi
authors.affiliation: 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.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Berger
authors.affiliation: 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.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.affiliation: 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.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D017510:Protein Folding; D060066:Protein Interaction Maps; D022021:Tacrolimus Binding Proteins / Q000378:metabolism
chemical_list: C115725:FKBP6 protein, human; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D022021:Tacrolimus Binding Proteins