title: Non-canonical Interactions between Heat Shock Cognate Protein 70 (Hsc70) and Bcl2-associated Anthanogene (BAG) Co-Chaperones Are Important for Client Release.
abstract: Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70. The release of nucleotide is known to be mediated by interactions between the conserved BAG domain and the Hsc70 NBD. However, less is known about the regions required for client release, and it is often assumed that this activity also requires the BAG domain. It is important to better understand this step because it determines how long clients remain in the inactive, bound state. Here, we report the surprising observation that truncated versions of either human Bag1 or Bag3, comprised only the BAG domain, promoted rapid release of nucleotide, but not client, in vitro Rather, we found that a non-canonical interaction between Bag1/3 and the Hsc70 SBD is sufficient for accelerating this step. Moreover, client release did not seem to require the BAG domain or Hsc70 NBD. These results suggest that Bag1 and Bag3 control the stability of the Hsc70-client complex using at least two distinct protein-protein contacts, providing a previously under-appreciated layer of molecular regulation in the human Hsc70 system.
authors.affiliation: From the Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109 and.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Rauch
authors.affiliation: From the Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109 and.
authors.forename: Erik R P
authors.initials: ER
authors.lastname: Zuiderweg
authors.affiliation: From the Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109 and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158 jason.gestwicki@ucsf.edu.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D050883:HSC70 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D046912:Multiprotein Complexes; D014157:Transcription Factors
keywords: 70 kilodalton heat shock protein (Hsp70); molecular chaperone; nuclear magnetic resonance (NMR); protein complex; protein-protein interaction