title: BAG3 Is a Modular, Scaffolding Protein that physically Links Heat Shock Protein 70 (Hsp70) to the Small Heat Shock Proteins.
abstract: Small heat shock proteins (sHsps) are a family of ATP-independent molecular chaperones that are important for binding and stabilizing unfolded proteins. In this task, the sHsps have been proposed to coordinate with ATP-dependent chaperones, including heat shock protein 70 (Hsp70). However, it is not yet clear how these two important components of the chaperone network are linked. We report that the Hsp70 co-chaperone, BAG3, is a modular, scaffolding factor to bring together sHsps and Hsp70s. Using domain deletions and point mutations, we found that BAG3 uses both of its IPV motifs to interact with sHsps, including Hsp27 (HspB1), αB-crystallin (HspB5), Hsp22 (HspB8), and Hsp20 (HspB6). BAG3 does not appear to be a passive scaffolding factor; rather, its binding promoted de-oligomerization of Hsp27, likely by competing for the self-interactions that normally stabilize large oligomers. BAG3 bound to Hsp70 at the same time as Hsp22, Hsp27, or αB-crystallin, suggesting that it might physically bring the chaperone families together into a complex. Indeed, addition of BAG3 coordinated the ability of Hsp22 and Hsp70 to refold denatured luciferase in vitro. Together, these results suggest that BAG3 physically and functionally links Hsp70 and sHsps.
authors.affiliation: Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Rauch
authors.affiliation: Department of Biological Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Tse
authors.affiliation: Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Freilich
authors.affiliation: Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Sue-Ann
authors.initials: SA
authors.lastname: Mok
authors.affiliation: Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Leah N
authors.initials: LN
authors.lastname: Makley
authors.affiliation: Department of Biological Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Southworth
authors.affiliation: Department of Pharmaceutical Chemistry, Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA 94158, USA. Electronic address: jason.gestwicki@ucsf.edu.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D050888:Heat-Shock Proteins, Small / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D018840:HSP70 Heat-Shock Proteins; D050888:Heat-Shock Proteins, Small
keywords: Hsp27; chaperones; intrinsically disordered proteins; protein folding; proteostasis