title: The C-terminal BAG domain of BAG5 induces conformational changes of the Hsp70 nucleotide-binding domain for ADP-ATP exchange.
abstract: ADP-ATP exchange by the molecular chaperone Hsp70 is enhanced by several cochaperones. BAG5 consists of five BAG domains and associates with the nucleotide-binding domain (NBD) of Hsp70. The overexpression of BAG5 in the cytosol reportedly disturbs Hsp70-mediated protein refolding and induces Parkinson's disease. In the present study, we found that the fifth BAG domain (BD5) of BAG5 is responsible for the interaction between Hsp70 and BAG5. We also determined the crystal structures of the BD5*NBD complex. BD5 binding caused two different types of NBD conformational changes, which both disrupted the nucleotide-binding groove. In fact, BD5 reduced the affinity of the NBD for ADP. Moreover, BD5, as well as the full-length BAG5, accelerated Hsp70-mediated refolding in an in vitro assay. Therefore, BAG5 can function as the nucleotide exchange factor of Hsp70 for the enhancement of protein refolding.
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Arakawa
authors.forename: Noriko
authors.initials: N
authors.lastname: Handa
authors.forename: Noboru
authors.initials: N
authors.lastname: Ohsawa
authors.forename: Meiri
authors.initials: M
authors.lastname: Shida
authors.forename: Takanori
authors.initials: T
authors.lastname: Kigawa
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Hayashi
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000244:Adenosine Diphosphate / Q000737:chemistry* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D017434:Protein Structure, Tertiary
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C496515:BAG5 protein, human; D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate