title: Stabilizing the Hsp70-Tau Complex Promotes Turnover in Models of Tauopathy.
abstract: Heat shock protein 70 (Hsp70) is a chaperone that normally scans the proteome and initiates the turnover of some proteins (termed clients) by linking them to the degradation pathways. This activity is critical to normal protein homeostasis, yet it appears to fail in diseases associated with abnormal protein accumulation. It is not clear why Hsp70 promotes client degradation under some conditions, while sparing that protein under others. Here, we used a combination of chemical biology and genetic strategies to systematically perturb the affinity of Hsp70 for the model client, tau. This approach revealed that tight complexes between Hsp70 and tau were associated with enhanced turnover while transient interactions favored tau retention. These results suggest that client affinity is one important parameter governing Hsp70-mediated quality control.
authors: Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94158, USA.
authors: Zapporah T
authors: ZT
authors: Young
authors: Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94158, USA.
authors: Jennifer N
authors: JN
authors: Rauch
authors: Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94158, USA.
authors: Victoria A
authors: VA
authors: Assimon
authors: Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA.
authors: Umesh K
authors: UK
authors: Jinwal
authors: Department of Pathology, University of California at San Francisco, San Francisco, CA 94158, USA.
authors: Misol
authors: M
authors: Ahn
authors: Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94158, USA.
authors: Xiaokai
authors: X
authors: Li
authors: Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94158, USA.
authors: Bryan M
authors: BM
authors: Dunyak
authors: Department of Pathology, University of California at San Francisco, San Francisco, CA 94158, USA.
authors: Atta
authors: A
authors: Ahmad
authors: McLaughlin Research Institute, Great Falls, MT 59405, USA.
authors: George A
authors: GA
authors: Carlson
authors: Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94158, USA.
authors: Sharan R
authors: SR
authors: Srinivasan
authors: Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Erik R P
authors: ER
authors: Zuiderweg
authors: Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA.
authors: Chad A
authors: CA
authors: Dickey
authors: Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94158, USA; Sandler Neuroscience Center, University of California at San Francisco, Room 311, 675 Nelson Rising Lane, San Francisco, CA 94158, USA. Electronic address: jason.gestwicki@ucsf.edu.
authors: Jason E
authors: JE
authors: Gestwicki
mesh_terms: D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D055550:Protein Stability / Q000187:drug effects; D013329:Structure-Activity Relationship; D024801:Tauopathies / Q000188:drug therapy* / Q000378:metabolism*; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D018840:HSP70 Heat-Shock Proteins; C000624707:JG-48 compound; D053778:Thiazolidines; D016875:tau Proteins