2. Academic Validation
  3. Stabilizing the Hsp70-Tau Complex Promotes Turnover in Models of Tauopathy

Stabilizing the Hsp70-Tau Complex Promotes Turnover in Models of Tauopathy

  • Cell Chem Biol. 2016 Aug 18;23(8):992-1001. doi: 10.1016/j.chembiol.2016.04.014.
Zapporah T Young 1,  Jennifer N Rauch 1,  Victoria A Assimon 1,  Umesh K Jinwal 2,  Misol Ahn 3,  Xiaokai Li 1,  Bryan M Dunyak 1,  Atta Ahmad 3,  George A Carlson 4,  Sharan R Srinivasan 1,  Erik R P Zuiderweg 5,  Chad A Dickey 2,  Jason E Gestwicki 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94158, USA.
  • 2 Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA.
  • 3 Department of Pathology, University of California at San Francisco, San Francisco, CA 94158, USA.
  • 4 McLaughlin Research Institute, Great Falls, MT 59405, USA.
  • 5 Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
  • 6 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.
PMID: 27499529 DOI: 10.1016/j.chembiol.2016.04.014
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.

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