Journal
STRUCTURE
Volume 23, Issue 3, Pages 472-482Publisher
CELL PRESS
DOI: 10.1016/j.str.2015.01.003
Keywords
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Funding
- US NIH [R01-GM080271, R00-NS073936, T32-HL007914]
- Burroughs Wellcome Foundation Collaborative Research Travel Grant [1014031]
- Miami University
- Research and Education Program, a component of the Advancing a Healthier Wisconsin endowment at the Medical College of Wisconsin
- US Department of Energy at Lawrence Berkeley National Laboratory [DE-AC03-76SF00098]
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The ubiquitin ligase CHIP plays an important role in cytosolic protein quality control by ubiquitinating proteins chaperoned by Hsp70/Hsc70 and Hsp90, thereby targeting such substrate proteins for degradation. We present a 2.91 angstrom resolution structure of the tetratricopeptide repeat (TPR) domain of CHIP in complex with the a-helical lid subdomain and unstructured tail of Hsc70. Surprisingly, the CHIP-TPR interacts with determinants within both the Hsc70-lid subdomain and the C-terminal PTIEEVD motif of the tail, exhibiting an atypical mode of interaction between chaperones and TPR domains. We demonstrate that the interaction between CHIP and the Hsc70-lid subdomain is required for proper ubiquitination of Hsp70/Hsc70 or Hsp70/Hsc70-bound substrate proteins. Posttranslational modifications of the Hsc70 lid and tail disrupt key contacts with the CHIP-TPR and may regulate CHIP-mediated ubiquitination. Our study shows how CHIP docks onto Hsp70/Hsc70 and defines a bipartite mode of interaction between TPR domains and their binding partners.
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