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Structure. 2015 Mar 3;23(3):472-482. doi: 10.1016/j.str.2015.01.003. Epub 2015 Feb 12.

A bipartite interaction between Hsp70 and CHIP regulates ubiquitination of chaperoned client proteins.

Author information

1
Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA.
2
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
3
Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
4
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
5
Molecular Biology Consortium, Beamline 4.2.2, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
6
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: misras@ccf.org.
7
Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA. Electronic address: pagerc@miamioh.edu.

Abstract

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 Å resolution structure of the tetratricopeptide repeat (TPR) domain of CHIP in complex with the α-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.

PMID:
25684577
PMCID:
PMC4351142
DOI:
10.1016/j.str.2015.01.003
[Indexed for MEDLINE]
Free PMC Article

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