A Bipartite Interaction between Hsp70 and CHIP Regulates Ubiquitination of Chaperoned Client Proteins

Huaqun Zhang; Joseph Amick; Ritu Chakravarti; Stephanie Santarriaga; Simon Schlanger; Cameron McGlone; Michelle Dare; Jay C. Nix; K. Matthew Scaglione; Dennis J. Stuehr; Saurav Misra; Richard C. Page

doi:10.1016/j.str.2015.01.003

A Bipartite Interaction between Hsp70 and CHIP Regulates Ubiquitination of Chaperoned Client Proteins

Huaqun Zhang, Joseph Amick, Ritu Chakravarti, Stephanie Santarriaga, Simon Schlanger, Cameron McGlone, Michelle Dare, Jay C. Nix, K. Matthew Scaglione, Dennis J. Stuehr, Saurav Misra, Richard C. Page

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78 Scopus citations

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.

Original language	English
Pages (from-to)	472-482
Number of pages	11
Journal	Structure
Volume	23
Issue number	3
DOIs	https://doi.org/10.1016/j.str.2015.01.003
State	Published - Mar 3 2015

Bibliographical note

Publisher Copyright:
©2015 Elsevier Ltd. All rights reserved.

Funding

The authors acknowledge financial support from the US NIH (R01-GM080271 to S.M., R00-NS073936 to K.M.S. and T32-HL007914 to R.C.P.). R.C.P. was also supported by Burroughs Wellcome Foundation Collaborative Research Travel Grant 1014031 and institutional funds from Miami University. K.M.S. was also funded through the Research and Education Program, a component of the Advancing a Healthier Wisconsin endowment at the Medical College of Wisconsin. The Advanced Light Source is supported by the US Department of Energy under contract number DE-AC03-76SF00098 at Lawrence Berkeley National Laboratory.

Funders	Funder number
US Department of Energy	DE-AC03-76SF00098
National Institutes of Health (NIH)	R01-GM080271, R00-NS073936, T32-HL007914
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute Family Blood Pressure Program	P01HL076491
National Heart, Lung, and Blood Institute Family Blood Pressure Program
Burroughs Wellcome Fund	1014031
Burroughs Wellcome Fund
Lawrence Berkeley National Laboratory
Miami Clinical and Translational Science Institute, University of Miami

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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title = "A Bipartite Interaction between Hsp70 and CHIP Regulates Ubiquitination of Chaperoned Client Proteins",

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 {\AA} 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.",

author = "Huaqun Zhang and Joseph Amick and Ritu Chakravarti and Stephanie Santarriaga and Simon Schlanger and Cameron McGlone and Michelle Dare and Nix, \{Jay C.\} and Scaglione, \{K. Matthew\} and Stuehr, \{Dennis J.\} and Saurav Misra and Page, \{Richard C.\}",

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doi = "10.1016/j.str.2015.01.003",

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AU - Chakravarti, Ritu

AU - Santarriaga, Stephanie

AU - Schlanger, Simon

AU - McGlone, Cameron

AU - Dare, Michelle

AU - Nix, Jay C.

AU - Scaglione, K. Matthew

AU - Stuehr, Dennis J.

AU - Misra, Saurav

AU - Page, Richard C.

PY - 2015/3/3

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N2 - 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.

AB - 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.

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A Bipartite Interaction between Hsp70 and CHIP Regulates Ubiquitination of Chaperoned Client Proteins

Abstract

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