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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 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. Here, 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.

Authors:
 [1];  [2];  [2];  [3];  [2];  [1];  [2];  [4];  [3];  [2];  [2];  [1]
  1. Miami Univ., Oxford, OH (United States)
  2. Cleveland Clinic, Cleveland, OH (United States). Lerner Research Institute
  3. Medical College of Wisconsin, Milwaukee, WI (United States)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1242309
Alternate Identifier(s):
OSTI ID: 1257837
Grant/Contract Number:  
AC03-76SF00098; R01-GM080271; R00-NS073936; T32-HL007914; 1014031
Resource Type:
Journal Article: Published Article
Journal Name:
Structure
Additional Journal Information:
Journal Volume: 23; Journal Issue: 3; Journal ID: ISSN 0969-2126
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Zhang, Huaqun, Amick, Joseph, Chakravarti, Ritu, Santarriaga, Stephanie, Schlanger, Simon, McGlone, Cameron, Dare, Michelle, Nix, Jay C., Scaglione, K. Matthew, Stuehr, Dennis J., Misra, Saurav, and Page, Richard C. A Bipartite Interaction between Hsp70 and CHIP Regulates Ubiquitination of Chaperoned Client Proteins. United States: N. p., 2015. Web. doi:10.1016/j.str.2015.01.003.
Zhang, Huaqun, Amick, Joseph, Chakravarti, Ritu, Santarriaga, Stephanie, Schlanger, Simon, McGlone, Cameron, Dare, Michelle, Nix, Jay C., Scaglione, K. Matthew, Stuehr, Dennis J., Misra, Saurav, & Page, Richard C. A Bipartite Interaction between Hsp70 and CHIP Regulates Ubiquitination of Chaperoned Client Proteins. United States. doi:10.1016/j.str.2015.01.003.
Zhang, Huaqun, Amick, Joseph, Chakravarti, Ritu, Santarriaga, Stephanie, Schlanger, Simon, McGlone, Cameron, Dare, Michelle, Nix, Jay C., Scaglione, K. Matthew, Stuehr, Dennis J., Misra, Saurav, and Page, Richard C. Thu . "A Bipartite Interaction between Hsp70 and CHIP Regulates Ubiquitination of Chaperoned Client Proteins". United States. doi:10.1016/j.str.2015.01.003.
@article{osti_1242309,
title = {A Bipartite Interaction between Hsp70 and CHIP Regulates Ubiquitination of Chaperoned Client Proteins},
author = {Zhang, Huaqun and Amick, Joseph and Chakravarti, Ritu and Santarriaga, Stephanie and Schlanger, Simon and McGlone, Cameron and Dare, Michelle and Nix, Jay C. and Scaglione, K. Matthew and Stuehr, Dennis J. and Misra, Saurav and Page, Richard C.},
abstractNote = {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. Here, 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.},
doi = {10.1016/j.str.2015.01.003},
journal = {Structure},
number = 3,
volume = 23,
place = {United States},
year = {Thu Feb 12 00:00:00 EST 2015},
month = {Thu Feb 12 00:00:00 EST 2015}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1016/j.str.2015.01.003

Citation Metrics:
Cited by: 19 works
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