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

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.

doi:10.1016/j.str.2015.01.003

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

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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:: 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.

Publication Date:: Sun Mar 01 00:00:00 EST 2015

Research Org.:: Lawrence Berkeley National Laboratory (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:: Published Article

Journal Name:: Structure

Additional Journal Information:: Journal Name: Structure Journal Volume: 23 Journal Issue: 3; Journal ID: ISSN 0969-2126

Publisher:: Elsevier

Country of Publication:: United Kingdom

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 Kingdom: N. p., 2015. 
Web.  doi:10.1016/j.str.2015.01.003.

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                    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 Kingdom.  https://doi.org/10.1016/j.str.2015.01.003

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                    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. Sun .  
"A Bipartite Interaction between Hsp70 and CHIP Regulates Ubiquitination of Chaperoned Client Proteins".  United Kingdom.  https://doi.org/10.1016/j.str.2015.01.003.

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@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 Kingdom},

  year         = {Sun Mar 01 00:00:00 EST 2015},

  month        = {Sun Mar 01 00:00:00 EST 2015}

}

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