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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Crystallography, X-Ray
  • HSC70 Heat-Shock Proteins / chemistry*
  • HSC70 Heat-Shock Proteins / metabolism
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Structure, Secondary
  • Ubiquitin-Protein Ligases / chemistry*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination*


  • HSC70 Heat-Shock Proteins
  • HSPA8 protein, human
  • STUB1 protein, human
  • Ubiquitin-Protein Ligases

Associated data

  • PDB/4KBQ