A bipartite interaction between Hsp70 and CHIP regulates ubiquitination of chaperoned client proteins. Structure 2015 Mar 03;23(3):472-482
Date
02/17/2015Pubmed ID
25684577Pubmed Central ID
PMC4351142DOI
10.1016/j.str.2015.01.003Scopus ID
2-s2.0-84923919615 (requires institutional sign-in at Scopus site) 79 CitationsAbstract
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.
Author List
Zhang H, Amick J, Chakravarti R, Santarriaga S, Schlanger S, McGlone C, Dare M, Nix JC, Scaglione KM, Stuehr DJ, Misra S, Page RCMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAnimals
Cell Line
Crystallography, X-Ray
HSC70 Heat-Shock Proteins
Humans
Mice
Models, Molecular
Molecular Sequence Data
Protein Binding
Protein Interaction Domains and Motifs
Protein Structure, Secondary
Ubiquitin-Protein Ligases
Ubiquitination
