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. 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: Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA.
authors: Huaqun
authors: H
authors: Zhang
authors: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Joseph
authors: J
authors: Amick
authors: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Ritu
authors: R
authors: Chakravarti
authors: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors: Stephanie
authors: S
authors: Santarriaga
authors: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Simon
authors: S
authors: Schlanger
authors: Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA.
authors: Cameron
authors: C
authors: McGlone
authors: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Michelle
authors: M
authors: Dare
authors: Molecular Biology Consortium, Beamline 4.2.2, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors: Jay C
authors: JC
authors: Nix
authors: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors: K Matthew
authors: KM
authors: Scaglione
authors: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Dennis J
authors: DJ
authors: Stuehr
authors: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: misras@ccf.org.
authors: Saurav
authors: S
authors: Misra
authors: Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA. Electronic address: pagerc@miamioh.edu.
authors: Richard C
authors: RC
authors: Page
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D050883:HSC70 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases