Ca2+/S100 Proteins Act as Upstream Regulators of the Chaperone-associated Ubiquitin Ligase CHIP (C Terminus of Hsc70-interacting Protein)
| Autor: | Hiroshi Tokumitsu, Fuminori Yamaguchi, Seiko Shimamoto, Ryoji Kobayashi, Yasuo Kubota |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Proteasome Endopeptidase Complex
Proline Ubiquitin-Protein Ligases Blotting Western Ubiquitin-conjugating enzyme Biology Protein degradation Biochemistry DNA-binding protein F-box protein Smad1 Protein Heat Shock Transcription Factors Cell Line Tumor Calcium-binding protein Humans HSP70 Heat-Shock Proteins HSP90 Heat-Shock Proteins Molecular Biology Binding Sites Chemotactic Factors Lysine Calcium-Binding Proteins S100 Proteins Ubiquitination Cell Biology Neoplasm Proteins Ubiquitin ligase Cell biology Hsp70 DNA-Binding Proteins Tetratricopeptide Mutation biology.protein Calcium Tumor Suppressor Protein p53 Signal Transduction Protein Binding Transcription Factors |
| Zdroj: | Journal of Biological Chemistry. 288:7158-7168 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m112.436758 |
| Popis: | The U-box E3 ubiquitin ligase CHIP (C terminus of Hsc70-interacting protein) binds Hsp90 and/or Hsp70 via its tetratricopeptide repeat (TPR), facilitating ubiquitination of the chaperone-bound client proteins. Mechanisms that regulate the activity of CHIP are, at present, poorly understood. We previously reported that Ca2+/S100 proteins directly associate with the TPR proteins, such as Hsp70/Hsp90-organizing protein (Hop), kinesin light chain, Tom70, FKBP52, CyP40, and protein phosphatase 5 (PP5), leading to the dissociation of the interactions of the TPR proteins with their target proteins. Therefore, we have hypothesized that Ca2+/S100 proteins can interact with CHIP and regulate its function. GST pulldown assays indicated that Ca2+/S100A2 and S100P bind to the TPR domain and lead to interference with the interactions of CHIP with Hsp70, Hsp90, HSF1, and Smad1. In vitro ubiquitination assays indicated that Ca2+/S100A2 and S100P are efficient and specific inhibitors of CHIP-mediated ubiquitination of Hsp70, Hsp90, HSF1, and Smad1. Overexpression of S100A2 and S100P suppressed CHIP-chaperone complex-dependent mutant p53 ubiquitination and degradation in Hep3B cells. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway. Background: CHIP is a U-box E3 ubiquitin ligase that facilitates the proteasomal degradation of many client proteins. Results: Ca2+/S100 proteins directly interact with CHIP and suppress the ubiquitination and degradation of the client proteins. Conclusion: We have identified S100 proteins as novel Ca2+-dependent regulators of the CHIP-proteasome pathway. Significance: This is the first indication that S100 proteins form a link between Ca2+ signal transduction and the CHIP-proteasome pathway. |
| Databáze: | OpenAIRE |
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