Protein–protein interactions modulate the docking-dependent E3-ubiquitin ligase activity of Carboxy-terminus of Hsc70-interacting protein (CHIP)
CHIP is a tetratricopeptide repeat (TPR) domain protein that functions as an E3-ubiquitin ligase. As well as linking the molecular chaperones to the ubiquitin proteasome system, CHIP also has a docking-dependent mode where it ubiquitinates native substrates, thereby regulating their steady state lev...
| Main Authors: | , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2018
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| Online Access: | https://hdl.handle.net/10356/88869 http://hdl.handle.net/10220/46059 |
| _version_ | 1811692977835212800 |
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| author | Narayan, Vikram Landré, Vivien Ning, Jia Hernychova, Lenka Muller, Petr Verma, Chandra Walkinshaw, Malcolm D. Blackburn, Elizabeth A. Ball, Kathryn L. |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Narayan, Vikram Landré, Vivien Ning, Jia Hernychova, Lenka Muller, Petr Verma, Chandra Walkinshaw, Malcolm D. Blackburn, Elizabeth A. Ball, Kathryn L. |
| author_sort | Narayan, Vikram |
| collection | NTU |
| description | CHIP is a tetratricopeptide repeat (TPR) domain protein that functions as an E3-ubiquitin ligase. As well as linking the molecular chaperones to the ubiquitin proteasome system, CHIP also has a docking-dependent mode where it ubiquitinates native substrates, thereby regulating their steady state levels and/or function. Here we explore the effect of Hsp70 on the docking-dependent E3-ligase activity of CHIP. The TPR-domain is revealed as a binding site for allosteric modulators involved in determining CHIP's dynamic conformation and activity. Biochemical, biophysical and modeling evidence demonstrate that Hsp70-binding to the TPR, or Hsp70-mimetic mutations, regulate CHIP-mediated ubiquitination of p53 and IRF-1 through effects on U-box activity and substrate binding. HDX-MS was used to establish that conformational-inhibition-signals extended from the TPR-domain to the U-box. This underscores inter-domain allosteric regulation of CHIP by the core molecular chaperones. Defining the chaperone-associated TPR-domain of CHIP as a manager of inter-domain communication highlights the potential for scaffolding modules to regulate, as well as assemble, complexes that are fundamental to protein homeostatic control. |
| first_indexed | 2024-10-01T06:44:22Z |
| format | Journal Article |
| id | ntu-10356/88869 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:44:22Z |
| publishDate | 2018 |
| record_format | dspace |
| spelling | ntu-10356/888692023-02-28T16:58:27Z Protein–protein interactions modulate the docking-dependent E3-ubiquitin ligase activity of Carboxy-terminus of Hsc70-interacting protein (CHIP) Narayan, Vikram Landré, Vivien Ning, Jia Hernychova, Lenka Muller, Petr Verma, Chandra Walkinshaw, Malcolm D. Blackburn, Elizabeth A. Ball, Kathryn L. School of Biological Sciences DRNTU::Science::Biological sciences Ubiquitin Protein Ligase Protein Structure CHIP is a tetratricopeptide repeat (TPR) domain protein that functions as an E3-ubiquitin ligase. As well as linking the molecular chaperones to the ubiquitin proteasome system, CHIP also has a docking-dependent mode where it ubiquitinates native substrates, thereby regulating their steady state levels and/or function. Here we explore the effect of Hsp70 on the docking-dependent E3-ligase activity of CHIP. The TPR-domain is revealed as a binding site for allosteric modulators involved in determining CHIP's dynamic conformation and activity. Biochemical, biophysical and modeling evidence demonstrate that Hsp70-binding to the TPR, or Hsp70-mimetic mutations, regulate CHIP-mediated ubiquitination of p53 and IRF-1 through effects on U-box activity and substrate binding. HDX-MS was used to establish that conformational-inhibition-signals extended from the TPR-domain to the U-box. This underscores inter-domain allosteric regulation of CHIP by the core molecular chaperones. Defining the chaperone-associated TPR-domain of CHIP as a manager of inter-domain communication highlights the potential for scaffolding modules to regulate, as well as assemble, complexes that are fundamental to protein homeostatic control. Published version 2018-09-20T04:14:17Z 2019-12-06T17:12:45Z 2018-09-20T04:14:17Z 2019-12-06T17:12:45Z 2015 Journal Article Narayan, V., Landré, V., Ning, J., Hernychova, L., Muller, P., Verma, C., . . . Ball, K. L. (2015). Protein–protein interactions modulate the docking-dependent E3-ubiquitin ligase activity of Carboxy-terminus of Hsc70-interacting protein (CHIP). Molecular & Cellular Proteomics, 14(11), 2973-2987. doi:10.1074/mcp.M115.051169 1535-9476 https://hdl.handle.net/10356/88869 http://hdl.handle.net/10220/46059 10.1074/mcp.M115.051169 26330542 en Molecular & Cellular Proteomics © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license. This paper is available on line at http://www.mcponline.org. 15 p. application/pdf |
| spellingShingle | DRNTU::Science::Biological sciences Ubiquitin Protein Ligase Protein Structure Narayan, Vikram Landré, Vivien Ning, Jia Hernychova, Lenka Muller, Petr Verma, Chandra Walkinshaw, Malcolm D. Blackburn, Elizabeth A. Ball, Kathryn L. Protein–protein interactions modulate the docking-dependent E3-ubiquitin ligase activity of Carboxy-terminus of Hsc70-interacting protein (CHIP) |
| title | Protein–protein interactions modulate the docking-dependent E3-ubiquitin ligase activity of Carboxy-terminus of Hsc70-interacting protein (CHIP) |
| title_full | Protein–protein interactions modulate the docking-dependent E3-ubiquitin ligase activity of Carboxy-terminus of Hsc70-interacting protein (CHIP) |
| title_fullStr | Protein–protein interactions modulate the docking-dependent E3-ubiquitin ligase activity of Carboxy-terminus of Hsc70-interacting protein (CHIP) |
| title_full_unstemmed | Protein–protein interactions modulate the docking-dependent E3-ubiquitin ligase activity of Carboxy-terminus of Hsc70-interacting protein (CHIP) |
| title_short | Protein–protein interactions modulate the docking-dependent E3-ubiquitin ligase activity of Carboxy-terminus of Hsc70-interacting protein (CHIP) |
| title_sort | protein protein interactions modulate the docking dependent e3 ubiquitin ligase activity of carboxy terminus of hsc70 interacting protein chip |
| topic | DRNTU::Science::Biological sciences Ubiquitin Protein Ligase Protein Structure |
| url | https://hdl.handle.net/10356/88869 http://hdl.handle.net/10220/46059 |
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