Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/88869
Title: Protein–protein interactions modulate the docking-dependent E3-ubiquitin ligase activity of Carboxy-terminus of Hsc70-interacting protein (CHIP)
Authors: Narayan, Vikram
Landré, Vivien
Ning, Jia
Hernychova, Lenka
Muller, Petr
Verma, Chandra
Walkinshaw, Malcolm D.
Blackburn, Elizabeth A.
Ball, Kathryn L.
Keywords: DRNTU::Science::Biological sciences
Ubiquitin Protein Ligase
Protein Structure
Issue Date: 2015
Source: 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
Series/Report no.: Molecular & Cellular Proteomics
Abstract: 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.
URI: https://hdl.handle.net/10356/88869
http://hdl.handle.net/10220/46059
ISSN: 1535-9476
DOI: http://dx.doi.org/10.1074/mcp.M115.051169
Rights: © 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.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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