Protein–Protein Interactions Modulate the Docking-Dependent E3-Ubiquitin Ligase Activity of Carboxy-Terminus of Hsc70-Interacting Protein (CHIP)*
Copyright policy )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 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.
- National University of Singapore Singapore
- University College London United Kingdom
- University of Edinburgh United Kingdom
- Cancer Research UK United Kingdom
- Institute of Structural and Molecular Biology, University College London, London, UK United Kingdom
Models, Molecular, protein p53, Gene Expression, protein binding, STUB1 protein, carboxyl terminus of hsc70 interacting protein, Protein Structure, Secondary, biochemical analysis, binding affinity, Protein Interaction Mapping, chaperone, heat shock protein 70, tetratricopeptide repeat protein, u box activity, genetics, Lymphocytes, mass spectrometry, allosterism, conformational transition, protein function, unclassified drug, enzyme activity, :Science::Biological sciences [DRNTU], regulator protein, priority journal, protein protein interaction, ubiquitin protein ligase E3, deuterium hydrogen exchange, Protein Binding, 570, Protein Structure, Proteasome Endopeptidase Complex, regulatory mechanism, Ubiquitin-Protein Ligases, interferon regulatory factor 1, lymphocyte, ubiquitination, chemistry, Article, Allosteric Regulation, protein conformation, tetratricopeptide repeat, Cell Line, Tumor, Ubiquitin Protein Ligase, Humans, controlled study, HSP70 Heat-Shock Proteins, human, protein structure, enzyme specificity, mouse, carboxy terminal sequence, nonhuman, Binding Sites, binding site, Research, Ubiquitination, molecular docking, molecular dynamics, Protein Structure, Tertiary, ubiquitin protein ligase, Kinetics, proteasome, kinetics, cytology, gene expression, mutation, Tumor Suppressor Protein p53, Interferon Regulatory Factor-1
Models, Molecular, protein p53, Gene Expression, protein binding, STUB1 protein, carboxyl terminus of hsc70 interacting protein, Protein Structure, Secondary, biochemical analysis, binding affinity, Protein Interaction Mapping, chaperone, heat shock protein 70, tetratricopeptide repeat protein, u box activity, genetics, Lymphocytes, mass spectrometry, allosterism, conformational transition, protein function, unclassified drug, enzyme activity, :Science::Biological sciences [DRNTU], regulator protein, priority journal, protein protein interaction, ubiquitin protein ligase E3, deuterium hydrogen exchange, Protein Binding, 570, Protein Structure, Proteasome Endopeptidase Complex, regulatory mechanism, Ubiquitin-Protein Ligases, interferon regulatory factor 1, lymphocyte, ubiquitination, chemistry, Article, Allosteric Regulation, protein conformation, tetratricopeptide repeat, Cell Line, Tumor, Ubiquitin Protein Ligase, Humans, controlled study, HSP70 Heat-Shock Proteins, human, protein structure, enzyme specificity, mouse, carboxy terminal sequence, nonhuman, Binding Sites, binding site, Research, Ubiquitination, molecular docking, molecular dynamics, Protein Structure, Tertiary, ubiquitin protein ligase, Kinetics, proteasome, kinetics, cytology, gene expression, mutation, Tumor Suppressor Protein p53, Interferon Regulatory Factor-1
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