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.

• MeSH
• alosterická regulace MeSH
• exprese genu MeSH
• interferonový regulační faktor 1 genetika   metabolismus   MeSH
• kinetika MeSH
• lidé MeSH
• lymfocyty cytologie   metabolismus   MeSH
• mapování interakce mezi proteiny MeSH
• molekulární modely MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• proteasomový endopeptidasový komplex metabolismus   MeSH
• proteiny tepelného šoku HSP70 chemie   genetika   metabolismus   MeSH
• sekundární struktura proteinů MeSH
• terciární struktura proteinů MeSH
• ubikvitinace MeSH
• ubikvitinligasy chemie   genetika   metabolismus   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH