Protein–Protein Interactions Modulate the Docking-Dependent E3-Ubiquitin Ligase Activity of Carboxy-Terminus of Hsc70-Interacting Protein (CHIP)*

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. 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. Tetratricopeptide repeats (TPR)1 are versatile structural modules conserved from E. coli to man, which function in fundamental processes such as transcriptional control, kinase signaling, protein folding and immunity (1.Cerveny L. Straskova A. Dankova V. Hartlova A. Ceckova M. Staud F. Stulik J. 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These data suggest that flexible TPR-domain structures may be an advantage when it comes to setting up protein interaction networks (10.Dunker A.K. Cortese M.S. Romero P. Iakoucheva L.M. Uversky V.N. Flexible nets. The roles of intrinsic disorder in protein interaction networks.FEBS J. 2005; 272: 5129-5148Crossref PubMed Scopus (918) Google Scholar). A subset of the TPR-domain proteins is known to with the of molecular chaperones through interaction with a conserved and as CHIP of is an E3-ligase with a domain and a U-box that is for binding and E3-ligase activity. CHIP functions as an Hsp70 P. C. of a tetratricopeptide protein that with proteins and regulates Biol. PubMed Scopus Google linking the molecular chaperones to the ubiquitin proteasome Hsp70 is as a that also as a CHIP and an that has to the CHIP can also with native to This docking-dependent substrate ubiquitination activity can on the steady state levels V. E. V. P. ubiquitination of the protein by the ubiquitin ligase Biol. Full Text Full Text PDF PubMed Scopus Google C. a the and proteasome Stress Chaperones. 2003; PubMed Scopus Google or activity C. The ubiquitin ligase CHIP through Biol. 2013; PubMed Scopus Google of the a dynamic role for the TPR-domain in the regulation of CHIP and function is Using such as p53 and we the TPR-domain of CHIP as a site for allosteric of U-box function and E3-ligase activity V. E. V. P. ubiquitination of the protein by the ubiquitin ligase Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, V. A. R. CHIP chaperones p53 Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). of the TPR-domain and can allosteric regulation of E3-ligase activity in to were used and were and and were from was in to and used as were from and were with a and an the were in was from and from IRF-1 and and were and to the was from into to and as for by of and was from and p53 was as of p53 Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). Hsp70 was from ubiquitin and from and from and were and are as V. E. V. P. ubiquitination of the protein by the ubiquitin ligase Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). of CHIP is in in the were in with and and were were and into the to the of the CHIP or was by a into with to a of The exchange was and was by the of in 5 and by in was and an were and on a for the were an 5 and a of in by in The and the were was an mass with with a on the The was in the and a was for was by of the from and mass were the protein of the CHIP protein with the mass for of mass for of and or were The was to was with of was in mode with in the and the data were D. D. M.J. for the of exchange 2012; PubMed Scopus Google Scholar). were protein or was on in Hsp70 was a with in in with were in A of the protein and/or of was in for was the or and was a were in to the Hsp70 was to and with a in of or to of The was for and an CHIP the was as that was and a of CHIP or ubiquitination were as E. V. M. of the IRF-1 domain in and PubMed Scopus Google Scholar). ubiquitination M. E. regulation of E3-ubiquitin ligase 2006; Full Text Full Text PDF PubMed Scopus Google were with or CHIP for up to as and by the of were in a Hsp70 with CHIP and/or of or were to the ubiquitination for to the and The E2 was for which as was and were for a to the the with was and the on was to in and used or was to 5 in the of Hsp70 a were to a of 5 were on a and was an by from to with a was in of were in were a were into to a of to CHIP was from 5 to a of was the to a were in were for and were with the by the CHIP protein was with in as were by of and for 5 were by and with CHIP 5 and was and the in The of CHIP in complex with M. M. M. P. C. structures of the CHIP E3 ubiquitin ligase and a 2005; 20: Full Text Full Text PDF PubMed Scopus Google Scholar)) was used as the for were into the to CHIP the were on the CHIP with from where A and are the CHIP and and are the to A and the CHIP and the CHIP with to is in the are in the activity of CHIP where the E3-ligase and thereby regulating their steady state and/or activity and V. E. V. P. ubiquitination of the protein by the ubiquitin ligase Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, C. a the and proteasome Stress Chaperones. 2003; PubMed Scopus Google Scholar, C. The ubiquitin ligase CHIP through Biol. 2013; PubMed Scopus Google Scholar). the where CHIP as a the molecular chaperones and the ubiquitin proteasome system, the TPR-domain to a in the of Hsp70 or the ubiquitination of proteins C. a the and proteasome Stress Chaperones. 2003; PubMed Scopus Google Scholar). the core molecular chaperones the activity of CHIP as a docking-dependent ligase V. E. V. P. ubiquitination of the protein by the ubiquitin ligase Biol. Full Text Full Text PDF PubMed Scopus Google for native proteins has been on determining the E3-ligase activity of CHIP in the with CHIP in an conformation docking-dependent the effect of Hsp70 on CHIP-mediated ubiquitination was p53 and IRF-1 as V. E. V. P. ubiquitination of the protein by the ubiquitin ligase Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, C. M. J. The ubiquitin ligase CHIP is to p53 for Biol. 2005; Full Text Full Text PDF PubMed Scopus Google we that of CHIP with or with substrate ubiquitination and of to the ubiquitination also IRF-1 by CHIP that the conserved the of Hsp70 and be involved in CHIP with J. C. N. J. of suggests a the of to the Biol. Full Text Full Text PDF PubMed Scopus Google where Hsp70 ubiquitination of IRF-1 and it the of a Hsp70 Hsp70 CHIP in the of IRF-1 or p53 and of CHIP was in the Hsp70 can as an or of CHIP E3-ligase activity on the The data suggest that Hsp70 can ubiquitination of p53 and IRF-1 through interaction with the TPR-domain of CHIP. in to to Hsp70 can also to p53 and IRF-1 M.S. M.J. binding in the protein Biol. 272: Full Text Full Text PDF PubMed Scopus Google Scholar, V. M. A. M. regulation of the protein by core of the molecular Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). Although a recent on the TPR-domain of CHIP suggests that the of Hsp70 and a from the Hsp70 J. R. C. M. A interaction Hsp70 CHIP regulates ubiquitination of Full Text Full Text PDF PubMed Scopus Google studies on CHIP suggest that it with the conserved of Hsp70 (9.Graf C. Stankiewicz M. Nikolay R. Mayer M.P. Insights into the conformational dynamics of the E3 ubiquitin ligase CHIP in complex with chaperones and E2 enzymes.Biochemistry. 2010; 49: 2121-2129Crossref PubMed Scopus (43) Google Scholar). to we used a from Hsp70 or that to the TPR-domain of CHIP and and to CHIP was with the Hsp70 ubiquitination of IRF-1 was with a and a on the of also ubiquitination of with data the more to CHIP the Hsp70 it was as an of IRF-1 ubiquitination of p53 and CHIP and were also by the was data that ubiquitination of was by the Hsp70 that the of the complex may be to that of the complexes As a for in binding to we that it has effect on the activity of the E3-ligase in a p53 ubiquitination where the of the the of the were to in The data demonstrate that binding of an ligand to the TPR-domain of CHIP was to docking-dependent E3-ligase activity. studies in to the flexible of the the or Hsp70 of the TPR is and has (9.Graf C. Stankiewicz M. Nikolay R. Mayer M.P. Insights into the conformational dynamics of the E3 ubiquitin ligase CHIP in complex with chaperones and E2 enzymes.Biochemistry. 2010; 49: 2121-2129Crossref PubMed Scopus (43) Google Scholar). that the from a flexible to a more TPR the activity of CHIP. that of TPR-domain to a that formation A on studies of and J. Full Text Full Text PDF PubMed Google may the effect of Hsp70-binding on the of CHIP is of two that are to a the of and of to has been to Hsp70 binding. The protein may a to the effect of the TPR-domain in the of and of and CHIP we that the was and biophysical dynamic and the protein that was in binding to protein was to to a from Hsp70 in a where the protein with a As been used in to the of CHIP P. N. A. and of kinase by role of the protein 2004; PubMed Scopus Google Scholar, M. E. C. L. E3 ubiquitin ligase CHIP a for Sci. A. PubMed Scopus Google Scholar, L. of protein by Biol. 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Stankiewicz M. Nikolay R. Mayer M.P. Insights into the conformational dynamics of the E3 ubiquitin ligase CHIP in complex with chaperones and E2 enzymes.Biochemistry. 2010; 49: 2121-2129Crossref PubMed Scopus (43) Google Scholar). are with that CHIP has a and is more to in The CHIP when it is to or when it an that has been as a binding of CHIP P. N. A. and of kinase by role of the protein 2004; PubMed Scopus Google Scholar, M. E. C. L. E3 ubiquitin ligase CHIP a for Sci. A. PubMed Scopus Google Scholar, L. of protein by Biol. Full Text Full Text PDF PubMed Scopus (43) Google biophysical are in of a The of to hydrogen with protein the and is well with studies the formation of structures A on studies of and J. Full Text Full Text PDF PubMed Google of to the and more and more to fold into an the from the we and CHIP in a with a of and This suggests that of the is a CHIP has a of when with the of an of These data the modeling which suggests that the of CHIP is flexible the the for in of the CHIP were a was the TPR-domain of CHIP with the of This was binding and in were the two U-box of the in the conformation and were binding or of The for a where of CHIP is to function. studies that the CHIP is and that the U-box of of the is for E2 binding of the of the U-box from the to the with U-box for CHIP The suggest that changes in TPR-domain and U-box the of that the of of the two U-box with of the TPR-domains and binding or is evidence that the TPR-domain is as a for allosteric which regulate CHIP activity. of on the dynamic of the U-box the of or of the evidence to the allosteric regulation of the U-box through the TPR-domain of CHIP by were The can as the for as binding to the U-box allosteric changes in which substrate ubiquitination or the of ubiquitin to ubiquitin of an complex an allosteric 2012; Full Text Full Text PDF PubMed Scopus Google Scholar, E. M. the ubiquitin ligase CHIP and ubiquitin Struct. Biol. PubMed Scopus Google Scholar). changes in CHIP are to the we up an and the of ubiquitin from in to CHIP of CHIP ubiquitin from and the protein a to ubiquitin from the the activity of the was that of CHIP and a U-box that can with the the of to was an it with a CHIP. of the to A the of the ligase to through changes in binding The binding for IRF-1 on CHIP is the TPR-domain is for complex the domain and U-box are V. E. V. P. ubiquitination of the protein by the ubiquitin ligase Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). we TPR-domain conformational changes in CHIP Using protein interaction we that Hsp70 was to with IRF-1 for binding to CHIP when the ligase was in the As the TPR-domain is for IRF-1 binding to CHIP V. E. V. P. ubiquitination of the protein by the ubiquitin ligase Biol. Full Text Full Text PDF PubMed Scopus Google the suggests that the conformation of CHIP has a for IRF-1 CHIP in we to the IRF-1 was and CHIP was in the binding to IRF-1 was when the was and CHIP was on the the and proteins well to IRF-1 the as to Hsp70 when with CHIP the data suggest that CHIP in flexible to IRF-1 in binding of CHIP or to IRF-1 a in conformation a effect of binding or on IRF-1 and with data V. E. V. P. ubiquitination of the protein by the ubiquitin ligase Biol. Full Text Full Text PDF PubMed Scopus Google IRF-1 and Hsp70 for binding to the site on CHIP. the TPR-domain of CHIP can regulate through effects on substrate and E2 binding. the allosteric by which changes in the TPR-domain of CHIP can in an of CHIP-mediated ubiquitin from the complex and we HDX-MS deuterium exchange by mass to changes in the for CHIP as a of dynamic conformational and CHIP were in the of deuterium for of up to and to by CHIP and were of the and the The data for the was the of CHIP is and and F. M. P. L. P. The assembly and of the molecular Full Text Full Text PDF PubMed Scopus Google to the the amino The a in in the TPR-domain of with the TPR of deuterium the The data evidence that with CHIP in a to that by (9.Graf C. Stankiewicz M. Nikolay R. Mayer M.P. Insights into the conformational dynamics of the E3 ubiquitin ligase CHIP in complex with chaperones and E2 enzymes.Biochemistry. 2010; 49: 2121-2129Crossref PubMed Scopus (43) Google Scholar). of the TPR-domain and U-box for the and the of we can are in TPR-domain in in changes are to the U-box in the TPR-domain to in deuterium in the U-box domain in to the TPR-domain This is of a more rigid with the The CHIP U-box structural with the that are in R. the to ubiquitin Biochem. Sci. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). conserved structural a to a and two crystallographic of that the U-box a for the interactions the the and HDX-MS data in the and the of the U-box and the The recent of the protein and has ubiquitin to the site of the E2 with with of the domain of A. of a E3 ligase and E2 for 2012; PubMed Scopus Google Scholar). the CHIP protein complex the binding mode in that changes to the of the U-box for the of ubiquitin from the complex to the TPR-domains are protein interaction modules to which are as scaffolds for the assembly of multi-protein demonstrate that the of a TPR-domain can the for allosteric regulation through of conformational in with recent on the potential of scaffolds and intrinsic disorder to allosteric of complexes J. and intrinsic disorder in an 2012; PubMed Scopus Google Scholar, R. The role of in the 2013; PubMed Scopus Google Scholar, R. A of scaffolding suggests that scaffolding proteins can regulation and of complexes through 2013; Scopus Google we that protein interactions that TPR on CHIP and regulate E3-ligase activity. crystallographic of the Rap proteins from the that TPR-domains an invariant on ligand binding by that interaction of the TPR with changes in the conformation of the protein as a whole (6.Parashar V. Jeffrey P.D. Neiditch M.B. Conformational change-induced repeat domain expansion regulates Rap phosphatase quorum-sensing signal receptors.PLoS Biol. 2013; 11: e1001512Crossref PubMed Scopus (49) Google Scholar). with a (9.Graf C. Stankiewicz M. Nikolay R. Mayer M.P. Insights into the conformational dynamics of the E3 ubiquitin ligase CHIP in complex with chaperones and E2 enzymes.Biochemistry. 2010; 49: 2121-2129Crossref PubMed Scopus (43) Google the TPR-domain in CHIP HDX-MS we that it is and that the amino are the of to of intrinsic disorder for in the TPR-domain of CHIP with the a of which is ligand binding or the of amino we in of and protein in the TPR and the U-box of the and in the two U-box HDX-MS of CHIP that and are to allosteric regulation of the CHIP U-box. is that ligand binding (9.Graf C. Stankiewicz M. Nikolay R. Mayer M.P. Insights into the conformational dynamics of the E3 ubiquitin ligase CHIP in complex with chaperones and E2 enzymes.Biochemistry. 2010; 49: 2121-2129Crossref PubMed Scopus (43) Google Scholar)) or of the TPR as well as in the of and intrinsic to be of the allosteric by which such as Hsp70 can activity. The HDX-MS with that the suggest the that the of CHIP as a functional the conformational to the This is by data that is to and with a This be by the TPR the U-box and an The that can be by the TPR-domain and that of the TPR-domain through the in the protein and are as potential of E3-ligase on that in proteins and is for the been as the flexible of the E3-ligase complexes function to a of the the E2 and the substrate to ubiquitination as well as an in the to J. R. The role of in the Biochem. Mol. Biol. 2013; PubMed Scopus Google Scholar). flexible regions of the E3-ligase in nuclear a disordered ubiquitin ligase Full Text Full Text PDF PubMed Scopus Google and the ligase D. conformational of the E3 Sci. A. 2013; PubMed Scopus Google in substrate by the recognition of or we a by which E3-ligase structural can regulate changes in the of TPR-domain and are to the U-box of CHIP. interactions are to the of allosteric changes in the which the ubiquitin A. of a E3 ligase and E2 for 2012; PubMed Scopus Google Scholar, J. R. The role of in the Biochem. Mol. Biol. 2013; PubMed Scopus Google Scholar, E. J. into the allosteric of a by ubiquitin Sci. A. 2005; PubMed Scopus Google Scholar). CHIP in which the TPR has been is in to to substrate and the in and of ubiquitin to the substrate the TPR-domain in CHIP the it to as an E3-ligase can also as an where the of a more can This be on the of the substrate and/or the of as we that Hsp70 can the ubiquitination of the where it the of p53 and it be that Hsp70 can with CHIP in and that on the or on J. R. C. M. A interaction Hsp70 CHIP regulates ubiquitination of Full Text Full Text PDF PubMed Scopus Google Scholar, P. E. P. R. of Hsp70 and regulates binding to CHIP and to protein 2013; PubMed Scopus Google Scholar). the that allosteric is when are and when a fold-on-binding is Structural intrinsic and in nuclear as Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, R. of via allosteric and protein Sci. A. PubMed Scopus Google Scholar). also that intrinsic scaffolding and can be in a as well as in multi-protein The evidence that Hsp70 is as a for CHIP in the protein is to the of CHIP activity. demonstrate that Hsp70 can CHIP function as a docking-dependent E3-ligase by as a of IRF-1 and p53 the we that Hsp70 can also CHIP-mediated substrate as it for J. C. N. J. of suggests a the of to the Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). Hsp70 of by CHIP can be by the Hsp70 that Hsp70 through an interaction with the substrate through binding to the TPR-domain of CHIP. for the regulation of CHIP by Hsp70 comes from studies on L. R. L. Molecular of the regulation of protein by of protein Biol. Full Text Full Text PDF PubMed Scopus Google where Hsp70 CHIP-mediated ubiquitination and from where of by is of by protein is by 5 PubMed Scopus Google Scholar). the function of TPR-domains to allosteric roles the to the activity of in protein that are to and which a role in the of and The of TPR-domains to with and structures N. Zarivach R. Structural and functional discussion of the tetra-trico-peptide repeat, a protein interaction module.Structure. 2012; 20: 397-405Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, A. C. F. C. by TPR and of in Hsp70 Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, M. of and as for tetratricopeptide repeat (TPR) J. PubMed Scopus Google to that and/or can be for the potential for allosteric and the The of for of and with data with tetratricopeptide repeat of