View source for 9dyb


==CHIP-TPR in complex with the phosphorylated Hsp70 tail==
<StructureSection load='9dyb' size='340' side='right'caption='[[9dyb]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9dyb]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9DYB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9DYB FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9dyb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9dyb OCA], [https://pdbe.org/9dyb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9dyb RCSB], [https://www.ebi.ac.uk/pdbsum/9dyb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9dyb ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CHIP_HUMAN CHIP_HUMAN] Cerebellar ataxia - hypogonadism. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/CHIP_HUMAN CHIP_HUMAN] E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation. Collaborates with ATXN3 in the degradation of misfolded chaperone substrates: ATXN3 restricting the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. Ubiquitinates NOS1 in concert with Hsp70 and Hsp40. Modulates the activity of several chaperone complexes, including Hsp70, Hsc70 and Hsp90. Mediates transfer of non-canonical short ubiquitin chains to HSPA8 that have no effect on HSPA8 degradation. Mediates polyubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair: catalyzes polyubiquitination by amplifying the HUWE1/ARF-BP1-dependent monoubiquitination and leading to POLB-degradation by the proteasome. Mediates polyubiquitination of CYP3A4. Ubiquitinates EPHA2 and may regulate the receptor stability and activity through proteasomal degradation.<ref>PMID:10330192</ref> <ref>PMID:11146632</ref> <ref>PMID:11557750</ref> <ref>PMID:15466472</ref> <ref>PMID:19103148</ref> <ref>PMID:19567782</ref> <ref>PMID:19713937</ref> <ref>PMID:23990462</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Protein quality control is crucial for cellular homeostasis, involving the heat shock response, the ubiquitin-proteasome system, and the autophagy-lysosome pathway. Central to these systems are the chaperone homologs heat shock protein 70 (HSP70) and heat shock cognate 70 (HSC70), which manage protein folding and degradation. This study investigated the impact of the C-terminal phosphorylation of HSP70 on its interaction with the co-chaperone CHIP (C-terminus of HSC70 interacting protein), an E3 ligase that ubiquitinates protein substrates for degradation. Using both cell-free and cell-based approaches, including X-ray crystallography, biolayer interferometry, and live cell biocomplementation assays, we demonstrate that phosphorylation at HSP70 T636 reduces CHIP's binding affinity, shifting the preference toward other co-chaperones like HOP. Structural analysis reveals that phosphorylation disrupts key hydrogen bonds, altering binding dynamics. We engineered a CHIP variant (CHIP-G132N) to restore binding affinity to phosphorylated HSP70. While CHIP-G132N effectively restored binding without additional functional domains, its effectiveness was diminished in full-length phosphomimetic constructs in cell-free and in-cell assays, suggesting that additional interactions may influence binding. Functional assays indicate that phosphorylation of HSP70 affects its stability and degradation, with implications for diseases such as cancer and neurodegeneration. Our findings highlight the complexity of chaperone-co-chaperone interactions and underscore the importance of post-translational modifications in regulating protein quality control mechanisms. By elucidating the molecular details of HSP70 and CHIP interactions, our study provides a foundation for developing therapeutic interventions for diseases characterized by proteostasis imbalance.

Phosphorylation-State Modulated Binding of HSP70: Structural Insights and Compensatory Protein Engineering.,Stewart M, Paththamperuma C, McCann C, Cottingim K, Zhang H, DelVecchio R, Peng I, Fennimore E, Nix JC, Saeed MN, George K, Makaroff K, Colie M, Paulakonis E, Almeida MF, Afolayan AJ, Brown NG, Page RC, Schisler JC bioRxiv [Preprint]. 2025 Feb 17:2025.02.17.637997. doi: , 10.1101/2025.02.17.637997. PMID:40027613<ref>PMID:40027613</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9dyb" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Nix JC]]
[[Category: Page RC]]
[[Category: Zhang H]]