View source for 6efk


==Crystal structure of the human CHIP TPR domain in complex with a 5mer acetylated HSP70 peptide==
<StructureSection load='6efk' size='340' side='right'caption='[[6efk]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6efk]] is a 4 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=6EFK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EFK 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]] 1.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=6efk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6efk OCA], [https://pdbe.org/6efk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6efk RCSB], [https://www.ebi.ac.uk/pdbsum/6efk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6efk 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-protein interactions between E3 ubiquitin ligases and protein termini help shape the proteome. These interactions are sensitive to proteolysis, which alters the ensemble of cellular N and C termini. Here we describe a mechanism wherein caspase activity reveals latent C termini that are then recognized by the E3 ubiquitin ligase CHIP. Using expanded knowledge of CHIP's binding specificity, we predicted hundreds of putative interactions arising from caspase activity. Subsequent validation experiments confirmed that CHIP binds the latent C termini at tau(D421) and caspase-6(D179). CHIP binding to tau(D421), but not tau(FL), promoted its ubiquitination, while binding to caspase-6(D179) mediated ubiquitin-independent inhibition. Given that caspase activity generates tau(D421) in Alzheimer's disease (AD), these results suggested a concise model for CHIP regulation of tau homeostasis. Indeed, we find that loss of CHIP expression in AD coincides with the accumulation of tau(D421) and caspase-6(D179). These results illustrate an unanticipated link between caspases and protein homeostasis.

Specificity for latent C termini links the E3 ubiquitin ligase CHIP to caspases.,Ravalin M, Theofilas P, Basu K, Opoku-Nsiah KA, Assimon VA, Medina-Cleghorn D, Chen YF, Bohn MF, Arkin M, Grinberg LT, Craik CS, Gestwicki JE Nat Chem Biol. 2019 Aug;15(8):786-794. doi: 10.1038/s41589-019-0322-6. Epub 2019 , Jul 18. PMID:31320752<ref>PMID:31320752</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6efk" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Basu K]]
[[Category: Bohn M-F]]
[[Category: Craik CS]]
[[Category: Gestwicki JE]]
[[Category: Ravalin M]]