5c23

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'''Unreleased structure'''
 
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The entry 5c23 is ON HOLD until Paper Publication
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==Parkin (S65DUblR0RBR)==
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<StructureSection load='5c23' size='340' side='right'caption='[[5c23]], [[Resolution|resolution]] 2.37&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5c23]] 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=5C23 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5C23 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.37&#8491;</td></tr>
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<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=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5c23 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c23 OCA], [https://pdbe.org/5c23 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5c23 RCSB], [https://www.ebi.ac.uk/pdbsum/5c23 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5c23 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/PRKN_HUMAN PRKN_HUMAN] Young adult-onset Parkinsonism. Disease susceptibility may be associated with variations affecting the gene represented in this entry. Heterozygous mutations act as susceptibility alleles for late-onset Parkinson disease (PubMed:12730996 and PubMed:12629236). The disease is caused by mutations affecting the gene represented in this entry. Defects in PRKN may be involved in the development and/or progression of ovarian cancer.
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== Function ==
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[https://www.uniprot.org/uniprot/PRKN_HUMAN PRKN_HUMAN] Functions within a multiprotein E3 ubiquitin ligase complex, catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPT5, TOMM20, USP30, ZNF746 and AIMP2 (PubMed:10973942, PubMed:10888878, PubMed:11431533, PubMed:12150907, PubMed:12628165, PubMed:16135753, PubMed:21376232, PubMed:23754282, PubMed:23620051, PubMed:24660806, PubMed:24751536). Mediates monoubiquitination as well as 'Lys-6', 'Lys-11', 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context (PubMed:19229105, PubMed:20889974, PubMed:25621951). Participates in the removal and/or detoxification of abnormally folded or damaged protein by mediating 'Lys-63'-linked polyubiquitination of misfolded proteins such as PARK7: 'Lys-63'-linked polyubiquitinated misfolded proteins are then recognized by HDAC6, leading to their recruitment to aggresomes, followed by degradation (PubMed:17846173, PubMed:19229105). Mediates 'Lys-63'-linked polyubiquitination of a 22 kDa O-linked glycosylated isoform of SNCAIP, possibly playing a role in Lewy-body formation (PubMed:11590439, PubMed:11431533, PubMed:19229105, PubMed:11590439, PubMed:15728840). Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy (PubMed:20889974). Promotes the autophagic degradation of dysfunctional depolarized mitochondria (mitophagy) by promoting the ubiquitination of mitochondrial proteins such as TOMM20, RHOT1/MIRO1 and USP30 (PubMed:19029340, PubMed:19966284, PubMed:23620051, PubMed:24896179, PubMed:25527291). Preferentially assembles 'Lys-6'-, 'Lys-11'- and 'Lys-63'-linked polyubiquitin chains following mitochondrial damage, leading to mitophagy (PubMed:25621951). Mediates 'Lys-48'-linked polyubiquitination of ZNF746, followed by degradation of ZNF746 by the proteasome; possibly playing a role in the regulation of neuron death (PubMed:21376232). Limits the production of reactive oxygen species (ROS). Regulates cyclin-E during neuronal apoptosis. In collaboration with CHPF isoform 2, may enhance cell viability and protect cells from oxidative stress (PubMed:22082830). Independently of its ubiquitin ligase activity, protects from apoptosis by the transcriptional repression of p53/TP53 (PubMed:19801972). May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity (PubMed:11439185). May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. May represent a tumor suppressor gene.<ref>PMID:10888878</ref> <ref>PMID:10973942</ref> <ref>PMID:11431533</ref> <ref>PMID:11590439</ref> <ref>PMID:12628165</ref> <ref>PMID:12719539</ref> <ref>PMID:15105460</ref> <ref>PMID:15728840</ref> <ref>PMID:16135753</ref> <ref>PMID:17846173</ref> <ref>PMID:18541373</ref> <ref>PMID:19029340</ref> <ref>PMID:19229105</ref> <ref>PMID:19801972</ref> <ref>PMID:19966284</ref> <ref>PMID:20889974</ref> <ref>PMID:21376232</ref> <ref>PMID:21532592</ref> <ref>PMID:22082830</ref> <ref>PMID:23620051</ref> <ref>PMID:23754282</ref> <ref>PMID:23933751</ref> <ref>PMID:24660806</ref> <ref>PMID:24751536</ref> <ref>PMID:24784582</ref> <ref>PMID:24896179</ref> <ref>PMID:25527291</ref> <ref>PMID:25621951</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The PARK2 gene is mutated in 50% of autosomal recessive juvenile parkinsonism (ARJP) cases. It encodes parkin, an E3 ubiquitin ligase of the RBR family. Parkin exists in an autoinhibited state that is activated by phosphorylation of its N-terminal ubiquitin-like (Ubl) domain and binding of phosphoubiquitin. We describe the 1.8 A crystal structure of human parkin in its fully inhibited state and identify the key interfaces to maintain parkin inhibition. We identify the phosphoubiquitin-binding interface, provide a model for the phosphoubiquitin-parkin complex and show how phosphorylation of the Ubl domain primes parkin for optimal phosphoubiquitin binding. Furthermore, we demonstrate that the addition of phosphoubiquitin leads to displacement of the Ubl domain through loss of structure, unveiling a ubiquitin-binding site used by the E2~Ub conjugate, thus leading to active parkin. We find the role of the Ubl domain is to prevent parkin activity in the absence of the phosphorylation signals, and propose a model for parkin inhibition, optimization for phosphoubiquitin recruitment, release of inhibition by the Ubl domain and engagement with an E2~Ub conjugate. Taken together, this model provides a mechanistic framework for activating parkin.
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Authors: Kumar, A., Aguirre, J.D., Condos, T.E.C., Martinez-Torres, R.J., Chaugule, V.K., Toth, R., Sundaramoorthy, R., Mercier, P., Knebel, A., Spratt, D.E., Barber, K.R., Shaw, G.S., Walden, H.
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Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis.,Kumar A, Aguirre JD, Condos TE, Martinez-Torres RJ, Chaugule VK, Toth R, Sundaramoorthy R, Mercier P, Knebel A, Spratt DE, Barber KR, Shaw GS, Walden H EMBO J. 2015 Aug 7. pii: e201592337. PMID:26254304<ref>PMID:26254304</ref>
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Description:
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Mercier, P]]
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<div class="pdbe-citations 5c23" style="background-color:#fffaf0;"></div>
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[[Category: Toth, R]]
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[[Category: Walden, H]]
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==See Also==
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[[Category: Shaw, G.S]]
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*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
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[[Category: Kumar, A]]
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== References ==
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[[Category: Spratt, D.E]]
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<references/>
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[[Category: Chaugule, V.K]]
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__TOC__
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[[Category: Aguirre, J.D]]
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</StructureSection>
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[[Category: Barber, K.R]]
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[[Category: Homo sapiens]]
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[[Category: Condos, T.E.C]]
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[[Category: Large Structures]]
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[[Category: Sundaramoorthy, R]]
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[[Category: Aguirre JD]]
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[[Category: Knebel, A]]
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[[Category: Barber KR]]
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[[Category: Martinez-Torres, R.J]]
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[[Category: Chaugule VK]]
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[[Category: Condos TEC]]
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[[Category: Knebel A]]
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[[Category: Kumar A]]
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[[Category: Martinez-Torres RJ]]
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[[Category: Mercier P]]
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[[Category: Shaw GS]]
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[[Category: Spratt DE]]
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[[Category: Sundaramoorthy R]]
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[[Category: Toth R]]
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[[Category: Walden H]]

Current revision

Parkin (S65DUblR0RBR)

PDB ID 5c23

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