4bm9: Difference between revisions

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-{{STRUCTURE_4bm9|  PDB=4bm9  |  SCENE=  }}
-===Structure of the autoinhibited Parkin catalytic domain===
-{{ABSTRACT_PUBMED_23727886}}
-==Disease==
+==Structure of the autoinhibited Parkin catalytic domain==
-[[http://www.uniprot.org/uniprot/PRKN2_HUMAN PRKN2_HUMAN]] Defects in PARK2 are a cause of Parkinson disease (PARK) [MIM:[http://omim.org/entry/168600 168600]]. A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features.<ref>PMID:10888878</ref> <ref>PMID:20889974</ref> <ref>PMID:19966284</ref> <ref>PMID:21376232</ref> <ref>PMID:11590439</ref> <ref>PMID:12925569</ref> <ref>PMID:11431533</ref> <ref>PMID:9560156</ref> <ref>PMID:17360614</ref> <ref>PMID:9731209</ref> <ref>PMID:10072423</ref> <ref>PMID:10939576</ref> <ref>PMID:10824074</ref> <ref>PMID:11179010</ref> <ref>PMID:11487568</ref> <ref>PMID:11163284</ref> <ref>PMID:12116199</ref> <ref>PMID:12112109</ref> <ref>PMID:12114481</ref> <ref>PMID:12397156</ref> <ref>PMID:11971093</ref> <ref>PMID:12362318</ref> <ref>PMID:12730996</ref> <ref>PMID:12629236</ref> <ref>PMID:20404107</ref>   Defects in PARK2 are the cause of Parkinson disease type 2 (PARK2) [MIM:[http://omim.org/entry/600116 600116]]; also known as early-onset parkinsonism with diurnal fluctuation (EPDF) or autosomal recessive juvenile Parkinson disease (PDJ). A neurodegenerative disorder characterized by bradykinesia, rigidity, postural instability, tremor, and onset usually befor 40. It differs from classic Parkinson disease by early DOPA-induced dyskinesia, diurnal fluctuation of the symptoms, sleep benefit, dystonia and hyper-reflexia. Dementia is absent. Pathologically, patients show loss of dopaminergic neurons in the substantia nigra, similar to that seen in Parkinson disease; however, Lewy bodies (intraneuronal accumulations of aggregated proteins) are absent.<ref>PMID:20889974</ref> <ref>PMID:11590439</ref> <ref>PMID:9560156</ref> <ref>PMID:17360614</ref> <ref>PMID:9731209</ref> <ref>PMID:10072423</ref> <ref>PMID:10939576</ref> <ref>PMID:11487568</ref> <ref>PMID:11163284</ref> <ref>PMID:12112109</ref>   Note=Defects in PARK2 may be involved in the development and/or progression of ovarian cancer.
+<StructureSection load='4bm9' size='340' side='right'caption='[[4bm9]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4bm9]] is a 1 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=4BM9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BM9 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]] 2.25&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4bm9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bm9 OCA], [https://pdbe.org/4bm9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bm9 RCSB], [https://www.ebi.ac.uk/pdbsum/4bm9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bm9 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[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.
+== Function ==
+[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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Mutations in the protein Parkin are associated with Parkinson's disease (PD), the second most common neurodegenerative disease in men. Parkin is an E3 ubiquitin (Ub) ligase of the structurally uncharacterized RING-in-between-RING(IBR)-RING (RBR) family, which, in an HECT-like fashion, forms a catalytic thioester intermediate with Ub. We here report the crystal structure of human Parkin spanning the Unique Parkin domain (UPD, also annotated as RING0) and RBR domains, revealing a tightly packed structure with unanticipated domain interfaces. The UPD adopts a novel elongated Zn-binding fold, while RING2 resembles an IBR domain. Two key interactions keep Parkin in an autoinhibited conformation. A linker that connects the IBR with the RING2 over a 50-A distance blocks the conserved E2 approximately Ub binding site of RING1. RING2 forms a hydrophobic interface with the UPD, burying the catalytic Cys431, which is part of a conserved catalytic triad. Opening of intra-domain interfaces activates Parkin, and enables Ub-based suicide probes to modify Cys431. The structure further reveals a putative phospho-peptide docking site in the UPD, and explains many PD-causing mutations.
-==Function==
+Structure of the human Parkin ligase domain in an autoinhibited state.,Wauer T, Komander D EMBO J. 2013 May 31. doi: 10.1038/emboj.2013.125. PMID:23727886<ref>PMID:23727886</ref>
-[[http://www.uniprot.org/uniprot/PRKN2_HUMAN PRKN2_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, STUB1, a 22 kDa O-linked glycosylated isoform of SNCAIP, SEPT5, ZNF746 and AIMP2. Mediates monoubiquitination as well as 'Lys-48'-linked and 'Lys-63'-linked polyubiquitination of substrates depending on the context. 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. Mediates 'Lys-63'-linked polyubiquitination of SNCAIP, possibly playing a role in Lewy-body formation. Mediates monoubiquitination of BCL2, thereby acting as a positive regulator of autophagy. Promotes the autophagic degradation of dysfunctional depolarized mitochondria. Mediates 'Lys-48'-linked polyubiquitination of ZNF746, followed by degradation of ZNF746 by the proteasome; possibly playing a role in role in regulation of neuron death. Limits the production of reactive oxygen species (ROS). Loss of this ubiquitin ligase activity appears to be the mechanism underlying pathogenesis of PARK2. May protect neurons against alpha synuclein toxicity, proteasomal dysfunction, GPR37 accumulation, and kainate-induced excitotoxicity. May play a role in controlling neurotransmitter trafficking at the presynaptic terminal and in calcium-dependent exocytosis. Regulates cyclin-E during neuronal apoptosis. May represent a tumor suppressor gene.<ref>PMID:10973942</ref> <ref>PMID:10888878</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:19029340</ref> <ref>PMID:18541373</ref> <ref>PMID:20889974</ref> <ref>PMID:19966284</ref> <ref>PMID:21376232</ref> <ref>PMID:21532592</ref>
-==About this Structure==
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[4bm9]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BM9 OCA].
+</div>
+<div class="pdbe-citations 4bm9" style="background-color:#fffaf0;"></div>
-==Reference==
+== References ==
-<ref group="xtra">PMID:023727886</ref><references group="xtra"/><references/>
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Komander, D.]]
+[[Category: Large Structures]]
-[[Category: Wauer, T.]]
+[[Category: Komander D]]
-[[Category: Ligase]]
+[[Category: Wauer T]]
-[[Category: Neurodegenerative disease]]