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==Type2 alpha-synuclein filament assembled in vitro by wild-type and mutant (7 residues insertion) protein== | ==Type2 alpha-synuclein filament assembled in vitro by wild-type and mutant (7 residues insertion) protein== | ||
<StructureSection load='8ceb' size='340' side='right'caption='[[8ceb]], [[Resolution|resolution]] 2. | <StructureSection load='8ceb' size='340' side='right'caption='[[8ceb]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8ceb]] 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=8CEB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CEB FirstGlance]. <br> | <table><tr><td colspan='2'>[[8ceb]] 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=8CEB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CEB FirstGlance]. <br> | ||
</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=8ceb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ceb OCA], [https://pdbe.org/8ceb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ceb RCSB], [https://www.ebi.ac.uk/pdbsum/8ceb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ceb ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.8Å</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=8ceb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ceb OCA], [https://pdbe.org/8ceb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ceb RCSB], [https://www.ebi.ac.uk/pdbsum/8ceb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ceb ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | == Disease == | ||
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== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/SYUA_HUMAN SYUA_HUMAN] May be involved in the regulation of dopamine release and transport. Induces fibrillization of microtubule-associated protein tau. Reduces neuronal responsiveness to various apoptotic stimuli, leading to a decreased caspase-3 activation. | [https://www.uniprot.org/uniprot/SYUA_HUMAN SYUA_HUMAN] May be involved in the regulation of dopamine release and transport. Induces fibrillization of microtubule-associated protein tau. Reduces neuronal responsiveness to various apoptotic stimuli, leading to a decreased caspase-3 activation. | ||
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== Publication Abstract from PubMed == | |||
A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant alpha-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion of MAAAEKT after residue 22 of alpha-synuclein, resulting in a protein of 147 amino acids. Both wild-type and mutant proteins were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new alpha-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36-100 of wild-type alpha-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA Type I and Type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. In vitro assembly of recombinant wild-type alpha-synuclein, its insertion mutant and their mixture yielded structures that were distinct from those of JOS filaments. Our findings provide insight into a possible mechanism of JOS fibrillation in which mutant alpha-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation. | |||
New SNCA mutation and structures of alpha-synuclein filaments from juvenile-onset synucleinopathy.,Yang Y, Garringer HJ, Shi Y, Lovestam S, Peak-Chew S, Zhang X, Kotecha A, Bacioglu M, Koto A, Takao M, Spillantini MG, Ghetti B, Vidal R, Murzin AG, Scheres SHW, Goedert M Acta Neuropathol. 2023 May;145(5):561-572. doi: 10.1007/s00401-023-02550-8. Epub , 2023 Feb 27. PMID:36847833<ref>PMID:36847833</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
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== References == | == References == | ||
<references/> | <references/> | ||