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| | ==Crystal structure of AXH domain complex with Capicua== | | ==Crystal structure of AXH domain complex with Capicua== |
| - | <StructureSection load='4j2j' size='340' side='right' caption='[[4j2j]], [[Resolution|resolution]] 2.50Å' scene=''> | + | <StructureSection load='4j2j' size='340' side='right'caption='[[4j2j]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4j2j]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4J2J OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4J2J FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4j2j]] is a 6 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=4J2J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4J2J FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4j2l|4j2l]]</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=4j2j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j2j OCA], [https://pdbe.org/4j2j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4j2j RCSB], [https://www.ebi.ac.uk/pdbsum/4j2j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4j2j ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ATXN1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CIC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4j2j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4j2j OCA], [http://pdbe.org/4j2j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4j2j RCSB], [http://www.ebi.ac.uk/pdbsum/4j2j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4j2j ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/ATX1_HUMAN ATX1_HUMAN]] Spinocerebellar ataxia type 1. Defects in ATXN1 are the cause of spinocerebellar ataxia type 1 (SCA1) [MIM:[http://omim.org/entry/164400 164400]]; also known as olivopontocerebellar atrophy I (OPCA I or OPCA1). Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to cerebellum degeneration with variable involvement of the brainstem and spinal cord. SCA1 belongs to the autosomal dominant cerebellar ataxias type I (ADCA I) which are characterized by cerebellar ataxia in combination with additional clinical features like optic atrophy, ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy and dementia. SCA1 is caused by expansion of a CAG repeat in the coding region of ATXN1. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.<ref>PMID:7951322</ref> <ref>PMID:8634720</ref> | + | [https://www.uniprot.org/uniprot/ATX1_HUMAN ATX1_HUMAN] Spinocerebellar ataxia type 1. Defects in ATXN1 are the cause of spinocerebellar ataxia type 1 (SCA1) [MIM:[https://omim.org/entry/164400 164400]; also known as olivopontocerebellar atrophy I (OPCA I or OPCA1). Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to cerebellum degeneration with variable involvement of the brainstem and spinal cord. SCA1 belongs to the autosomal dominant cerebellar ataxias type I (ADCA I) which are characterized by cerebellar ataxia in combination with additional clinical features like optic atrophy, ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy and dementia. SCA1 is caused by expansion of a CAG repeat in the coding region of ATXN1. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.<ref>PMID:7951322</ref> <ref>PMID:8634720</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ATX1_HUMAN ATX1_HUMAN]] Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor. Binds to the HEY promoter and might assist, along with NCOR2, RBPJ-mediated repression. Binds RNA in vitro. May be involved in RNA metabolism. The expansion of the polyglutamine tract may alter this function.<ref>PMID:21475249</ref> [[http://www.uniprot.org/uniprot/CIC_HUMAN CIC_HUMAN]] Transcriptional repressor which may play a role in development of the central nervous system (CNS).<ref>PMID:12393275</ref> | + | [https://www.uniprot.org/uniprot/ATX1_HUMAN ATX1_HUMAN] Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor. Binds to the HEY promoter and might assist, along with NCOR2, RBPJ-mediated repression. Binds RNA in vitro. May be involved in RNA metabolism. The expansion of the polyglutamine tract may alter this function.<ref>PMID:21475249</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Kim, E]] | + | [[Category: Large Structures]] |
| - | [[Category: Song, J J]] | + | [[Category: Kim E]] |
| - | [[Category: Axh domain]] | + | [[Category: Song J-J]] |
| - | [[Category: Capicua]]
| + | |
| - | [[Category: Protein-protein interaction]]
| + | |
| - | [[Category: Transcription regulator]]
| + | |
| Structural highlights
Disease
ATX1_HUMAN Spinocerebellar ataxia type 1. Defects in ATXN1 are the cause of spinocerebellar ataxia type 1 (SCA1) [MIM:164400; also known as olivopontocerebellar atrophy I (OPCA I or OPCA1). Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to cerebellum degeneration with variable involvement of the brainstem and spinal cord. SCA1 belongs to the autosomal dominant cerebellar ataxias type I (ADCA I) which are characterized by cerebellar ataxia in combination with additional clinical features like optic atrophy, ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy and dementia. SCA1 is caused by expansion of a CAG repeat in the coding region of ATXN1. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.[1] [2]
Function
ATX1_HUMAN Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor. Binds to the HEY promoter and might assist, along with NCOR2, RBPJ-mediated repression. Binds RNA in vitro. May be involved in RNA metabolism. The expansion of the polyglutamine tract may alter this function.[3]
Publication Abstract from PubMed
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by polyglutamine expansion in Ataxin-1 (ATXN1). ATXN1 binds to the transcriptional repressor Capicua (CIC), and the interaction plays a critical role in SCA1 pathogenesis whereby reducing CIC levels rescues SCA1-like phenotypes in a mouse model. The ATXN1/HBP1 (AXH) domain of ATXN1 mediates its homodimerization as well as the interaction with CIC. Here, we present the crystal structure of ATXN1's AXH domain bound to CIC and show that the binding pocket of the AXH domain to CIC overlaps with the homodimerization pocket of the AXH domain. Thus, the binding to CIC disrupts the homodimerization of ATXN1. Furthermore, the binding of CIC reconfigures the complex to allow another form of dimerization mediated by CIC, showing the intricacy of protein complex formation and reconfiguration by ATXN1 and CIC. Identifying the surfaces mediating the interactions between CIC and ATXN1 reveals a critical role for CIC in the reconfiguration of the AXH dimers and might provide insight into ways to target the ATXN1/CIC interactions to modulate SCA1 pathogenesis.
Structural basis of protein complex formation and reconfiguration by polyglutamine disease protein Ataxin-1 and Capicua.,Kim E, Lu HC, Zoghbi HY, Song JJ Genes Dev. 2013 Mar 15;27(6):590-5. doi: 10.1101/gad.212068.112. PMID:23512657[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Banfi S, Servadio A, Chung MY, Kwiatkowski TJ Jr, McCall AE, Duvick LA, Shen Y, Roth EJ, Orr HT, Zoghbi HY. Identification and characterization of the gene causing type 1 spinocerebellar ataxia. Nat Genet. 1994 Aug;7(4):513-20. PMID:7951322 doi:http://dx.doi.org/10.1038/ng0894-513
- ↑ Quan F, Janas J, Popovich BW. A novel CAG repeat configuration in the SCA1 gene: implications for the molecular diagnostics of spinocerebellar ataxia type 1. Hum Mol Genet. 1995 Dec;4(12):2411-3. PMID:8634720
- ↑ Tong X, Gui H, Jin F, Heck BW, Lin P, Ma J, Fondell JD, Tsai CC. Ataxin-1 and Brother of ataxin-1 are components of the Notch signalling pathway. EMBO Rep. 2011 May;12(5):428-35. doi: 10.1038/embor.2011.49. Epub 2011 Apr 8. PMID:21475249 doi:10.1038/embor.2011.49
- ↑ Kim E, Lu HC, Zoghbi HY, Song JJ. Structural basis of protein complex formation and reconfiguration by polyglutamine disease protein Ataxin-1 and Capicua. Genes Dev. 2013 Mar 15;27(6):590-5. doi: 10.1101/gad.212068.112. PMID:23512657 doi:http://dx.doi.org/10.1101/gad.212068.112
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