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| | ==Ataxin-3 Carboxy Terminal Region - Crystal C2 (triclinic)== | | ==Ataxin-3 Carboxy Terminal Region - Crystal C2 (triclinic)== |
| - | <StructureSection load='4wth' size='340' side='right' caption='[[4wth]], [[Resolution|resolution]] 2.25Å' scene=''> | + | <StructureSection load='4wth' size='340' side='right'caption='[[4wth]], [[Resolution|resolution]] 2.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wth]] is a 2 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=4WTH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WTH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wth]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WTH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WTH FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MAL:MALTOSE'>MAL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.25Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ys9|4ys9]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=PRD_900001:alpha-maltose'>PRD_900001</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ATXN3, ATX3, MJD, MJD1, SCA3 ([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'>[https://proteopedia.org/fgij/fg.htm?mol=4wth FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wth OCA], [https://pdbe.org/4wth PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wth RCSB], [https://www.ebi.ac.uk/pdbsum/4wth PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wth ProSAT]</span></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=4wth FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wth OCA], [http://pdbe.org/4wth PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wth RCSB], [http://www.ebi.ac.uk/pdbsum/4wth PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wth ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/ATX3_HUMAN ATX3_HUMAN] Defects in ATXN3 are the cause of spinocerebellar ataxia type 3 (SCA3) [MIM:[https://omim.org/entry/109150 109150]; also known as Machado-Joseph disease (MJD). 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 degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA3 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. The molecular defect in SCA3 is the a CAG repeat expansion in ATXN3 coding region. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.<ref>PMID:7874163</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MALE_ECO57 MALE_ECO57]] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides (By similarity). | + | [https://www.uniprot.org/uniprot/MALE_ECOLI MALE_ECOLI] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.[https://www.uniprot.org/uniprot/ATX3_HUMAN ATX3_HUMAN] Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates. Binds long polyubiquitin chains and trims them, while it has weak or no activity against chains of 4 or less ubiquitins. Involved in degradation of misfolded chaperone substrates via its interaction with STUB1/CHIP: recruited to monoubiquitinated STUB1/CHIP, and restricts the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. In response to misfolded substrate ubiquitination, mediates deubiquitination of monoubiquitinated STUB1/CHIP. Interacts with key regulators of transcription and represses transcription: acts as a histone-binding protein that regulates transcription.<ref>PMID:12297501</ref> <ref>PMID:17696782</ref> <ref>PMID:16118278</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: Escherichia coli]] |
| - | [[Category: Kim, M]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Zhemkov, V A]] | + | [[Category: Large Structures]] |
| - | [[Category: Ataxin-3]] | + | [[Category: Kim M]] |
| - | [[Category: Nerve tissue protein]] | + | [[Category: Zhemkov VA]] |
| - | [[Category: Polyglutamine helix]]
| + | |
| - | [[Category: Polyq]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Triplet repeat disorder]]
| + | |
| Structural highlights
Disease
ATX3_HUMAN Defects in ATXN3 are the cause of spinocerebellar ataxia type 3 (SCA3) [MIM:109150; also known as Machado-Joseph disease (MJD). 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 degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA3 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. The molecular defect in SCA3 is the a CAG repeat expansion in ATXN3 coding region. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.[1]
Function
MALE_ECOLI Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.ATX3_HUMAN Deubiquitinating enzyme involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates. Binds long polyubiquitin chains and trims them, while it has weak or no activity against chains of 4 or less ubiquitins. Involved in degradation of misfolded chaperone substrates via its interaction with STUB1/CHIP: recruited to monoubiquitinated STUB1/CHIP, and restricts the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. In response to misfolded substrate ubiquitination, mediates deubiquitination of monoubiquitinated STUB1/CHIP. Interacts with key regulators of transcription and represses transcription: acts as a histone-binding protein that regulates transcription.[2] [3] [4]
Publication Abstract from PubMed
An expansion of polyglutamine (polyQ) sequence in ataxin-3 protein causes spinocerebellar ataxia type 3, an inherited neurodegenerative disorder. The crystal structure of the polyQ-containing carboxy-terminal fragment of human ataxin-3 was solved at 2.2-A resolution. The Atxn3 carboxy-terminal fragment including 14 glutamine residues adopts both random coil and alpha-helical conformations in the crystal structure. The polyQ sequence in alpha-helical structure is stabilized by intrahelical hydrogen bonds mediated by glutamine side chains. The intrahelical hydrogen-bond interactions between glutamine side chains along the axis of the polyQ alpha-helix stabilize the secondary structure. Analysis of this structure furthers our understanding of the polyQ-structural characteristics that likely underlie the pathogenesis of polyQ-expansion disorders.
The 2.2-Angstrom resolution crystal structure of the carboxy-terminal region of ataxin-3.,Zhemkov VA, Kulminskaya AA, Bezprozvanny IB, Kim M FEBS Open Bio. 2016 Feb 18;6(3):168-78. doi: 10.1002/2211-5463.12029. eCollection, 2016 Mar. PMID:27047745[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I, et al.. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994 Nov;8(3):221-8. PMID:7874163 doi:http://dx.doi.org/10.1038/ng1194-221
- ↑ Li F, Macfarlan T, Pittman RN, Chakravarti D. Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities. J Biol Chem. 2002 Nov 22;277(47):45004-12. Epub 2002 Sep 23. PMID:12297501 doi:10.1074/jbc.M205259200
- ↑ Tzvetkov N, Breuer P. Josephin domain-containing proteins from a variety of species are active de-ubiquitination enzymes. Biol Chem. 2007 Sep;388(9):973-8. PMID:17696782 doi:10.1515/BC.2007.107
- ↑ Mao Y, Senic-Matuglia F, Di Fiore PP, Polo S, Hodsdon ME, De Camilli P. Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain. Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12700-5. Epub 2005 Aug 23. PMID:16118278
- ↑ Zhemkov VA, Kulminskaya AA, Bezprozvanny IB, Kim M. The 2.2-Angstrom resolution crystal structure of the carboxy-terminal region of ataxin-3. FEBS Open Bio. 2016 Feb 18;6(3):168-78. doi: 10.1002/2211-5463.12029. eCollection, 2016 Mar. PMID:27047745 doi:http://dx.doi.org/10.1002/2211-5463.12029
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