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| | ==Crystal structure of the double homeodomain of DUX4 in complex with DNA== | | ==Crystal structure of the double homeodomain of DUX4 in complex with DNA== |
| - | <StructureSection load='6e8c' size='340' side='right' caption='[[6e8c]], [[Resolution|resolution]] 2.12Å' scene=''> | + | <StructureSection load='6e8c' size='340' side='right'caption='[[6e8c]], [[Resolution|resolution]] 2.12Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6e8c]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E8C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6E8C FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6e8c]] is a 3 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=6E8C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6E8C FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</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]] 2.12Å</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=6e8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e8c OCA], [http://pdbe.org/6e8c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6e8c RCSB], [http://www.ebi.ac.uk/pdbsum/6e8c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6e8c ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</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=6e8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e8c OCA], [https://pdbe.org/6e8c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6e8c RCSB], [https://www.ebi.ac.uk/pdbsum/6e8c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6e8c ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/DUX4_HUMAN DUX4_HUMAN]] Facioscapulohumeral dystrophy. The gene represented in this entry is involved in disease pathogenesis. The disease is caused by deletion of an integral number of units of a 3.3-kb tandem repeats, termed D4Z4 macrosatellite, located on chromosome 4q35. In unaffected subjects, the D4Z4 array consists of 11-150 repeats, while in FSHD1 patients, the array is reduced to 1-10 repeats (PubMed:19320656). DUX4 is located in D4Z4 macrosatellite which is epigenetically repressed in somatic tissues. D4Z4 chromatin relaxation in FSHD1 results in inefficient epigenetic repression of DUX4 and a variegated pattern of DUX4 protein expression in a subset of skeletal muscle nuclei. Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death.<ref>PMID:19320656</ref> | + | [https://www.uniprot.org/uniprot/DUX4_HUMAN DUX4_HUMAN] Facioscapulohumeral dystrophy. The gene represented in this entry is involved in disease pathogenesis. The disease is caused by deletion of an integral number of units of a 3.3-kb tandem repeats, termed D4Z4 macrosatellite, located on chromosome 4q35. In unaffected subjects, the D4Z4 array consists of 11-150 repeats, while in FSHD1 patients, the array is reduced to 1-10 repeats (PubMed:19320656). DUX4 is located in D4Z4 macrosatellite which is epigenetically repressed in somatic tissues. D4Z4 chromatin relaxation in FSHD1 results in inefficient epigenetic repression of DUX4 and a variegated pattern of DUX4 protein expression in a subset of skeletal muscle nuclei. Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death.<ref>PMID:19320656</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DUX4_HUMAN DUX4_HUMAN]] Involved in transcriptional regulation. May regulate microRNA (miRNA) expression.<ref>PMID:10433963</ref> <ref>PMID:24145033</ref> | + | [https://www.uniprot.org/uniprot/DUX4_HUMAN DUX4_HUMAN] Involved in transcriptional regulation. May regulate microRNA (miRNA) expression.<ref>PMID:10433963</ref> <ref>PMID:24145033</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: Aihara, H]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Banerjee, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Bohl, T E]] | + | [[Category: Aihara H]] |
| - | [[Category: Bosnakovski, D]] | + | [[Category: Banerjee S]] |
| - | [[Category: Dinh, T]] | + | [[Category: Bohl TE]] |
| - | [[Category: Kurahashi, K]] | + | [[Category: Bosnakovski D]] |
| - | [[Category: Kyba, M]] | + | [[Category: Dinh T]] |
| - | [[Category: Lee, J K]] | + | [[Category: Kurahashi K]] |
| - | [[Category: Shi, K]] | + | [[Category: Kyba M]] |
| - | [[Category: Toso, E A]] | + | [[Category: Lee JK]] |
| - | [[Category: Dna binding protein]]
| + | [[Category: Shi K]] |
| - | [[Category: Dna binding protein-dna complex]]
| + | [[Category: Toso EA]] |
| - | [[Category: Double homeodomain]]
| + | |
| - | [[Category: Transcription factor]]
| + | |
| - | [[Category: Transcription-dna complex]]
| + | |
| Structural highlights
Disease
DUX4_HUMAN Facioscapulohumeral dystrophy. The gene represented in this entry is involved in disease pathogenesis. The disease is caused by deletion of an integral number of units of a 3.3-kb tandem repeats, termed D4Z4 macrosatellite, located on chromosome 4q35. In unaffected subjects, the D4Z4 array consists of 11-150 repeats, while in FSHD1 patients, the array is reduced to 1-10 repeats (PubMed:19320656). DUX4 is located in D4Z4 macrosatellite which is epigenetically repressed in somatic tissues. D4Z4 chromatin relaxation in FSHD1 results in inefficient epigenetic repression of DUX4 and a variegated pattern of DUX4 protein expression in a subset of skeletal muscle nuclei. Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death.[1]
Function
DUX4_HUMAN Involved in transcriptional regulation. May regulate microRNA (miRNA) expression.[2] [3]
Publication Abstract from PubMed
Double homeobox (DUX) transcription factors are unique to eutherian mammals. DUX4 regulates expression of repetitive elements during early embryogenesis, but misexpression of DUX4 causes facioscapulohumeral muscular dystrophy (FSHD) and translocations overexpressing the DUX4 double homeodomain cause B cell leukemia. Here, we report the crystal structure of the tandem homeodomains of DUX4 bound to DNA. The homeodomains bind DNA in a head-to-head fashion, with the linker making anchoring DNA minor-groove interactions and unique protein contacts. Remarkably, despite being tandem duplicates, the DUX4 homeodomains recognize different core sequences. This results from an arginine-to-glutamate mutation, unique to primates, causing alternative positioning of a key arginine side chain in the recognition helix. Mutational studies demonstrate that this primate-specific change is responsible for the divergence in sequence recognition that likely drove coevolution of embryonically regulated repeats in primates. Our work provides a framework for understanding the endogenous function of DUX4 and its role in FSHD and cancer.
Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA.,Lee JK, Bosnakovski D, Toso EA, Dinh T, Banerjee S, Bohl TE, Shi K, Orellana K, Kyba M, Aihara H Cell Rep. 2018 Dec 11;25(11):2955-2962.e3. doi: 10.1016/j.celrep.2018.11.060. PMID:30540931[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mostacciuolo ML, Pastorello E, Vazza G, Miorin M, Angelini C, Tomelleri G, Galluzzi G, Trevisan CP. Facioscapulohumeral muscular dystrophy: epidemiological and molecular study in a north-east Italian population sample. Clin Genet. 2009 Jun;75(6):550-5. doi: 10.1111/j.1399-0004.2009.01158.x. Epub, 2009 Mar 23. PMID:19320656 doi:http://dx.doi.org/10.1111/j.1399-0004.2009.01158.x
- ↑ Gabriels J, Beckers MC, Ding H, De Vriese A, Plaisance S, van der Maarel SM, Padberg GW, Frants RR, Hewitt JE, Collen D, Belayew A. Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gene. 1999 Aug 5;236(1):25-32. PMID:10433963
- ↑ Dmitriev P, Stankevicins L, Ansseau E, Petrov A, Barat A, Dessen P, Robert T, Turki A, Lazar V, Labourer E, Belayew A, Carnac G, Laoudj-Chenivesse D, Lipinski M, Vassetzky YS. Defective regulation of microRNA target genes in myoblasts from facioscapulohumeral dystrophy patients. J Biol Chem. 2013 Dec 6;288(49):34989-5002. doi: 10.1074/jbc.M113.504522. Epub, 2013 Oct 20. PMID:24145033 doi:http://dx.doi.org/10.1074/jbc.M113.504522
- ↑ Lee JK, Bosnakovski D, Toso EA, Dinh T, Banerjee S, Bohl TE, Shi K, Orellana K, Kyba M, Aihara H. Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA. Cell Rep. 2018 Dec 11;25(11):2955-2962.e3. doi: 10.1016/j.celrep.2018.11.060. PMID:30540931 doi:http://dx.doi.org/10.1016/j.celrep.2018.11.060
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