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5z2s

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Revision as of 06:21, 20 June 2018

Crystal structure of DUX4-HD2 domain

Structural highlights

5z2s is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:	DUX4, DUX10 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Oncogenic fusions are major drivers in leukemogenesis and may serve as potent targets for treatment. DUX4/IGHs have been shown to trigger the abnormal expression of ERGalt through binding to DUX4-Responsive-Element (DRE), which leads to B-cell differentiation arrest and a full-fledged B-ALL. Here, we determined the crystal structures of Apo- and DNADRE-bound DUX4HD2 and revealed a clamp-like transactivation mechanism via the double homeobox domain. Biophysical characterization showed that mutations in the interacting interfaces significantly impaired the DNA binding affinity of DUX4 homeobox. These mutations, when introduced into DUX4/IGH, abrogated its transactivation activity in Reh cells. More importantly, the structure-based mutants significantly impaired the inhibitory effects of DUX4/IGH upon B-cell differentiation in mouse progenitor cells. All these results help to define a key DUX4/IGH-DRE recognition/step in B-ALL.

Structural basis of DUX4/IGH-driven transactivation.,Dong X, Zhang W, Wu H, Huang J, Zhang M, Wang P, Zhang H, Chen Z, Chen SJ, Meng G Leukemia. 2018 Mar 15. pii: 10.1038/s41375-018-0093-1. doi:, 10.1038/s41375-018-0093-1. PMID:29572508^[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
↑ Dong X, Zhang W, Wu H, Huang J, Zhang M, Wang P, Zhang H, Chen Z, Chen SJ, Meng G. Structural basis of DUX4/IGH-driven transactivation. Leukemia. 2018 Mar 15. pii: 10.1038/s41375-018-0093-1. doi:, 10.1038/s41375-018-0093-1. PMID:29572508 doi:http://dx.doi.org/10.1038/s41375-018-0093-1

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5z2s"

@@ Line 3: / Line 3: @@
 <StructureSection load='5z2s' size='340' side='right' caption='[[5z2s]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5z2s]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Z2S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5Z2S FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5z2s]] is a 1 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=5Z2S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5Z2S FirstGlance]. <br>
-</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=5z2s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5z2s OCA], [http://pdbe.org/5z2s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5z2s RCSB], [http://www.ebi.ac.uk/pdbsum/5z2s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5z2s ProSAT]</span></td></tr>
+</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DUX4, DUX10 ([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=5z2s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5z2s OCA], [http://pdbe.org/5z2s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5z2s RCSB], [http://www.ebi.ac.uk/pdbsum/5z2s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5z2s ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 23: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Chen, S]]
 [[Category: Chen, Z]]

5z2s

From Proteopedia

Revision as of 06:21, 20 June 2018

Crystal structure of DUX4-HD2 domain

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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