5zfw

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of human DUX4 homeodomains bound to A11G DNA mutant

Structural highlights

5zfw is a 3 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.103Å
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

DUX4 plays critical role in the molecular pathogenesis of the neuromuscular disorder facioscapulohumeral muscular dystrophy and acute lymphoblastic leukemia in humans. As a master transcription regulator, DUX4 can also bind the promoters and activate the transcription of hundreds ZGA-associated genes. Here we report on the structural and biochemical studies of DUX4 double homeodomains (DUX4-DH), representing the only structures contain both homeodomain 1 (HD1) and homeodomain 2 (HD2). HD1 and HD2 adopt classical homeobox fold; via the helix inserted into the major groove and the N-terminal extended loop inserted into the minor groove, HD1 and HD2 recognize the box1 (5'-TAA-3') and box2 (5'-TGA-3') nucleotides of the consensus sequence, respectively. Among the box1 and box2 linking nucleotides (CCTAA), the two adenine residues are reported to be highly conserved; however, they are not directly recognized by DUX4-DH in the structures. Besides different nucleotides, our ITC analysis indicated that DUX4-DH can also tolerate various changes in the linker length. Our studies not only revealed the basis for target DNA recognition by DUX4, but also advanced our understanding on multiple gene activation by DUX4.

Structural basis for multiple gene regulation by human DUX4.,Li Y, Wu B, Liu H, Gao Y, Yang C, Chen X, Zhang J, Chen Y, Gu Y, Li J, Ma J, Gan J Biochem Biophys Res Commun. 2018 Oct 12. pii: S0006-291X(18)32202-2. doi:, 10.1016/j.bbrc.2018.10.056. PMID:30322619^[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
↑ Li Y, Wu B, Liu H, Gao Y, Yang C, Chen X, Zhang J, Chen Y, Gu Y, Li J, Ma J, Gan J. Structural basis for multiple gene regulation by human DUX4. Biochem Biophys Res Commun. 2018 Oct 12. pii: S0006-291X(18)32202-2. doi:, 10.1016/j.bbrc.2018.10.056. PMID:30322619 doi:http://dx.doi.org/10.1016/j.bbrc.2018.10.056

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/5zfw"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human DUX4 homeodomains bound to A11G DNA mutant==
-<StructureSection load='5zfw' size='340' side='right' caption='[[5zfw]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+<StructureSection load='5zfw' size='340' side='right'caption='[[5zfw]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5zfw]] is a 3 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=5ZFW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZFW FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5zfw]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZFW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZFW FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DUX4L4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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]] 2.103&#8491;</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=5zfw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zfw OCA], [http://pdbe.org/5zfw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zfw RCSB], [http://www.ebi.ac.uk/pdbsum/5zfw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zfw ProSAT]</span></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=5zfw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zfw OCA], [https://pdbe.org/5zfw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zfw RCSB], [https://www.ebi.ac.uk/pdbsum/5zfw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zfw ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[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 ==
-[[http://www.uniprot.org/uniprot/DU4L4_HUMAN DU4L4_HUMAN]] May be involved in transcriptional regulation.
+[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;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Gan, J H]]
+[[Category: Large Structures]]
-[[Category: Li, Y Y]]
+[[Category: Synthetic construct]]
-[[Category: Wu, B X]]
+[[Category: Gan JH]]
-[[Category: Dna recognition]]
+[[Category: Li YY]]
-[[Category: Dux4]]
+[[Category: Wu BX]]
-[[Category: Homeodomain]]
-[[Category: Transcription-dna complex]]

5zfw

From Proteopedia

Current revision

Crystal structure of human DUX4 homeodomains bound to A11G DNA mutant

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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