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6u81

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Revision as of 10:33, 26 February 2020

Crystal Structure of the Double Homeodomain of DUX4 in Complex with a DNA aptamer

Structural highlights

6u81 is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
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

Aberrant expression of the transcription factor double homeobox protein 4 (DUX4) can lead to a number of diseases including facio-scapulo-humeral muscular dystrophy (FSHD), acute lymphoblastic leukemia, and sarcomas. Inhibition of DUX4 may represent a therapeutic strategy for these diseases. By applying Systematic Evolution of Ligands by EXponential Enrichment (SELEX), we identified aptamers against DUX4 with specific secondary structural elements conveying high affinity to DUX4 as assessed by fluorescence resonance energy transfer and fluorescence polarization techniques. Sequences analysis of these aptamers revealed the presence of two consensus DUX4 motifs in a reverse complementary fashion forming hairpins interspersed with bulge loops at distinct positions that enlarged the binding surface with the DUX4 protein, as determined by crystal structure analysis. We demonstrate that insertion of specific structural elements into transcription factor binding oligonucleotides can enhance specificity and affinity.

DNA aptamers against the DUX4 protein reveal novel therapeutic implications for FSHD.,Klingler C, Ashley J, Shi K, Stiefvater A, Kyba M, Sinnreich M, Aihara H, Kinter J FASEB J. 2020 Feb 5. doi: 10.1096/fj.201902696. PMID:32020675^[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
↑ Klingler C, Ashley J, Shi K, Stiefvater A, Kyba M, Sinnreich M, Aihara H, Kinter J. DNA aptamers against the DUX4 protein reveal novel therapeutic implications for FSHD. FASEB J. 2020 Feb 5. doi: 10.1096/fj.201902696. PMID:32020675 doi:http://dx.doi.org/10.1096/fj.201902696

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/6u81"

@@ Line 3: / Line 3: @@
 <StructureSection load='6u81' size='340' side='right'caption='[[6u81]], [[Resolution|resolution]] 2.34&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6u81]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U81 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6U81 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6u81]] 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=6U81 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6U81 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></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=6u81 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u81 OCA], [http://pdbe.org/6u81 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6u81 RCSB], [http://www.ebi.ac.uk/pdbsum/6u81 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6u81 ProSAT]</span></td></tr>
 </table>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Aihara, H]]

6u81

From Proteopedia

Revision as of 10:33, 26 February 2020

Crystal Structure of the Double Homeodomain of DUX4 in Complex with a DNA aptamer

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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