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{{STRUCTURE_3qlc|  PDB=3qlc  |  SCENE=  }}
==Complex structure of ATRX ADD domain bound to unmodified H3 1-15 peptide==
===Complex structure of ATRX ADD domain bound to unmodified H3 1-15 peptide===
<StructureSection load='3qlc' size='340' side='right' caption='[[3qlc]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 
== Structural highlights ==
==Disease==
<table><tr><td colspan='2'>[[3qlc]] is a 4 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=3QLC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QLC FirstGlance]. <br>
[[http://www.uniprot.org/uniprot/ATRX_HUMAN ATRX_HUMAN]] Defects in ATRX are the cause of alpha-thalassemia mental retardation syndrome X-linked (ATRX) [MIM:[http://omim.org/entry/301040 301040]]. ATR-X is an X-linked disorder comprising severe psychomotor retardation, facial dysmorphism, urogenital abnormalities, and alpha-thalassemia. An essential phenotypic trait are hemoglobin H erythrocyte inclusions.<ref>PMID:8968741</ref><ref>PMID:7697714</ref><ref>PMID:9043863</ref><ref>PMID:9326931</ref><ref>PMID:10660327</ref><ref>PMID:10417298</ref><ref>PMID:10204841</ref><ref>PMID:10995512</ref><ref>PMID:12116232</ref><ref>PMID:16955409</ref> Defects in ATRX are the cause of mental retardation syndromic X-linked with hypotonic facies syndrome type 1 (MRXSHF1) [MIM:[http://omim.org/entry/309580 309580]]; also called Carpenter-Waziri syndrome (CWS), Juberg-Marsidi syndrome (JMS), Smith-Fineman-Myers syndrome type 1 (SFM1). Clinical features include severe mental retardation, dysmorphic facies, and a highly skewed X-inactivation pattern in carrier women. Other more variable features include hypogonadism, deafness, renal anomalies, and mild skeletal defects.<ref>PMID:10751095</ref><ref>PMID:8630485</ref><ref>PMID:10398237</ref><ref>PMID:11050622</ref><ref>PMID:16222662</ref><ref>PMID:15565397</ref> Defects in ATRX are a cause of alpha-thalassemia myelodysplasia syndrome (ATMDS) [MIM:[http://omim.org/entry/300448 300448]]. In this disorder, alpha-thalassemia occurs as an acquired abnormality in association with a multilineage myelodysplasia.<ref>PMID:12858175</ref>  
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><br>
 
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ql9|3ql9]], [[3qla|3qla]], [[3qln|3qln]]</td></tr>
==Function==
<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ATRX, RAD54L, XH2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA_helicase DNA helicase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.4.12 3.6.4.12] </span></td></tr>
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3qlc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qlc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qlc RCSB], [http://www.ebi.ac.uk/pdbsum/3qlc PDBsum]</span></td></tr>
<table>
== Disease ==
[[http://www.uniprot.org/uniprot/ATRX_HUMAN ATRX_HUMAN]] Defects in ATRX are the cause of alpha-thalassemia mental retardation syndrome X-linked (ATRX) [MIM:[http://omim.org/entry/301040 301040]]. ATR-X is an X-linked disorder comprising severe psychomotor retardation, facial dysmorphism, urogenital abnormalities, and alpha-thalassemia. An essential phenotypic trait are hemoglobin H erythrocyte inclusions.<ref>PMID:8968741</ref> <ref>PMID:7697714</ref> <ref>PMID:9043863</ref> <ref>PMID:9326931</ref> <ref>PMID:10660327</ref> <ref>PMID:10417298</ref> <ref>PMID:10204841</ref> <ref>PMID:10995512</ref> <ref>PMID:12116232</ref> <ref>PMID:16955409</ref>   Defects in ATRX are the cause of mental retardation syndromic X-linked with hypotonic facies syndrome type 1 (MRXSHF1) [MIM:[http://omim.org/entry/309580 309580]]; also called Carpenter-Waziri syndrome (CWS), Juberg-Marsidi syndrome (JMS), Smith-Fineman-Myers syndrome type 1 (SFM1). Clinical features include severe mental retardation, dysmorphic facies, and a highly skewed X-inactivation pattern in carrier women. Other more variable features include hypogonadism, deafness, renal anomalies, and mild skeletal defects.<ref>PMID:10751095</ref> <ref>PMID:8630485</ref> <ref>PMID:10398237</ref> <ref>PMID:11050622</ref> <ref>PMID:16222662</ref> <ref>PMID:15565397</ref>   Defects in ATRX are a cause of alpha-thalassemia myelodysplasia syndrome (ATMDS) [MIM:[http://omim.org/entry/300448 300448]]. In this disorder, alpha-thalassemia occurs as an acquired abnormality in association with a multilineage myelodysplasia.<ref>PMID:12858175</ref>
== Function ==
[[http://www.uniprot.org/uniprot/ATRX_HUMAN ATRX_HUMAN]] Could be a global transcriptional regulator. Modifies gene expression by affecting chromatin. May be involved in brain development and facial morphogenesis.  
[[http://www.uniprot.org/uniprot/ATRX_HUMAN ATRX_HUMAN]] Could be a global transcriptional regulator. Modifies gene expression by affecting chromatin. May be involved in brain development and facial morphogenesis.  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
ATR-X (alpha-thalassemia/mental retardation, X-linked) syndrome is a human congenital disorder that causes severe intellectual disabilities. Mutations in the ATRX gene, which encodes an ATP-dependent chromatin-remodeler, are responsible for the syndrome. Approximately 50% of the missense mutations in affected persons are clustered in a cysteine-rich domain termed ADD (ATRX-DNMT3-DNMT3L, ADD(ATRX)), whose function has remained elusive. Here we identify ADD(ATRX) as a previously unknown histone H3-binding module, whose binding is promoted by lysine 9 trimethylation (H3K9me3) but inhibited by lysine 4 trimethylation (H3K4me3). The cocrystal structure of ADD(ATRX) bound to H3(1-15)K9me3 peptide reveals an atypical composite H3K9me3-binding pocket, which is distinct from the conventional trimethyllysine-binding aromatic cage. Notably, H3K9me3-pocket mutants and ATR-X syndrome mutants are defective in both H3K9me3 binding and localization at pericentromeric heterochromatin; thus, we have discovered a unique histone-recognition mechanism underlying the ATR-X etiology.


==About this Structure==
ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome.,Iwase S, Xiang B, Ghosh S, Ren T, Lewis PW, Cochrane JC, Allis CD, Picketts DJ, Patel DJ, Li H, Shi Y Nat Struct Mol Biol. 2011 Jun 12;18(7):769-76. doi: 10.1038/nsmb.2062. PMID:21666679<ref>PMID:21666679</ref>
[[3qlc]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QLC OCA].
 
==See Also==
*[[Helicase|Helicase]]


==Reference==
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
<references group="xtra"/><references/>
</div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: DNA helicase]]
[[Category: DNA helicase]]
[[Category: Homo sapiens]]
[[Category: Human]]
[[Category: Li, H.]]
[[Category: Li, H.]]
[[Category: Patel, D J.]]
[[Category: Patel, D J.]]

Revision as of 16:14, 18 May 2014

Complex structure of ATRX ADD domain bound to unmodified H3 1-15 peptideComplex structure of ATRX ADD domain bound to unmodified H3 1-15 peptide

Structural highlights

3qlc is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:3ql9, 3qla, 3qln
Gene:ATRX, RAD54L, XH2 (HUMAN)
Activity:DNA helicase, with EC number 3.6.4.12
Resources:FirstGlance, OCA, RCSB, PDBsum

Disease

[ATRX_HUMAN] Defects in ATRX are the cause of alpha-thalassemia mental retardation syndrome X-linked (ATRX) [MIM:301040]. ATR-X is an X-linked disorder comprising severe psychomotor retardation, facial dysmorphism, urogenital abnormalities, and alpha-thalassemia. An essential phenotypic trait are hemoglobin H erythrocyte inclusions.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Defects in ATRX are the cause of mental retardation syndromic X-linked with hypotonic facies syndrome type 1 (MRXSHF1) [MIM:309580]; also called Carpenter-Waziri syndrome (CWS), Juberg-Marsidi syndrome (JMS), Smith-Fineman-Myers syndrome type 1 (SFM1). Clinical features include severe mental retardation, dysmorphic facies, and a highly skewed X-inactivation pattern in carrier women. Other more variable features include hypogonadism, deafness, renal anomalies, and mild skeletal defects.[11] [12] [13] [14] [15] [16] Defects in ATRX are a cause of alpha-thalassemia myelodysplasia syndrome (ATMDS) [MIM:300448]. In this disorder, alpha-thalassemia occurs as an acquired abnormality in association with a multilineage myelodysplasia.[17]

Function

[ATRX_HUMAN] Could be a global transcriptional regulator. Modifies gene expression by affecting chromatin. May be involved in brain development and facial morphogenesis.

Publication Abstract from PubMed

ATR-X (alpha-thalassemia/mental retardation, X-linked) syndrome is a human congenital disorder that causes severe intellectual disabilities. Mutations in the ATRX gene, which encodes an ATP-dependent chromatin-remodeler, are responsible for the syndrome. Approximately 50% of the missense mutations in affected persons are clustered in a cysteine-rich domain termed ADD (ATRX-DNMT3-DNMT3L, ADD(ATRX)), whose function has remained elusive. Here we identify ADD(ATRX) as a previously unknown histone H3-binding module, whose binding is promoted by lysine 9 trimethylation (H3K9me3) but inhibited by lysine 4 trimethylation (H3K4me3). The cocrystal structure of ADD(ATRX) bound to H3(1-15)K9me3 peptide reveals an atypical composite H3K9me3-binding pocket, which is distinct from the conventional trimethyllysine-binding aromatic cage. Notably, H3K9me3-pocket mutants and ATR-X syndrome mutants are defective in both H3K9me3 binding and localization at pericentromeric heterochromatin; thus, we have discovered a unique histone-recognition mechanism underlying the ATR-X etiology.

ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome.,Iwase S, Xiang B, Ghosh S, Ren T, Lewis PW, Cochrane JC, Allis CD, Picketts DJ, Patel DJ, Li H, Shi Y Nat Struct Mol Biol. 2011 Jun 12;18(7):769-76. doi: 10.1038/nsmb.2062. PMID:21666679[18]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Picketts DJ, Higgs DR, Bachoo S, Blake DJ, Quarrell OW, Gibbons RJ. ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome. Hum Mol Genet. 1996 Dec;5(12):1899-907. PMID:8968741
  2. ↑ Gibbons RJ, Picketts DJ, Villard L, Higgs DR. Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome). Cell. 1995 Mar 24;80(6):837-45. PMID:7697714
  3. ↑ Villard L, Lacombe D, Fontes M. A point mutation in the XNP gene, associated with an ATR-X phenotype without alpha-thalassemia. Eur J Hum Genet. 1996;4(6):316-20. PMID:9043863
  4. ↑ Gibbons RJ, Bachoo S, Picketts DJ, Aftimos S, Asenbauer B, Bergoffen J, Berry SA, Dahl N, Fryer A, Keppler K, Kurosawa K, Levin ML, Masuno M, Neri G, Pierpont ME, Slaney SF, Higgs DR. Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain. Nat Genet. 1997 Oct;17(2):146-8. PMID:9326931 doi:10.1038/ng1097-146
  5. ↑ Fichera M, Romano C, Castiglia L, Failla P, Ruberto C, Amata S, Greco D, Cardoso C, Fontes M, Ragusa A. New mutations in XNP/ATR-X gene: a further contribution to genotype/phenotype relationship in ATR/X syndrome. Mutations in brief no. 176. Online. Hum Mutat. 1998;12(3):214. PMID:10660327
  6. ↑ Lossi AM, Millan JM, Villard L, Orellana C, Cardoso C, Prieto F, Fontes M, Martinez F. Mutation of the XNP/ATR-X gene in a family with severe mental retardation, spastic paraplegia and skewed pattern of X inactivation: demonstration that the mutation is involved in the inactivation bias. Am J Hum Genet. 1999 Aug;65(2):558-62. PMID:10417298 doi:10.1086/302499
  7. ↑ Villard L, Bonino MC, Abidi F, Ragusa A, Belougne J, Lossi AM, Seaver L, Bonnefont JP, Romano C, Fichera M, Lacombe D, Hanauer A, Philip N, Schwartz C, Fontes M. Evaluation of a mutation screening strategy for sporadic cases of ATR-X syndrome. J Med Genet. 1999 Mar;36(3):183-6. PMID:10204841
  8. ↑ Wada T, Kubota T, Fukushima Y, Saitoh S. Molecular genetic study of japanese patients with X-linked alpha-thalassemia/mental retardation syndrome (ATR-X). Am J Med Genet. 2000 Sep 18;94(3):242-8. PMID:10995512
  9. ↑ Yntema HG, Poppelaars FA, Derksen E, Oudakker AR, van Roosmalen T, Jacobs A, Obbema H, Brunner HG, Hamel BC, van Bokhoven H. Expanding phenotype of XNP mutations: mild to moderate mental retardation. Am J Med Genet. 2002 Jul 1;110(3):243-7. PMID:12116232 doi:10.1002/ajmg.10446
  10. ↑ Badens C, Martini N, Courrier S, DesPortes V, Touraine R, Levy N, Edery P. ATRX syndrome in a girl with a heterozygous mutation in the ATRX Zn finger domain and a totally skewed X-inactivation pattern. Am J Med Genet A. 2006 Oct 15;140(20):2212-5. PMID:16955409 doi:10.1002/ajmg.a.31400
  11. ↑ Villard L, Fontes M, Ades LC, Gecz J. Identification of a mutation in the XNP/ATR-X gene in a family reported as Smith-Fineman-Myers syndrome. Am J Med Genet. 2000 Mar 6;91(1):83-5. PMID:10751095
  12. ↑ Villard L, Gecz J, Mattei JF, Fontes M, Saugier-Veber P, Munnich A, Lyonnet S. XNP mutation in a large family with Juberg-Marsidi syndrome. Nat Genet. 1996 Apr;12(4):359-60. PMID:8630485 doi:http://dx.doi.org/10.1038/ng0496-359
  13. ↑ Abidi F, Schwartz CE, Carpenter NJ, Villard L, Fontes M, Curtis M. Carpenter-Waziri syndrome results from a mutation in XNP. Am J Med Genet. 1999 Jul 30;85(3):249-51. PMID:10398237
  14. ↑ Stevenson RE, Abidi F, Schwartz CE, Lubs HA, Holmes LB. Holmes-Gang syndrome is allelic with XLMR-hypotonic face syndrome. Am J Med Genet. 2000 Oct 23;94(5):383-5. PMID:11050622
  15. ↑ Leahy RT, Philip RK, Gibbons RJ, Fisher C, Suri M, Reardon W. Asplenia in ATR-X syndrome: a second report. Am J Med Genet A. 2005 Nov 15;139(1):37-9. PMID:16222662 doi:10.1002/ajmg.a.30990
  16. ↑ Wieland I, Sabathil J, Ostendorf A, Rittinger O, Ropke A, Winnepenninckx B, Kooy F, Holinski-Feder E, Wieacker P. A missense mutation in the coiled-coil motif of the HP1-interacting domain of ATR-X in a family with X-linked mental retardation. Neurogenetics. 2005 Feb;6(1):45-7. PMID:15565397 doi:10.1007/s10048-004-0190-3
  17. ↑ Gibbons RJ, Pellagatti A, Garrick D, Wood WG, Malik N, Ayyub H, Langford C, Boultwood J, Wainscoat JS, Higgs DR. Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS). Nat Genet. 2003 Aug;34(4):446-9. PMID:12858175 doi:10.1038/ng1213
  18. ↑ Iwase S, Xiang B, Ghosh S, Ren T, Lewis PW, Cochrane JC, Allis CD, Picketts DJ, Patel DJ, Li H, Shi Y. ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome. Nat Struct Mol Biol. 2011 Jun 12;18(7):769-76. doi: 10.1038/nsmb.2062. PMID:21666679 doi:http://dx.doi.org/10.1038/nsmb.2062

3qlc, resolution 2.50Å

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