title: ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome.
abstract: 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.
authors.affiliation: Division of Newborn Medicine, Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Iwase
authors.forename: Bin
authors.initials: B
authors.lastname: Xiang
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Ghosh
authors.forename: Ting
authors.initials: T
authors.lastname: Ren
authors.forename: Peter W
authors.initials: PW
authors.lastname: Lewis
authors.forename: Jesse C
authors.initials: JC
authors.lastname: Cochrane
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
authors.forename: David J
authors.initials: DJ
authors.lastname: Picketts
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D004265:DNA Helicases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D000075924:X-linked Nuclear Protein
chemical_list: D006570:Heterochromatin; D006657:Histones; D009687:Nuclear Proteins; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein