ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome

S Iwase, B Xiang, S Ghosh, T Ren, PW Lewis… - Nature structural & …, 2011 - nature.com
S Iwase, B Xiang, S Ghosh, T Ren, PW Lewis, JC Cochrane, CD Allis, DJ Picketts, DJ Patel
Nature structural & molecular biology, 2011nature.com
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, ADDATRX), whose function has
remained elusive. Here we identify ADDATRX as a previously unknown histone H3–binding …
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, ADDATRX), whose function has remained elusive. Here we identify ADDATRX 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 ADDATRX bound to H31–15K9me3 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.
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