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- Title
ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome.
- Authors
Shigeki Iwase; Bin Xiang; Ghosh, Sharmistha; Ren, Ting; Lewis, Peter W.; Cochrane, Jesse C.; Allis, C. David; Picketts, David J.; Patel, Dinshaw J.; Haitao Li; Yang Shi
- 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.
- Publication
Nature Structural & Molecular Biology, 2011, Vol 18, Issue 7, p769
- ISSN
1545-9993
- Publication type
Academic Journal
- DOI
10.1038/nsmb.2062