ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome Journal Article
| Authors: | Iwase, S.; Xiang, B.; Ghosh, S.; Ren, T.; Lewis, P. W.; Cochrane, J. C.; Allis, C. D.; Picketts, D. J.; Patel, D. J.; Li, H.; Shi, Y. |
| Article 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. © 2011 Nature America, Inc. All rights reserved. |
| Keywords: | unclassified drug; nonhuman; binding affinity; protein domain; protein localization; animal cell; mouse; nuclear protein; protein protein interaction; protein binding; amino acid sequence; molecular recognition; nucleotide sequence; histone h3; crystal structure; protein structure; dna methyltransferase; lysine; heterochromatin; chromatin assembly and disassembly; alpha thalassemia; histone methylation; protein atrx add; x linked mental retardation |
| Journal Title: | Nature Structural and Molecular Biology |
| Volume: | 18 |
| Issue: | 7 |
| ISSN: | 1545-9993 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2011-07-01 |
| Start Page: | 769 |
| End Page: | 776 |
| Language: | English |
| DOI: | 10.1038/nsmb.2062 |
| PROVIDER: | scopus |
| PMCID: | PMC3130887 |
| PUBMED: | 21666679 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 17 August 2011" - "CODEN: NSMBC" - "Source: Scopus" |
