期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 18, 期 7, 页码 777-U50出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2070
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资金
- Medical Research Council [MRC_U.1051.04.017(78934), MRC_U.1051.04.019(78936), MRC_U.1379.00.008(61147)]
- National Institute of Health Biomedical Research Centers
- Boehringer Ingelheim
- MRC [MC_U137961147, MC_U105178934, MC_U105184333] Funding Source: UKRI
- Medical Research Council [MC_U105184333, G1000801b, MC_U105178934, G1000801j, MC_U137961147] Funding Source: researchfish
Accurate read-out of chromatin modifications is essential for eukaryotic life. Mutations in the gene encoding X-linked ATRX protein cause a mental-retardation syndrome, whereas wild-type ATRX protein targets pericentric and telomeric heterochromatin for deposition of the histone variant H3.3 by means of a largely unknown mechanism. Here we show that the ADD domain of ATRX, in which most syndrome-causing mutations occur, engages the N-terminal tail of histone H3 through two rigidly oriented binding pockets, one for unmodified Lys4 and the other for di- or trimethylated Lys9. In vivo experiments show this combinatorial readout is required for ATRX localization, with recruitment enhanced by a third interaction through heterochromatin protein-1 (HP1) that also recognizes trimethylated Lys9. The cooperation of ATRX ADD domain and HP1 in chromatin recruitment results in a tripartite interaction that may span neighboring nucleosomes and illustrates how the 'histone-code' is interpreted by a combination of multivalent effector-chromatin interactions.
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