The ATRX-ADD domain binds to H3 tail peptides and reads the combined methylation state of K4 and K9
The ATRX-ADD domain binds to H3 tail peptides and reads the combined methylation state of K4 and K9
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DOI：
10.1093/hmg/ddr107
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发表时间：
2011-06-01
影响因子：
3.5
通讯作者：
Jeltsch, Albert
中科院分区：
文献类型：
--
作者：
Dhayalan, Arunkumar;Tamas, Raluca;Jeltsch, Albert
ATRX蛋白的突变与α-地中海贫血和精神发育迟滞X连锁综合征（ATR-X）有关。几乎一半的致病突变发生在其ATRX-Dnmt 3-Dnmt 3L（ADD）结构域中。通过采用肽阵列，染色质下拉和肽结合试验，我们显示了特异性结合的ADD域的H3组蛋白尾肽含有H3 K9 me 3。肽结合被H3 K4 me 3和H3 K4 me 2修饰标记的存在破坏，表明ATRX-ADD结构域具有这两个重要标记的组合读数（不存在H3 K4 me 2和H3 K4 me 3，存在H3 K9 me 3）。致病突变减少了ATRX-ADD与H3尾肽的结合。在H3 K9 me 3相互作用中失败的ATRX变体显示细胞中异染色质定位的丧失，这表明ATRX的ADD结构域的染色质靶向功能。H3 K9 me 3结合的破坏可能是ADD结构域中ATRX突变的一般致病性途径，这可以解释ATRX蛋白的这一部分中疾病突变的聚集。
Mutations in the ATRX protein are associated with the alpha-thalassemia and mental retardation X-linked syndrome (ATR-X). Almost half of the disease-causing mutations occur in its ATRX-Dnmt3-Dnmt3L (ADD) domain. By employing peptide arrays, chromatin pull-down and peptide binding assays, we show specific binding of the ADD domain to H3 histone tail peptides containing H3K9me3. Peptide binding was disrupted by the presence of the H3K4me3 and H3K4me2 modification marks indicating that the ATRX-ADD domain has a combined readout of these two important marks (absence of H3K4me2 and H3K4me3 and presence of H3K9me3). Disease-causing mutations reduced ATRX-ADD binding to H3 tail peptides. ATRX variants, which fail in the H3K9me3 interaction, show a loss of heterochromatic localization in cells, which indicates the chromatin targeting function of the ADD domain of ATRX. Disruption of H3K9me3 binding may be a general pathogenicity pathway of ATRX mutations in the ADD domain which may explain the clustering of disease mutations in this part of the ATRX protein.