ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome.
ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome.
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DOI：
10.1038/nsmb.2062
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发表时间：
2011-06-12
影响因子：
16.8
通讯作者：
Shi, Yang
中科院分区：
文献类型：
--
作者：
Iwase, Shigeki;Xiang, Bin;Ghosh, Sharmistha;Ren, Ting;Lewis, Peter W.;Cochrane, Jesse C.;Allis, C. David;Picketts, David J.;Patel, Dinshaw J.;Li, Haitao;Shi, Yang
ATR-X（α地中海贫血/智力迟钝，X连锁）综合征是一种导致严重智力残疾的人类先天性疾病。编码ATP依赖性染色质重塑蛋白的ATRX基因突变是该综合征的原因。大约50%的患者错义突变聚集在称为ADD（ATRX-DNMT 3-DNMT 3L，AD-DATRX）的富含半胱氨酸的结构域中，表明其重要性。然而，ADDATRX的功能仍然难以捉摸。在这里，我们确定ADDATRX作为一种新的组蛋白H3结合模块，其结合是促进赖氨酸9三甲基化（H3 K9 me 3），但抑制H3 K4 me 3。ADDATRX与H31- 15 K9 me 3肽结合的共晶结构揭示了非典型的复合H3 K9 me 3结合口袋，其不同于常规的三甲基赖氨酸结合芳族笼。重要的是，H3 K9 me 3-口袋突变体和ATR-X综合征突变体在H3 K9 me 3结合和定位于着丝粒周围异染色质方面都有缺陷。因此，我们发现了一个独特的组蛋白识别机制的ATR-X病因。
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 patient missense mutations are clustered in a cysteine-rich domain termed ADD (ATRX-DNMT3-DNMT3L, AD-DATRX), indicating its importance. However, the function of ADDATRX has remained elusive. Here we identify ADDATRX as a novel histone H3 binding module, whose binding is promoted by lysine 9 trimethylation (H3K9me3) but inhibited by H3K4me3. The co-crystal structures of ADDATRX bound to H31–15K9me3 peptide reveals an atypical composite H3K9me3-binding pocket, which is distinct from the conventional trimethyllysine-binding aromatic cage. Importantly, 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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影响因子：
10.5
作者：
Drane, Pascal;Ouararhni, Khalid;Hamiche, Ali
通讯作者：
Hamiche, Ali
影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
64.5
作者：
GIBBONS, RJ;PICKETTS, DJ;HIGGS, DR
通讯作者：
HIGGS, DR
影响因子：
11.4
作者：
Martens, JHA;O'Sullivan, RJ;Jenuwein, T
通讯作者：
Jenuwein, T