Structural basis for histone N-terminal recognition by human peptidylarginine deiminase 4
Structural basis for histone N-terminal recognition by human peptidylarginine deiminase 4
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DOI：
10.1073/pnas.0509639103
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发表时间：
2006-04-04
影响因子：
11.1
通讯作者：
Sato, M
中科院分区：
文献类型：
--
作者：
Arita, K;Shimizu, T;Sato, M
组蛋白精氨酸甲基化是一种与基因转录调控相关的翻译后修饰。与其他翻译后修饰不同，甲基化通常被认为是稳定的，且能使组蛋白精氨酸残基去甲基化的酶此前尚未被鉴定出来。然而，最近有研究表明，人肽基精氨酸脱亚氨酶4（PAD4），一种之前已知能在组蛋白中将精氨酸残基转化为瓜氨酸的钙离子依赖性酶，在体内和体外还能将单甲基化的精氨酸残基转化为瓜氨酸。该酶对组蛋白精氨酸残基的瓜氨酸化作用可拮抗组蛋白精氨酸甲基转移酶介导的甲基化，因此这是一种新的翻译后修饰方式，可调节组蛋白精氨酸甲基化水平及基因活性。在此，我们展示了与三个组蛋白N端肽结合的钙离子结合型PAD4突变体的晶体结构，每个组蛋白N端肽由10个氨基酸残基组成，其中包含一个该酶作用的靶标精氨酸残基（H3/精氨酸 - 8、H3/精氨酸 - 17和H4/精氨酸 - 3）。对于每个组蛋白N端肽，该酶在活性位点裂隙附近的分子表面诱导形成一种由五个连续残基组成的类似β - 转角的弯曲构象。其余五个残基则高度无序。该酶通过肽的主链原子识别每个肽，可能存在一种共有识别基序。据认为，该酶识别的肽的序列特异性相当宽泛。这些观察结果为理解组蛋白修饰酶对靶蛋白的识别提供了结构方面的见解，并阐释了PAD4如何靶向组蛋白N端尾部的多个精氨酸位点。
Histone arginine methylation is a posttranslational modification linked to the regulation of gene transcription. Unlike other posttranslational modifications, methylation has generally been regarded as stable, and enzymes that demethylate histone arginine residues have not been identified. However, it has recently been shown that human peptidylarginine deiminase 4 (PAD4), a Ca2+-dependent enzyme previously known to convert arginine residues to citrulline in histones, can also convert monomethylated arginine residues to citrulline both in vivo and in vitro. Citrullination of histone arginine residues by the enzyme antagonizes methylation by histone arginine methyltransferases and is thus a novel posttranslational modification that regulates the level of histone arginine methylation and gene activity. Here we present the crystal structures of a Ca2+-bound PAD4 mutant in complex with three histone N-terminal peptides, each consisting of 10 amino acid residues that include one target arginine residue for the enzyme (H3/Arg-8, H3/Arg-17, and H4/Arg-3). To each histone N-terminal peptide, the enzyme induces a beta-turn-like bent conformation composed of five successive residues at the molecular surface near the active site cleft. The remaining five residues are highly disordered. The enzyme recognizes each peptide through backbone atoms of the peptide with a possible consensus recognition motif. The sequence specificity of the peptide recognized by this enzyme is thought to be fairly broad. These observations provide structural insights into target protein recognition by histone modification enzymes and illustrate how PAD4 can target multiple arginine sites in the histone N-terminal tails.