The plant homeodomain finger of RAG2 recognizes histone H3 methylated at both lysine-4 and arginine-2
The plant homeodomain finger of RAG2 recognizes histone H3 methylated at both lysine-4 and arginine-2
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DOI：
10.1073/pnas.0709170104
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发表时间：
2007-11-27
影响因子：
11.1
通讯作者：
Yang, Wei
中科院分区：
文献类型：
--
作者：
Ramon-Maiques, Santiago;Kuo, Alex J.;Yang, Wei
免疫活化基因（RAG）1和RAG 2共同催化淋巴细胞中V（D）J基因重排，作为抗原受体组装和成熟的第一步。RAG 2在其C末端附近含有植物同源结构域（PHD）（RAG 2-PHD），其识别在赖氨酸4处甲基化的组蛋白H3（H3 K4 me）并影响V（D）J重组。我们在这里报告的晶体结构RAG 2-PHD单独和复杂的五个修改的H3肽。RAG 2-PHD的两个方面是独特的。首先，在不存在修饰肽的情况下，RAG 2-PHD的N-末端肽占据底物结合位点，这可能反映了自身调节机制。第二，与其他H3 K4 me 3结合PHD结构域相反，RAG 2-PHD用Tyr取代与精氨酸2（112）相互作用的羧酸根，导致与H3 K4 me 3的结合被R2的二甲基化增强而不是抑制。在严重联合免疫缺陷（SCID）患者中发现了5个参与组蛋白H3识别的残基突变。RAG 2-PHD结构的破坏似乎导致T和B淋巴细胞的缺失，而不能结合H3 K4 me 3与Omenn综合征有关。这项工作提供了染色质依赖的基因重组的分子基础，并提出了一个单一的蛋白质结构域，同时识别两个不同的组蛋白修饰，揭示了在读出组合组蛋白修饰的复杂性。
Recombination activating gene (RAG) 1 and RAG2 together catalyze V(D)J gene rearrangement in lymphocytes as the first step in the assembly and maturation of antigen receptors. RAG2 contains a plant homeodomain (PHD) near its C terminus (RAG2-PHD) that recognizes histone H3 methylated at lysine 4 (H3K4me) and influences V(D)J recombination. We report here crystal structures of RAG2-PHD alone and complexed with five modified H3 peptides. Two aspects of RAG2-PHD are unique. First, in the absence of the modified peptide, a peptide N-terminal to RAG2-PHD occupies the substrate-binding site, which may reflect an autoregulatory mechanism. Second, in contrast to other H3K4me3-binding PHD domains, RAG2-PHD substitutes a carboxylate that interacts with arginine 2 (112) with a Tyr, resulting in binding to H3K4me3 that is enhanced rather than inhibited by dimethylation of R2. Five residues involved in histone H3 recognition were found mutated in severe combined immunodeficiency (SCID) patients. Disruption of the RAG2-PHD structure appears to lead to the absence of T and B lymphocytes, whereas failure to bind H3K4me3 is linked to Omenn Syndrome. This work provides a molecular basis for chromatin-dependent gene recombination and presents a single protein domain that simultaneously recognizes two distinct histone modifications, revealing added complexity in the read-out of combinatorial histone modifications.