A PHD finger motif in the C terminus of RAG2 modulates recombination activity
A PHD finger motif in the C terminus of RAG2 modulates recombination activity
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DOI：
10.1074/jbc.m504731200
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发表时间：
2005-08-05
影响因子：
4.8
通讯作者：
Gozani, OP
中科院分区：
文献类型：
--
作者：
Elkin, SK;Ivanov, D;Gozani, OP
RAG 1和RAG 2蛋白催化V（D）J重组，并且对于产生抗原受体基因的多样性库和有效的免疫应答是必需的。RAG 2由重组反应所需的“核心”结构域和C-末端非必需或“非核心”区域组成。最近出现的证据表明，非核心区在重组反应中起着关键的调节作用，并且在免疫缺陷患者中已经确定了该区域的突变。在这里，我们提出了RAG 2蛋白的第一个结构数据，使用NMR光谱证明RAG 2的C末端包含一个非经典的PHD指。所有涉及免疫缺陷发展的RAG 2非核心突变均位于PHD指内，位于锌配位残基或邻近参与与信号分子磷酸肌醇结合的结构域表面上的α-螺旋的残基处。疾病和磷酸肌醇结合突变的功能分析揭示了非核心区域内的新的分子内相互作用，并表明PHD指采用两种不同的状态。我们提出了一个模型，其中这些状态之间的平衡调节重组活动。总之，这些数据将PHD指鉴定为RAG 2的新的和功能上重要的结构域。
The RAG1 and RAG2 proteins catalyze V( D) J recombination and are essential for generation of the diverse repertoire of antigen receptor genes and effective immune responses. RAG2 is composed of a "core" domain that is required for the recombination reaction and a C-terminal nonessential or "non-core" region. Recent evidence has emerged arguing that the non-core region plays a critical regulatory role in the recombination reaction, and mutations in this region have been identified in patients with immunodeficiencies. Here we present the first structural data for the RAG2 protein, using NMR spectroscopy to demonstrate that the C terminus of RAG2 contains a noncanonical PHD finger. All of the non-core mutations of RAG2 that are implicated in the development of immunodeficiencies are located within the PHD finger, at either zinc-coordinating residues or residues adjacent to an alpha-helix on the surface of the domain that participates in binding to the signaling molecules, phosphoinositides. Functional analysis of disease and phosphoinositide-binding mutations reveals novel intramolecular interactions within the noncore region and suggests that the PHD finger adopts two distinct states. We propose a model in which the equilibrium between these states modulates recombination activity. Together, these data identify the PHD finger as a novel and functionally important domain of RAG2.