期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 280, 期 31, 页码 28701-28710出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M504731200
关键词
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资金
- NIAID NIH HHS [R01 AI37587] Funding Source: Medline
- NIA NIH HHS [KO8AG19245, R01 AG16674] Funding Source: Medline
- NIGMS NIH HHS [R44 GM065683, R01 GM48026] Funding Source: Medline
- NINDS NIH HHS [R01 NS29632] Funding Source: Medline
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.
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