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J. Biol. Chem., Vol. 280, Issue 31, 28701-28710, August 5, 2005

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A PHD Finger Motif in the C Terminus of RAG2 Modulates Recombination Activity^*

From the ^aDepartment of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, the ^cDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, the ^dDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, ^fEchelon Biosciences, Inc., Salt Lake City, Utah 84108, the ^gDepartment of Medicinal Chemistry, the University of Utah, Salt Lake City, Utah 84108, and the ^eDepartment of Biological Sciences, Stanford University, Stanford, California 94305

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 -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 non-core 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.

Received for publication, April 29, 2005 , and in revised form, June 15, 2005.

^* This work was supported in part by National Institutes of Health Grants RO1 GM48026 (to M. A. O.), RO1 AI37587 (to G. W.), RO1 AG16674 (to J. Y.), RO1 NS29632 (to G. D. P.), and R44 GM065683 (to C. G. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Fig. S1.

^b These authors contributed equally to this work.

^h To whom correspondence may be addressed. E-mail: gerhard_wagner{at}hms.harvard.edu.

ⁱ To whom correspondence may be addressed. E-mail: oettinger{at}frodo.mgh.harvard.edu.

^j Supported by NIA, National Institutes of Health Grant KO8AG19245 and is a recipient of a Burroughs Wellcome Career Development Award in Biomedical Sciences. To whom correspondence may be addressed: Dept. of Biological Sciences, Stanford University, Stanford, CA 94305. Tel.: 650-736-7639; Fax: 650-725-8309; E-mail: ogozani{at}stanford.edu.

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