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J. Biol. Chem., Vol. 280, Issue 8, 7218-7227, February 25, 2005

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Structures of APRIL-Receptor Complexes

LIKE BCMA, TACI EMPLOYS ONLY A SINGLE CYSTEINE-RICH DOMAIN FOR HIGH AFFINITY LIGAND BINDING^*

Sarah G. Hymowitz, Darshana R. Patel, Heidi J. A. Wallweber, Steven Runyon, Minhong Yan, JianPing Yin, Stephanie K. Shriver, Nathaniel C. Gordon, Borlan Pan, Nicholas J. Skelton¶, Robert F. Kelley, and Melissa A. Starovasnik||**

From the Departments of Protein Engineering, Molecular Oncology, ^¶Medicinal Chemistry, and ^||Immunology, Genentech, Inc., South San Francisco, California 94080

TACI is a member of the tumor necrosis factor receptor superfamily and serves as a key regulator of B cell function. TACI binds two ligands, APRIL and BAFF, with high affinity and contains two cysteine-rich domains (CRDs) in its extracellular region; in contrast, BCMA and BR3, the other known high affinity receptors for APRIL and BAFF, respectively, contain only a single or partial CRD. However, another form of TACI exists wherein the N-terminal CRD is removed by alternative splicing. We find that this shorter form is capable of ligand-induced cell signaling and that the second CRD alone (TACI_d2) contains full affinity for both ligands. Furthermore, we report the solution structure and alanine-scanning mutagenesis of TACI_d2 along with co-crystal structures of APRIL·TACI_d2 and APRIL·BCMA complexes that together reveal the mechanism by which TACI engages high affinity ligand binding through a single CRD, and we highlight sources of ligand-receptor specificity within the APRIL/BAFF system.

Received for publication, October 14, 2004 , and in revised form, November 9, 2004.

^* 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 Tables S1–S4 and Fig. S1.

^** To whom correspondence should be addressed: Dept. of Protein Engineering, 1 DNA Way, South San Francisco, CA 94080. E-mail: star{at}gene.com.

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