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J. Biol. Chem., Vol. 280, Issue 11, 10149-10155, March 18, 2005

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CD80 Binding Polyproline Helical Peptide Inhibits T Cell Activation^*

Mythily Srinivasan, Debao Lu¶, Rajaraman Eri¶, David D. Brand||, Azizul Haque**, and Janice S. Blum**

From the Department of Oral Pathology, School of Dentistry, and the Department of ^**Microbiology and ^¶Immunology, The Indiana University-Purdue University, Indianapolis, Indiana 46202 and the ^||Department of Medicine, University of Tennessee and Research Service, Department of Veterans Affairs, Memphis, Tennessee 38104

The critical role played by the CD28/CD152-CD80/CD86 costimulatory molecules in mediating T cell activation and suppression provides attractive targets for therapeutic strategies. CD28 and CD152 share a conserved polyproline motif in the ligand-binding region. Similar proline-rich regions in globular domains preferentially adopt a polyproline type II (PP) helical conformation and are involved in transient ^IIprotein-protein interactions. Interestingly, in the human CD80-CD152 complex, Pro¹⁰² of CD152 restricts the preceding proline to PP_II helix in the binding orientation in relation to the shallow binding pocket of CD80. Peptide agents derived from binding sites of receptors that mimic the bioactive conformation have been shown to block receptor-ligand interactions. Contact preferences of the interface amino acids at the protein-protein interaction sites and the propensity of each residue to form PP_II helix were integrated in the design of novel peptide agents referred to as CD80 competitive antagonist peptides. Structural and functional studies suggest potential therapeutic value for select CD80 competitive antagonist peptides.

Received for publication, August 18, 2004 , and in revised form, November 17, 2004.

^* This work was supported in part by the Arthritis National Research Foundation Young Investigator Award (to M. S.). 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.

To whom correspondence should be addressed: Dept. of Oral Pathology, Medicine and Radiology, 1121 W. Michigan St., Indianapolis, IN 46202. Tel.: 317-278-9686; Fax: 317-278-3018; E-mail: mysriniv{at}iupui.edu.

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