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* Department of Microbiology and Immunology,
Department of Biochemistry,
Seaver Center for Bioinformatics,
Department of Physiology and Biophysics, and
¶ Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461
Inducible costimulator (ICOS) ligand (ICOSL), a B7-related transmembrane glycoprotein with extracellular IgV and IgC domains, binds to ICOS on activated T cells and delivers a positive costimulatory signal for optimal T cell function. Toward determining the structural features of ICOSL crucial for its costimulatory function, the present study shows that ICOSL displays a marked oligomerization potential, resembling more like B7-1 than B7-2. Use of ICOSL constructs lacking either the IgC or IgV domain demonstrates that receptor binding is mediated solely by the IgV domain but requires the IgC domain for maintaining the structural integrity of the protein. To map further the receptor recognition surface on ICOSL, a homology-based protein structure model of the ICOS:ICOSL complex was constructed. Based on predictions from the model, a series of mutations were generated targeting the potential receptor binding surface on ICOSL, and the mutants were tested for their biological function in terms of ICOS binding and T cell costimulation ability. The results provide experimental validation of the model and show that the receptor binding site on ICOSL is constituted chiefly by aromatic/hydrophobic residues. Critical ICOSL residues essential for ICOS binding map to the GFCC'C'' 
-sheet face of the IgV domain and approximately overlap with the B7-1/B7-2 motif(s) that recognize CD28/CTLA-4. Altogether, similar structural features of ICOSL and B7 isoforms suggest a close evolutionary relationship between these costimulatory ligands, yet differences at the same time explain their unique specificity for the cognate binding partners, ICOS and CD28/CTLA-4, respectively.
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.
1 This work was supported by National Institute of Health Grants 5 R01 AI07289 (to S.G.N.) and 5 R01 DK065247 (to S.C.A.), Center for AIDS Research Grant P30AI051519, and a postdoctoral fellowship (to K.C.) from Cancer Research Institute
2 Address correspondence and reprint requests to Dr. Stanley G. Nathenson or Dr. Steven C. Almo, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail address: nathenso{at}aecom.yu.edu or almo{at}aecom.yu.edu
3 Abbreviations used in this paper: ICOS, inducible costimulator; ICOSL, ICOS ligand; FRET, fluorescence resonance energy transfer; pbFRET, photobleaching-based FRET; CFP, cyan fluorescent protein; YFP, yellow fluorescent protein; CHO, Chinese hamster ovary.
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  K. Chattopadhyay, U. A. Ramagopal, M. Brenowitz, S. G. Nathenson, and S. C. Almo Evolution of GITRL immune function: Murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily PNAS, January 15, 2008; 105(2): 635 - 640. [Abstract] [Full Text] [PDF]
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