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Science 290 (5492): 816-819

Copyright © 2000 by the American Association for the Advancement of Science

Structure of Murine CTLA-4 and Its Role in Modulating T Cell Responsiveness

David A. Ostrov,12 Wuxian Shi,2 Jean-Claude D. Schwartz,1 Steven C. Almo,2* Stanley G. Nathenson13*

The effective regulation of T cell responses is dependent on opposing signals transmitted through two related cell-surface receptors, CD28 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Dimerization of CTLA-4 is required for the formation of high-avidity complexes with B7 ligands and for transmission of signals that attenuate T cell activation. We determined the crystal structure of the extracellular portion of CTLA-4 to 2.0 angstrom resolution. CTLA-4 belongs to the immunoglobulin superfamily and displays a strand topology similar to Valpha domains, with an unusual mode of dimerization that places the B7 binding sites distal to the dimerization interface. This organization allows each CTLA-4 dimer to bind two bivalent B7 molecules and suggests that a periodic arrangement of these components within the immunological synapse may contribute to the regulation of T cell responsiveness.

1 Department of Microbiology and Immunology,
2 Department of Biochemistry,
3 Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461. USA.
*   To whom correspondence should be addressed. E-mail: almo{at}aecom.yu.edu or nathenso{at}aecom.yu.edu


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