B7-1 and B7-2 are type I membrane proteins with an extracellular domain consisting of one immunoglobulin V (IgV)-like and one IgC-like domain, followed by a transmembrane anchor and short cyto-

plasmic tail. Mature B7-1 has 254 amino acids, is heavily glycosylated, and has a molecular weight of 45-70 kDa. Mature B7-2 has 304 amino acids, is heavily glycosylated, and has a molecular weight of 60-100 kDa. The genes for both B7-1 and B7-2 are located on human chromosome 3q21 and mouse chromosome 16B5.

Both B7-1 and B7-2 are counter-receptors for CD28, expressed on resting as well as activated T cells, and for CTLA4 (CD152), expressed on activated T cells. Dimeric CD28 has equivalent low avidity for both B7-1 and B7-2 (2400 nM) but dimeric CTLA-4 has a greater than 400-fold higher avidity for B7-1 than B7-2 (1 and 4 nM). Both B7-1 and B7-2 have very fast on/fast off rates but the binding kinetics differ, with B7-1 binding and dissociating more slowly.

B7-1 and B7-2 bind to the same general region on CD28 and CTLA4 but the amino acids critical for B7-1 or B7-2 binding are different. The CDR3 loop of the IgV-like domain of CD28 and CLTA4 contains a conserved MYPPPY motif (amino acids 99-104) important for both B7-1 and B7-2 binding. Tyrosine 104 is critical for binding to both B7-1 and B7-2. Residues 100, 99, 101 and 102 are important for differential binding of B7-1 versus B7-2.

Though B7-1 and B7-2 have similar structures, their extracellular domains have only 27% amino acid identity and other regions are even less conserved. B7-1 and B7-2 function well across species, suggesting that the ligand binding site is highly conserved. Conserved residues on the GFCC'C" face of the B7 IgV domain and on the ABED face of the B7 IgC domain are important for binding. The eight N-linked glycosylation sites of B7 are on the opposite side from the B7/CD28 interaction surface and do not contribute to binding. Thus, CD28 and CTLA4 use sequences in their CDR3 and CDR1 regions, much like antibodies, to bind to a surface on the side of the B7 IgV and IgC domains.

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