Immunoglobulin fold characteristics of B7–1 (CD80) and B7–2 (CD86)

B7–1 and B7–2 are expressed on antigen‐presenting cells and bind to the CD28 and CTLA‐4 receptors on T cells. These interactions trigger a costimulatory pathway that is essential for T‐cell activation. B7–1 and B7–2 are members of the immunoglobulin superfamily (IgSF) and, despite sharing common function, have only limited sequence similarity. The B7–1 extracellular region was previously subdivided into 2 IgSF domains, an N‐terminal V(ariable)‐like domain, followed by a C(onstant)‐like domain. We recently reported that the V‐like domains of B7–1 and B7–2 share some significant sequence similarities with 3 major histocompatibility complex (MHC)‐encoded members of the IgSF. We have now applied inverse folding methodology to assess the compatibility of the B7–1 and B7–2 extracellular region sequences with currently available 3‐dimensional structures. In these calculations, the sequences of the N‐terminal (V‐like) domains in B7–1 and B7–2 were not compatible with known structures, including the IgSF V‐set. In contrast, the sequences of the C‐like domains were compatible with IgSF C‐set structures and were best recognized by the β2‐microglobulin (β2m) domain of MHC Class I. A sequence comparison of the C‐like domains in the B7 molecules showed that 11 of 17 rigorously conserved residues in B7–1 and B7–2 are not IgSF C‐1 set consensus residues. When mapped onto the corresponding positions of the β2m structure, the conserved residues in B7 cluster on the surface, where they may interact with the B7 V‐like domain or other molecules.