A molecular model of inducible costimulator protein and three-dimensional analysis of its relation to the CD28 family of T cell-specific costimulatory receptors

Inducible costimulator protein (ICOS) has recently been identified as a new member of the CD28 family of T cell costimulatory molecules. A molecular m odel of the extracellular immunoglobulin-like domain of ICOS was built base d on the structure of CD152, another member of the CD28 family. Despite low sequence identity, ICOS shares consensus residues characteristic of immuno globulin variable-type domains with CD152 and CD28 and also some unique fea tures, suggesting that their three-dimensional structures are more similar to each other than to other proteins belonging to the immunoglobulin superf amily. The ICOS model was used to study sequence conservation in three dime nsions and to compare the distribution of N-linked glycosylation sites in t he extended CD28 family. The limited number of residues outside consensus/c ore positions that are conserved in ICOS and CD28 and/or CD152 are widely d istributed over the extracellular domain. A few residues in CD152 and CD28 that are critical for binding of CD80/CD86 are also conserved in ICOS. Howe ver, the region in ICOS that corresponds to the CD80/CD86 binding site is m asked by N-linked glycosylation. This suggests that this site is not availa ble for binding of CD80/CD86 or other ligands. ICOS has probably diverged e arly from CD28 and CD152 and developed the capacity to recognize ligand(s) other than CD80/CD86, very likely utilizing a different molecular region an d mechanism for binding.