A Molecular Model of Inducible Costimulator Protein and Three-Dimensional Analysis of its Relation to the CD28 Family of T Cell-Specific Costimulatory Receptors

Abstract

Inducible costimulator protein (ICOS) has recently been identified as a new member of the CD28 family of T cell costimulatory molecules. A molecular model of the extracellular immunoglobulin-like domain of ICOS was built based on the structure of CD152, another member of the CD28 family. Despite low sequence identity, ICOS shares consensus residues characteristic of immunoglobulin variable-type domains with CD152 and CD28 and also some unique features, suggesting that their three-dimensional structures are more similar to each other than to other proteins belonging to the immunoglobulin superfamily. The ICOS model was used to study sequence conservation in three dimensions and to compare the distribution of N-linked glycosylation sites in the extended CD28 family. The limited number of residues outside consensus/core positions that are conserved in ICOS and CD28 and/or CD152 are widely distributed over the extracellular domain. A few residues in CD152 and CD28 that are critical for binding of CD80/CD86 are also conserved in ICOS. However, the region in ICOS that corresponds to the CD80/CD86 binding site is masked by N-linked glycosylation. This suggests that this site is not available for binding of CD80/CD86 or other ligands. ICOS has probably diverged early from CD28 and CD152 and developed the capacity to recognize ligand(s) other than CD80/CD86, very likely utilizing a different molecular region and mechanism for binding.