STRUCTURAL DESIGN AND MOLECULAR EVOLUTION OF A CYTOKINE RECEPTOR SUPERFAMILY

A family of cytokine receptors comprising molecules specific for a diverse group of hematopoietic factors and growth hormones has been principally defined by a striking homology of binding domains. This work proposes that the ≃200-residue binding segment of the canonical cytokine receptor is composed of two discrete folding domains that share a significant sequence and structural resemblance. Analogous motifs are found in tandem ≃100-amino acid domains in the extracellular segments of a receptor family formed by the interferon-α/β and -γ receptors and tissue factor, a membrane tether for a coagulation protease. Domains from the receptor supergroup reveal clear evolutionary links to fibronectin type III structures, ≃90-amino acid modules that are typically found in cell surface molecules with adhesive functions. Predictive structural analysis of the shared receptor and fibronectin domains locates seven β-strands in conserved regions of the chain; these strands are modeled to fold into antiparallel β-sandwiches with a topology that is similar to immunoglobulin constant domains. These findings have strong implications for understanding the evolutionary emergence of an important class of regulatory molecules from primitive adhesive modules. In addition, the resulting double-barrel design of the receptors and the spatial clustering of conserved residues suggest a likely binding site for cytokine ligands.