The article by J. Fernando Bazan explores the structural design and molecular evolution of a cytokine receptor superfamily, focusing on hematopoietic factors, interferons, tissue factor, fibronectin, and immunoglobulins. The study highlights the striking homology of binding domains in these receptors, suggesting that the approximately 200-residue binding segment is composed of two distinct folding domains with significant sequence and structural resemblance. These domains are found in tandem within the extracellular segments of interferon-α/β and γ receptors, as well as tissue factor, a membrane receptor for a coagulation protease. The analysis reveals evolutionary links to fibronectin type III structures, approximately 90-amino acid modules typically found in cell surface molecules with adhesive functions. Predictive structural analysis of these shared receptor and fibronectin domains locates seven β-strands in conserved regions, which are modeled to form antiparallel β-sandwiches with a topology similar to immunoglobulin constant domains. This suggests the emergence of an important class of regulatory molecules from primitive adhesive modules. The double-barrel design of the receptors and the spatial clustering of conserved residues indicate a likely binding site for cytokine ligands. The findings have implications for understanding the evolutionary origins of cytokine receptors and their functional diversity.The article by J. Fernando Bazan explores the structural design and molecular evolution of a cytokine receptor superfamily, focusing on hematopoietic factors, interferons, tissue factor, fibronectin, and immunoglobulins. The study highlights the striking homology of binding domains in these receptors, suggesting that the approximately 200-residue binding segment is composed of two distinct folding domains with significant sequence and structural resemblance. These domains are found in tandem within the extracellular segments of interferon-α/β and γ receptors, as well as tissue factor, a membrane receptor for a coagulation protease. The analysis reveals evolutionary links to fibronectin type III structures, approximately 90-amino acid modules typically found in cell surface molecules with adhesive functions. Predictive structural analysis of these shared receptor and fibronectin domains locates seven β-strands in conserved regions, which are modeled to form antiparallel β-sandwiches with a topology similar to immunoglobulin constant domains. This suggests the emergence of an important class of regulatory molecules from primitive adhesive modules. The double-barrel design of the receptors and the spatial clustering of conserved residues indicate a likely binding site for cytokine ligands. The findings have implications for understanding the evolutionary origins of cytokine receptors and their functional diversity.