Human follitropin: Structure-activity relationships

Studies of human follitropin (hFSH) structure-activity relationships from the author' s laboratory are reviewed. These include mutagenesis studies that complemented the determination of the three dimensIonal structure of hFSH. Despite a large extracellular domain of the FSH receptor and the complexity and size of both the receptor and the hFSH molecule, only a handful of hFSH amino acids are required for high affinity interaction of hFSH with its receptor. These amino acids, contributed by both alpha and beta subunit chains, cluster together in a discrete location, brought together by protein folding and subunit association. Specificity of binding is enabled by the beta subunit, but both subunits contribute to high affinity in­ teractions with receptor. Structural differences exist between the three dimensional structures of glycosylated hFSH and de­ glycosylated placental glycoprotein hormone. Carbohydrate seems unlikely to play a major role in protein structure, ending speculation that glycosylation-dependent protein conformation is the key to signal transduction.