Follicle-stimulating hormone (FSH) — a glycoprotein hormone that comprises a common α-subunit and a hormone-specific β-subunit — is key to mammalian reproduction. It binds to the G-protein-coupled receptor FSHR on target cells and induces testicular and ovarian functions. To further understand this interaction, Fan and Hendrickson now describe the 2.9-Å-resolution crystal structure of partially deglycosylated FSH bound to the hormone-binding domain of FSHR (FSHRHB) in Nature.
FSHRHB is mainly composed of leucine-rich repeats, and these were found to wind up to form a curved tube. The central region of FSH binds to the concave face of this tube in a 'hand-clasp' manner. The interaction interface is large (2,600 Å2), with a high charge density, and their data indicate that this mode of binding is of relevance to all mammalian glycoprotein-hormone–receptor complexes. The authors analysed the interface contacts for determinants of specificity, and identified three key interaction sites on FSHR that vary among the different receptors and that contact residues that vary among the different hormones. These interaction sites involve both the α- and β-subunits of the hormones. They also found that, on binding FSHRHB, FSH undergoes a conformational change, which rigidifies the protruding loops that are thought to be involved in receptor activation. In addition, FSH–FSHRHB formed dimers, both in the crystals and at high concentrations in solution, so it will be interesting to determine whether dimerization is required for signal transduction. REFERENCE Fan, Q. R. & Hendrickson, W. A. Structure of human follicle-stimulating hormone in complex with its receptor. Nature 433, 269–277 (2005)
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