A stimulating structure

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)

Robust rings

For chromosomes to be accurately segregated to daughter cells, spindle microtubules must become attached to kinetochores — multiprotein complexes that assemble on centromeric DNA. One kinetochore component in Saccharomyces cerevisiae is the ten-subunit DASH complex, and mutations in this complex disrupt kinetochore-microtubule attachments and destabilize the spindle. New insights into this complex are now provided by Harrison and colleagues in Nature Structural & Molecular Biology.

They co-expressed the entire yeast complex in Escherichia coli, and purified a ∼210-kDa decamer that contained one copy of each subunit. The hydrodynamic properties of recombinant DASH indicated that it is representative of the in vivo complex. Electron microscopy (EM) studies showed that DASH is a globular complex, which oligomerizes to form closed rings and paired helices only in the presence of microtubules. These rings/helices encircle microtubules, although, in the EM images, there seemed to be a gap between the rings/helices and the microtubule. Harrison and co-workers therefore propose that extended polypeptides might project from DASH to contact the microtubule (such extensions might not be visible in these images). In addition, as helices only form at high DASH concentrations, they propose that it is the rings that are biologically relevant, and that rings are used to ensure that the kinetochores stay attached to dynamic microtubules. REFERENCE Miranda, J. L. et al. The yeast DASH complex forms closed rings on microtubules. Nature Struct. Mol. Biol. 12, 138–143 (2005)