Crystal structure of the NK1 fragment of HGF/SF suggests a novel mode for growth factor dimerization and receptor binding

Although ligand-induced receptor dimerization is a common prerequisite for receptor activation, the mode by which different growth factors bind their receptors and cause them to dimerize varies considerably. Here we report th e crystal structure at 2.5 Angstrom resolution of NK1, a receptor-binding f ragment and a natural splice variant of hepatocyte growth factor/scatter fa ctor (HGF/SF). NK1 assembles as a homodimer in the asymmetric unit, reveali ng a novel mode of growth factor dimerization produced by close packing of the N domain of one subunit and the kringle domain of the other, thus bring ing the two linkers in dose proximity. The structure suggests the presence of a binding site for heparan sulfate chains and a mechanism by which the N K1 dimer may engage two receptor molecules through clusters of amino acids located on each protomer and on opposite surfaces of the homodimer. We also report that short (14-mer) heparin fragments effectively dimerize NK1 in s olution, implying that heparan sulfate chains may stabilize the NK1 dimer, These results provide a basis for the agonistic activity of NK1 and have im plications for the mechanism of receptor binding of HCF/SF.