THE SOLUTION STRUCTURE OF THE N-TERMINAL DOMAIN OF HEPATOCYTE GROWTH-FACTOR REVEALS A POTENTIAL HEPARIN-BINDING SITE

Background: Hepatocyte growth factor (HGF) is a multipotent growth fac tor that transduces a wide range of biological signals, including mito genesis, motogenesis, and morphogenesis, The N-terminal (N) domain of HGF, containing a hairpin-loop region, is important for receptor bindi ng and the potent biological activities of HGF, The N domain is also t he primary binding site for heparin or heparan sulfate, which enhances receptor/ligand oligomerization and modulates receptor-dependent mito genesis. The rational design of artificial modulators of HGF signaling requires a detailed understanding of the structures of HGF and its re ceptor, as well as the role of heparin proteoglycan; this study repres ents the first step towards that goal, Results: We report here a high- resolution solution structure of the N domain of HGF. This first struc ture of HGF reveals a novel folding topology with a distinct pattern o f charge distribution and indicates a possible hepa-in-binding site. C onclusions: The hairpin-loop region of the N domain plays a major role in stabilizing the structure and contributes to a putative heparin-bi nding site, which explains why it is required for biological functions , These results suggest several basic and/or polar residues that may b e important for use in further mutational studies of heparin binding.