title: The solution structure of the N-terminal domain of hepatocyte growth factor reveals a potential heparin-binding site.
abstract: BACKGROUND
  Hepatocyte growth factor (HGF) is a multipotent growth factor that transduces a wide range of biological signals, including mitogenesis, motogenesis, and morphogenesis. The N-terminal (N) domain of HGF, containing a hairpin-loop region, is important for receptor binding and the potent biological activities of HGF. The N domain is also the primary binding site for heparin or heparan sulfate, which enhances, receptor/ligand oligomerization and modulates receptor-dependent mitogenesis. The rational design of artificial modulators of HGF signaling requires a detailed understanding of the structures of HGF and its receptor, as well as the role of heparin proteoglycan; this study represents the first step towards that goal.
  
  
  RESULTS
  We report here a high-resolution structure of the N domain of HGF. This first structure of HGF reveals a novel folding topology with a distinct pattern of charge distribution and indicates a possible heparin-binding site.
  
  
  CONCLUSIONS
  The hairpin-loop region of the N domain plays a major role in stabilizing the structure and contributes to a putative heparin-binding site, which explains why it is required for biological functions. These results suggest several basic and/or polar residues that may be important for use in further mutational studies of heparin binding.
authors.affiliation: Macromolecular NMR Section, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: M J
authors.initials: MJ
authors.lastname: Mazzulla
authors.forename: J D
authors.initials: JD
authors.lastname: Kaufman
authors.forename: S J
authors.initials: SJ
authors.lastname: Stahl
authors.forename: P T
authors.initials: PT
authors.lastname: Wingfield
authors.forename: J S
authors.initials: JS
authors.lastname: Rubin
authors.forename: D P
authors.initials: DP
authors.lastname: Bottaro
authors.forename: R A
authors.initials: RA
authors.lastname: Byrd
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry; D006493:Heparin / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor; D006493:Heparin