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 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.
Zhou
H
H
Macromolecular NMR Section, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
Mazzulla
M J
MJ
Kaufman
J D
JD
Stahl
S J
SJ
Wingfield
P T
PT
Rubin
J S
JS
Bottaro
D P
DP
Byrd
R A
RA
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
D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor; D006493:Heparin