Crystal structure of the NK1 fragment of human hepatocyte growth factor at 2.0 A resolution.
BACKGROUND
Hepatocyte growth factor (HGF) is a mitogen for hepatocytes and has also been implicated as an epithelial morphogen in tumor invasion. HGF activates its specific cellular receptor, c-met, through an aggregation mechanism potentiated by heparan sulfate glycosaminoglycans. HGF consists of an N-terminal (N) domain, four kringle domains (the first of which carries receptor-binding determinants), and an inactive serine-protease-like domain. NK1, a naturally occurring fragment of HGF, acts as an antagonist of HGF in the absence of heparin.


RESULTS
The N domain of NK1 consists of a central five-stranded antiparallel beta sheet flanked by an alpha helix and a two-stranded beta ribbon. The overall N domain structure in the context of the NK1 fragment is similar to the structure of the isolated domain; two lysines and an arginine residue coordinate a bound sulfate ion. The NK1 kringle domain is homologous to kringle 4 from plasminogen, except that the lysine-binding pocket is altered by the insertion of a glycine residue. Here, a HEPES molecule is bound in the pocket. The asymmetric unit of the crystal contains a 'head-to-tail' NK1 dimer. We use this dimer to propose a model of the NK2 fragment of HGF.


CONCLUSIONS
A cluster of exposed lysine and arginine residues in or near the hairpin-loop region of the N domain might form part of the NK1 heparin-binding site. In our NK2 model, both kringle domains pack loosely against the N domain, and a long, positively charged groove lines the interface. This groove might be involved in glycosaminoglycan binding. The HGF receptor-binding determinants are clustered near the binding pocket of the first kringle domain, opposite the N domain.
Ultsch
M
M
Department of Protein Engineering Genentech, Inc. 460 Point San Bruno Boulevard South San Francisco, CA 94080, USA.
Lokker
N A
NA
Godowski
P J
PJ
de Vos
A M
AM
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D019281:Dimerization; D017228:Hepatocyte Growth Factor / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D018082:Kringles; D008969:Molecular Sequence Data; D011487:Protein Conformation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met