title: Molecular evolution and domain structure of plasminogen-related growth factors (HGF/SF and HGF1/MSP).
abstract: Plasminogen-related growth factors, a new family of polypeptide growth factors with the basic domain organization and mechanism of activation of the blood proteinase plasminogen, include hepatocyte growth factor/scatter factor (HGF/SF), a potent effector of the growth, movement, and differentiation of epithelia and endothelia, and hepatocyte growth factor-like/macrophage stimulating protein (HGF1/MSP), an effector of macrophage chemotaxis and phagocytosis. Phylogeny of the serine proteinase domains and analysis of intron-exon boundaries and kringle sequences indicate that HGF/SF, HGF1/MSP, plasminogen, and apolipoprotein (a) have evolved from a common ancestral gene that consisted of an N-terminal domain corresponding to plasminogen activation peptide (PAP), 3 copies of the kringle domain, and a serine proteinase domain. Models of the N domains of HGF/SF, HGF1/MSP, and plasminogen, characterized by the presence of 4 conserved Cys residues forming a loop in a loop, have been modeled based on disulfide-bond constraints. There is a distinct pattern of charged and hydrophobic residues in the helix-strand-helix motif proposed for the PAP domain of HGF/SF; these may be important for receptor interaction. Three-dimensional structures of the 4 kringle and the serine proteinase domains of HGF/SF were constructed by comparative modeling using the suite of programs COMPOSER and were energy minimized. Docking of a lysine analogue indicates a putative lysine-binding pocket within kringle 2 (and possibly another in kringle 4). The models suggest a mechanism for the formation of a noncovalent HGF/SF homodimer that may be responsible for the activation of the Met receptor. These data provide evidence for the divergent evolution and structural similarity of plasminogen, HGF/SF, and HGF1/MSP, and highlight a new strategy for growth factor evolution, namely the adaptation of a proteolytic enzyme to a role in receptor activation.
authors.affiliation: Department of Crystallography, Birkbeck College, University of London, United Kingdom.
authors.forename: L E
authors.initials: LE
authors.lastname: Donate
authors.forename: E
authors.initials: E
authors.lastname: Gherardi
authors.forename: N
authors.initials: N
authors.lastname: Srinivasan
authors.forename: R
authors.initials: R
authors.lastname: Sowdhamini
authors.forename: S
authors.initials: S
authors.lastname: Aparicio
authors.forename: T L
authors.initials: TL
authors.lastname: Blundell
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001054:Apolipoproteins A / Q000737:chemistry / Q000235:genetics; D005075:Biological Evolution; D003198:Computer Simulation; D005174:Factor XII / Q000737:chemistry / Q000235:genetics; D005796:Genes; D006133:Growth Substances / Q000737:chemistry* / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000737:chemistry* / Q000235:genetics; D018082:Kringles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D010802:Phylogeny; D010958:Plasminogen / Q000737:chemistry* / Q000235:genetics; D010960:Plasminogen Activators / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary; D011516:Prothrombin / Q000737:chemistry / Q000235:genetics; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics
chemical_list: D001054:Apolipoproteins A; D006133:Growth Substances; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D011516:Prothrombin; D005174:Factor XII; D010958:Plasminogen; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D010960:Plasminogen Activators; D012697:Serine Endopeptidases