Functional map and domain structure of MET, the product of the c-met protooncogene and receptor for hepatocyte growth factor/scatter factor.
Little is known about the large ectodomain of MET, the product of the c-met protooncogene and receptor for hepatocyte growth factor/scatter factor (HGF/SF). Here, we establish by deletion mutagenesis that the HGF/SF and heparin-binding sites of MET are contained within a large N-terminal domain spanning the alpha-chain (amino acids 25-307) and the first 212 amino acids of the beta-chain (amino acids 308-519). Neither the cystine-rich domain (amino acids 520-561) nor the C-terminal half of MET (amino acids 562-932) bind HGF/SF or heparin directly. The MET ectodomain, which behaves as a rod-shaped monomer with a large Stokes radius in solution, binds HGF/SF in the absence or presence of heparin, and forms a stable HGF/SF-heparin-MET complex with 1:1:1 stoichiometry. We also show that the ligand-binding domain adopts a beta-propeller fold, which is similar to the N-terminal domain of alphaV integrin, and that the C-terminal half contains four Ig domains (amino acids 563-654, 657-738, 742-836, and 839-924) of the unusual structural E set, which could be modeled on bacterial enzymes. Our studies provide 3D models and a functional map of the MET ectodomain. They have broad implications for structure-function of the MET receptor and the related semaphorin and plexin proteins.
Gherardi
Ermanno
E
Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, United Kingdom. egherard@mrc-lmb.cam.ac.uk
Youles
Mark E
ME
Miguel
Ricardo N
RN
Blundell
Tom L
TL
Iamele
Luisa
L
Gough
Julian
J
Bandyopadhyay
Abhishek
A
Hartmann
Guido
G
Butler
P Jonathan G
PJ
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D006493:Heparin / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011519:Proto-Oncogenes; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
D046911:Macromolecular Substances; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D006493:Heparin; D019859:Proto-Oncogene Proteins c-met