Functional map and domain structure of MET, the product of the c-met protooncogene and receptor for hepatocyte growth factor/scatter factor

E. Gherardi, M. E. Youles, R. N. Miguel, T. L. Blundell, L. Iamele, J. Gough, A. Bandyopadhyay, G. Hartmann, P. J. Butler

Research output: Contribution to journalArticle (Academic Journal)

131 Citations (Scopus)

Abstract

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.
Translated title of the contributionFunctional map and domain structure of MET, the product of the c-met protooncogene and receptor for hepatocyte growth factor/scatter factor
Original languageEnglish
Article number12039-12044
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100 (21)
Publication statusPublished - 2003

Bibliographical note

Other identifier: 1040018

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