PMID- 14528000
OWN - NLM
STAT- MEDLINE
DCOM- 20031204
LR  - 20210107
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 100
IP  - 21
DP  - 2003 Oct 14
TI  - Functional map and domain structure of MET, the product of the c-met 
      protooncogene and receptor for hepatocyte growth factor/scatter factor.
PG  - 12039-44
AB  - 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.
FAU - Gherardi, Ermanno
AU  - Gherardi E
AD  - Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, United Kingdom. 
      egherard@mrc-lmb.cam.ac.uk
FAU - Youles, Mark E
AU  - Youles ME
FAU - Miguel, Ricardo N
AU  - Miguel RN
FAU - Blundell, Tom L
AU  - Blundell TL
FAU - Iamele, Luisa
AU  - Iamele L
FAU - Gough, Julian
AU  - Gough J
FAU - Bandyopadhyay, Abhishek
AU  - Bandyopadhyay A
FAU - Hartmann, Guido
AU  - Hartmann G
FAU - Butler, P Jonathan G
AU  - Butler PJ
LA  - eng
GR  - G9704528/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20031003
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Macromolecular Substances)
RN  - 0 (Recombinant Proteins)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - 9005-49-6 (Heparin)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Amino Acid Sequence
MH  - Binding Sites/genetics
MH  - Heparin/metabolism
MH  - Hepatocyte Growth Factor/chemistry/metabolism
MH  - Humans
MH  - In Vitro Techniques
MH  - Macromolecular Substances
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Protein Conformation
MH  - Protein Folding
MH  - Protein Structure, Tertiary
MH  - Proto-Oncogene Proteins c-met/*chemistry/genetics/*metabolism
MH  - Proto-Oncogenes
MH  - Recombinant Proteins/chemistry/genetics/metabolism
MH  - Sequence Deletion
PMC - PMC218709
EDAT- 2003/10/07 05:00
MHDA- 2003/12/05 05:00
PMCR- 2004/04/14
CRDT- 2003/10/07 05:00
PHST- 2003/10/07 05:00 [pubmed]
PHST- 2003/12/05 05:00 [medline]
PHST- 2003/10/07 05:00 [entrez]
PHST- 2004/04/14 00:00 [pmc-release]
AID - 2034936100 [pii]
AID - 10012039 [pii]
AID - 10.1073/pnas.2034936100 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12039-44. doi: 
      10.1073/pnas.2034936100. Epub 2003 Oct 3.