PMID- 16537482
OWN - NLM
STAT- MEDLINE
DCOM- 20060425
LR  - 20220129
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 103
IP  - 11
DP  - 2006 Mar 14
TI  - Structural basis of hepatocyte growth factor/scatter factor and MET signalling.
PG  - 4046-51
AB  - The polypeptide growth factor, hepatocyte growth factor/scatter factor (HGF/SF), 
      shares the multidomain structure and proteolytic mechanism of activation of 
      plasminogen and other complex serine proteinases. HGF/SF, however, has no 
      enzymatic activity. Instead, it controls the growth, morphogenesis, or migration 
      of epithelial, endothelial, and muscle progenitor cells through the receptor 
      tyrosine kinase MET. Using small-angle x-ray scattering and cryo-electron 
      microscopy, we show that conversion of pro(single-chain)HGF/SF into the active 
      two-chain form is associated with a major structural transition from a compact, 
      closed conformation to an elongated, open one. We also report the structure of a 
      complex between two-chain HGF/SF and the MET ectodomain (MET928) with 1:1 
      stoichiometry in which the N-terminal and first kringle domain of HGF/SF contact 
      the face of the seven-blade beta-propeller domain of MET harboring the loops 
      connecting the beta-strands b-c and d-a, whereas the C-terminal serine proteinase 
      homology domain binds the opposite "b" face. Finally, we describe a complex with 
      2:2 stoichiometry between two-chain HGF/SF and a truncated form of the MET 
      ectodomain (MET567), which is assembled around the dimerization interface seen in 
      the crystal structure of the NK1 fragment of HGF/SF and displays the features of 
      a functional, signaling unit. The study shows how the proteolytic mechanism of 
      activation of the complex proteinases has been adapted to cell signaling in 
      vertebrate organisms, offers a description of monomeric and dimeric 
      ligand-receptor complexes, and provides a foundation to the structural basis of 
      HGF/SF-MET signaling.
FAU - Gherardi, Ermanno
AU  - Gherardi E
AD  - Medical Research Council Centre and Laboratory of Molecular Biology, Hills Road, 
      Cambridge CB2 2QH, United Kingdom. egherard@mrc-lmb.cam.ac.uk
FAU - Sandin, Sara
AU  - Sandin S
FAU - Petoukhov, Maxim V
AU  - Petoukhov MV
FAU - Finch, John
AU  - Finch J
FAU - Youles, Mark E
AU  - Youles ME
FAU - Ofverstedt, Lars-Goran
AU  - Ofverstedt LG
FAU - Miguel, Ricardo N
AU  - Miguel RN
FAU - Blundell, Tom L
AU  - Blundell TL
FAU - Vande Woude, George F
AU  - Vande Woude GF
FAU - Skoglund, Ulf
AU  - Skoglund U
FAU - Svergun, Dmitri I
AU  - Svergun DI
LA  - eng
SI  - PDB/2CED
SI  - PDB/2CEE
SI  - PDB/2CEG
SI  - PDB/2CEW
GR  - G9704528/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060306
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 (Multiprotein Complexes)
RN  - 0 (Recombinant Proteins)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cryoelectron Microscopy
MH  - Dimerization
MH  - Dogs
MH  - Hepatocyte Growth Factor/*chemistry/genetics/*metabolism/pharmacology
MH  - Mice
MH  - Models, Molecular
MH  - Multiprotein Complexes
MH  - Protein Structure, Quaternary
MH  - Proto-Oncogene Proteins c-met/chemistry/genetics/*metabolism
MH  - Recombinant Proteins/chemistry/genetics/metabolism/pharmacology
MH  - Scattering, Radiation
MH  - Signal Transduction
MH  - X-Rays
PMC - PMC1449643
COIS- Conflict of interest statement: No conflicts declared.
EDAT- 2006/03/16 09:00
MHDA- 2006/04/28 09:00
PMCR- 2006/09/14
CRDT- 2006/03/16 09:00
PHST- 2006/03/16 09:00 [pubmed]
PHST- 2006/04/28 09:00 [medline]
PHST- 2006/03/16 09:00 [entrez]
PHST- 2006/09/14 00:00 [pmc-release]
AID - 0509040103 [pii]
AID - 1398 [pii]
AID - 10.1073/pnas.0509040103 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4046-51. doi: 
      10.1073/pnas.0509040103. Epub 2006 Mar 6.