Structural basis of hepatocyte growth factor/scatter factor and MET signalling.
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.
Medical Research Council Centre and Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom. egherard@mrc-lmb.cam.ac.uk
Ermanno
E
Gherardi
Sara
S
Sandin
Maxim V
MV
Petoukhov
John
J
Finch
Mark E
ME
Youles
Lars-Göran
LG
Ofverstedt
Ricardo N
RN
Miguel
Tom L
TL
Blundell
George F
GF
Vande Woude
Ulf
U
Skoglund
Dmitri I
DI
Svergun
D000818:Animals; D002460:Cell Line; D020285:Cryoelectron Microscopy; D019281:Dimerization; D004285:Dogs; D017228:Hepatocyte Growth Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D046912:Multiprotein Complexes; D020836:Protein Structure, Quaternary; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012542:Scattering, Radiation; D015398:Signal Transduction; D014965:X-Rays
D046912:Multiprotein Complexes; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met