Details

Autor(en) / Beteiligte

• Gherardi, Ermanno
• Sandin, Sara
• Petoukhov, Maxim V.
• Finch, John
• Youles, Mark E.
• Öfverstedt, Lars-Göran
• Miguel, Ricardo N.
• Blundell, Tom L.
• Vande Woude, George F.
• Skoglund, UIf
• Svergun, Dmitri I.

Titel

Structural Basis of Hepatocyte Growth Factor/Scatter Factor and MET Signalling

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2006-03, Vol.103 (11), p.4046-4051

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2006

Link zum Volltext

Quelle

Electronic Journals Library - Freely accessible e-journals

Beschreibungen/Notizen

• 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 cryoelectron 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 β-propeller domain of MET harboring the loops connecting the β-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.