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PDBsum entry 2ced
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Growth factor
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PDB id
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2ced
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References listed in PDB file
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Key reference
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Title
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Structural basis of hepatocyte growth factor/scatter factor and met signalling.
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Authors
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E.Gherardi,
S.Sandin,
M.V.Petoukhov,
J.Finch,
M.E.Youles,
L.G.Ofverstedt,
R.N.Miguel,
T.L.Blundell,
G.F.Vande woude,
U.Skoglund,
D.I.Svergun.
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Ref.
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Proc Natl Acad Sci U S A, 2006,
103,
4046-4051.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
percentage match of
91%.
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Abstract
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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.
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Figure 1.
Fig. 1. Domain structure and biological activity of the
three main proteins used in this study. (A) Domain structure.
(B) SDS/PAGE under reducing conditions. (C–E) Typical
appearance of colonies of MDCK cells under standard culture
conditions (C) or after addition of single-chain (D) or
two-chain (E) HGF/SF at the concentrations indicated. sc-SF,
single HGF/SF; tc-SF, two-chain HGF/SF.
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Figure 4.
Fig. 4. The 1:1 complex formed by two-chain HGF/SF and
MET928. (A and B) SAXS of the two-chain HGF/SF-MET928 complex.
(A) Scattering curve and ab initio model (28). (B) Rigid body
model (29) (MET928 in gray, two-chain HGF/SF in red). (C–K)
CET of the two-chain HGF/SF-MET928 complex. (C–E) Three views
of a typical 3D reconstruction. (F–H) Corresponding images
after low pass filtering. (I–K) Docking of the SAXS model of
the two-chain HGF/SF-MET928 complex into the EM density envelope
(MET  -propeller in blue; sp
domain of HGF/SF in green; other HGF/SF domains in yellow);
sc-SF, single-chain HGF/SF; tc-SF, two-chain HGF/SF.
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