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PDBsum entry 2uzy
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Signaling protein/receptor
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PDB id
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2uzy
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References listed in PDB file
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Key reference
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Title
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Structure of the human receptor tyrosine kinase met in complex with the listeria invasion protein inlb.
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Authors
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H.H.Niemann,
V.Jäger,
P.J.Butler,
J.Van den heuvel,
S.Schmidt,
D.Ferraris,
E.Gherardi,
D.W.Heinz.
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Ref.
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Cell, 2007,
130,
235-246.
[DOI no: ]
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PubMed id
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Abstract
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The tyrosine kinase Met, the product of the c-met proto-oncogene and the
receptor for hepatocyte growth factor/scatter factor (HGF/SF), mediates signals
critical for cell survival and migration. The human pathogen Listeria
monocytogenes exploits Met signaling for invasion of host cells via its surface
protein InlB. We present the crystal structure of the complex between a large
fragment of the human Met ectodomain and the Met-binding domain of InlB. The
concave face of the InlB leucine-rich repeat region interacts tightly with the
first immunoglobulin-like domain of the Met stalk, a domain which does not bind
HGF/SF. A second contact between InlB and the Met Sema domain locks the
otherwise flexible receptor in a rigid, signaling competent conformation. Full
Met activation requires the additional C-terminal domains of InlB which induce
heparin-mediated receptor clustering and potent signaling. Thus, although it
elicits a similar cellular response, InlB is not a structural mimic of HGF/SF.
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Figure 3.
Figure 3. Flexibility of the Free Met Ectodomain versus
Rigidity of the Complex with InlB[321]
(A) Overlay of the
Met[741]-InlB[321] complex (coloring as in Figure 2) with
Met[567] from the complex with the HGF/SF β chain (pink). The
structures were aligned on the PSI domain to visualize the large
relative rearrangement of the Sema domain.
(B) Overlay of
the Met-InlB complex from crystal form I (coloring as in Figure
2) and from crystal form II (pink). The structures were aligned
on InlB. The Met Ig1 and PSI domains and the InlB-proximal side
of the Sema domain align very well. The secondary interface
between the InlB IR and the Met Sema domain is preserved.
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Figure 4.
Figure 4. The Primary Interface between InlB LRR and Met Ig1
(A) The InlB LRR embraces only the top of Met Ig1 with the
unusual β-wing of the long B-C loop. The LRRs are numbered, and
the strands in Ig1 are labeled. Exposed aromatic side chains at
the concave face of the InlB LRR and the disulfide bond
connecting strands D and E of Met Ig1 are shown as sticks.
(B) Close-up showing InlB Y170^i and Y214^i interacting with
K599^M and K600^M of Met. Y170^i makes hydrogen bonds (dotted
orange lines) to the carbonyl of K599^M and the R602^M side
chain. The side chains of K599^M and K600^M are held in place by
an intra- and intermolecular salt bridge (dotted purple lines),
respectively.
(C) Side chains of residues from β strands
C, F, and G of the Met Ig1 domain form a hydrophobic pocket into
which W124^i from the concave face of the InlB LRR binds.
(D) Electrostatic potential of InlB[321] (left) and Met (right;
Ig2 omitted). In the open-book view, the surfaces involved in
binding are shown for both proteins. The negative charges (red)
on the InlB LRR face positive charges (blue) on Met Ig1.
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The above figures are
reprinted
by permission from Cell Press:
Cell
(2007,
130,
235-246)
copyright 2007.
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