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PDBsum entry 2c5d
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Signaling protein/receptor
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PDB id
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2c5d
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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 for gas6-Axl signalling.
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Authors
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T.Sasaki,
P.G.Knyazev,
N.J.Clout,
Y.Cheburkin,
W.Göhring,
A.Ullrich,
R.Timpl,
E.Hohenester.
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Ref.
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EMBO J, 2006,
25,
80-87.
[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
perfect match.
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Abstract
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Receptor tyrosine kinases of the Axl family are activated by the vitamin
K-dependent protein Gas6. Axl signalling plays important roles in cancer,
spermatogenesis, immunity, and platelet function. The crystal structure at 3.3 A
resolution of a minimal human Gas6/Axl complex reveals an assembly of 2:2
stoichiometry, in which the two immunoglobulin-like domains of the Axl
ectodomain are crosslinked by the first laminin G-like domain of Gas6, with no
direct Axl/Axl or Gas6/Gas6 contacts. There are two distinct Gas6/Axl contacts
of very different size, both featuring interactions between edge beta-strands.
Structure-based mutagenesis, protein binding assays and receptor activation
experiments demonstrate that both the major and minor Gas6 binding sites are
required for productive transmembrane signalling. Gas6-mediated Axl dimerisation
is likely to occur in two steps, with a high-affinity 1:1 Gas6/Axl complex
forming first. Only the minor Gas6 binding site is highly conserved in the other
Axl family receptors, Sky/Tyro3 and Mer. Specificity at the major contact is
suggested to result from the segregation of charged and apolar residues to
opposite faces of the newly formed beta-sheet.
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Figure 1.
Figure 1 Overall architecture of the Gas6-LG/Axl-IG complex.
Shown are three orthogonal views. (A) Top view, towards the cell
membrane harbouring the receptor. (B) Side view, with the cell
membrane at the bottom. (C) Front view, in the direction
indicated by the arrow in (B). Surface representations are shown
in (A) and (B), while a cartoon representation is shown in (C).
Gas6-LG is in cyan (N-terminal segment and LG1) and green (LG2),
Axl-IG is in yellow (IG1) and brown (IG2). In (C), the Gas6-LG
molecule at the back has been removed for clarity, a calcium ion
in the LG1-LG2 interface is shown as a pink sphere, and the
Gas6/Axl contact sites are labelled.
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Figure 3.
Figure 3 Detailed structure of the Gas6/Axl contact sites. (A)
Front view of the major contact, in a direction similar to
Figure 1C, showing the polar  -sheet
surface. (B) Back view of the major contact, showing the apolar
-sheet
surface. (C) Front view of the minor contact. Main chain traces
are shown in the colours used in Figure 1. Selected interface
residues are shown as sticks. The two N-acetylglucosamine
moities attached to Asn420^Gas6 are shown in pink. Hydrogen
bonds are shown as broken lines. Main-chain hydrogen bonds
between -strands
have been omitted for clarity.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
EMBO J
(2006,
25,
80-87)
copyright 2006.
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Secondary reference #1
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Title
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Crystal structure of a c-Terminal fragment of growth arrest-Specific protein gas6. Receptor tyrosine kinase activation by laminin g-Like domains.
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Authors
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T.Sasaki,
P.G.Knyazev,
Y.Cheburkin,
W.Göhring,
D.Tisi,
A.Ullrich,
R.Timpl,
E.Hohenester.
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Ref.
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J Biol Chem, 2002,
277,
44164-44170.
[DOI no: ]
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PubMed id
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Figure 2.
Fig. 2. The calcium-binding site in Gas6-LG. The view
direction is similar to that in Fig. 1A. LG1 and LG2 residues
are in cyan and green, respectively, and are labeled. The
calcium ion and two water molecules are shown as pink and red
spheres, respectively. Metal ion-ligand bonds are indicated by
black lines.
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Figure 4.
Fig. 4. The solvent-exposed hydrophobic patch in Gas6-LG.
The Gas6-LG structure is shown as a C  trace in
the same orientation as in Fig. 1A. Selected solvent-accessible
hydrophobic residues are shown in atomic detail and are labeled.
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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Secondary reference #2
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Title
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Ligand recognition and homophilic interactions in tyro3: structural insights into the axl/tyro3 receptor tyrosine kinase family.
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Authors
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C.Heiring,
B.Dahlbäck,
Y.A.Muller.
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Ref.
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J Biol Chem, 2004,
279,
6952-6958.
[DOI no: ]
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PubMed id
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Figure 3.
FIG. 3. Structural details in the Tyro3-D1D2 monomer. A,
stereoview of the interface between the first and second Ig
domains of Tyro3-D1D2. Hydrogen bonds are displayed as yellow
dots. The linker segment is shown in an all atom main chain
representation and the remaining parts as C  sketches. The high
number of interactions across the interface suggests a rigid
orientation of the domains. B, stereoview of the
cis-proline-rich BC and C'E loops of the second Ig domain.
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Figure 4.
FIG. 4. Dimer structure and interface of Tyro3-D1D2. A, the
surface representation of the Tyro3-D1D2 dimer (monomers in red
and green) viewed from two different angles shows that
dimerization occurs solely through interactions between the
N-terminal Ig domains (D1). The two monomers are related to each
other by a 2-fold symmetry. B, overview of the dimer interface.
Amino acids involved in the interface are shown as stick
representations in the case of one monomer; in the second
monomer, the corresponding amino acids are shown in a surface
representation and highlighted in dark green when they are part
of the contract surface. C, hydrogen bond network formed between
B-strand residues across the interface.
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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