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PDBsum entry 1wyx
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Cell adhesion
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PDB id
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1wyx
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References listed in PDB file
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Key reference
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Title
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The 1.1 a resolution crystal structure of the p130cas sh3 domain and ramifications for ligand selectivity.
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Authors
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M.Wisniewska,
B.Bossenmaier,
G.Georges,
F.Hesse,
M.Dangl,
K.P.Künkele,
I.Ioannidis,
R.Huber,
R.A.Engh.
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Ref.
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J Mol Biol, 2005,
347,
1005-1014.
[DOI no: ]
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PubMed id
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Abstract
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The Crk-associated tyrosine kinase substrate p130cas (CAS) is a docking protein
containing an SH3 domain near its N terminus, followed by a short proline-rich
segment, a large central substrate domain composed of 15 repeats of the four
amino acid sequence YxxP, a serine-rich region and a carboxy-terminal domain,
which possesses consensus binding sites for the SH2 and SH3 domains of Src (YDYV
and RPLPSPP, respectively). The SH3 domain of CAS mediates its interaction with
several proteins involved in signaling pathways such as focal adhesion kinase
(FAK), tyrosine phosphatases PTP1B and PTP-PEST, and the guanine nucleotide
exchange factor C3G. As a homolog of the corresponding Src docking domain, the
CAS SH3 domain binds to proline-rich sequences (PxxP) of its interacting
partners that can adopt a polyproline type II helix. We have determined a
high-resolution X-ray structure of the recombinant human CAS SH3 domain. The
domain, residues 1-69, crystallized in two related space groups, P2(1) and
C222(1), that provided diffraction data to 1.1 A and 2.1 A, respectively. The
crystal structure shows, in addition to the conserved SH3 domain architecture,
the way in which the CAS characteristic amino acids form an atypically charged
ligand-binding surface. This arrangement provides a rationale for the unusual
ligand recognition motif exhibited by the CAS SH3 domain. The structure enables
modelling of the docking interactions to its ligands, for example from focal
adhesion kinase, and supports structure-based drug design of inhibitors of the
CAS-FAK interaction.
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Figure 5.
Figure 5. The CA traces of the superposed SH3 domains of
CAS (green, cyan and blue indicate the monomer, chain A and B,
respectively), PI3K (orange) and a-spectrin (red).
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Figure 7.
Figure 7. Model of the FAK peptide bound to the CAS SH3
domain. (a) Peptide residues are shown in green and numbered
from 1 to 9. Residues that are involved in ligand binding are
shown in ball and stick representation (the highly conserved
amino acid residues are in cyan). (b) The CA traces of the
superposed CAS SH3-FAK peptide complex (magenta) and C-Src
SH3-App12 complex (cyan) (1QWE).31 (c) Interface of the CAS
SH3-peptide complex interactions. SH3 domain is shown as a
surface plot (residues in red, negatively charged; blue,
positively charged; white, neutral), FAK peptide is shown in
green.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2005,
347,
1005-1014)
copyright 2005.
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