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PDBsum entry 2rol
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Splicing/signaling protein
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PDB id
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2rol
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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 pxxdy motif recognition in sh3 binding.
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Authors
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O.Aitio,
M.Hellman,
T.Kesti,
I.Kleino,
O.Samuilova,
K.Pääkkönen,
H.Tossavainen,
K.Saksela,
P.Permi.
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Ref.
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J Mol Biol, 2008,
382,
167-178.
[DOI no: ]
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PubMed id
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Abstract
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We have determined the solution structure of epidermal growth factor receptor
pathway substrate 8 (Eps8) L1 Src homology 3 (SH3) domain in complex with the
PPVPNPDYEPIR peptide from the CD3epsilon cytoplasmic tail. Our structure reveals
the distinct structural features that account for the unusual specificity of the
Eps8 family SH3 domains for ligands containing a PxxDY motif instead of
canonical PxxP ligands. The CD3epsilon peptide binds Eps8L1 SH3 in a class II
orientation, but neither adopts a polyproline II helical conformation nor
engages the first proline-binding pocket of the SH3 ligand binding interface.
Ile531 of Eps8L1 SH3, instead of Tyr or Phe residues typically found in this
position in SH3 domains, renders this hydrophobic pocket smaller and nonoptimal
for binding to conventional PxxP peptides. A positively charged arginine at
position 512 in the n-Src loop of Eps8L1 SH3 plays a key role in PxxDY motif
recognition by forming a salt bridge to D7 of the CD3epsilon peptide. In
addition, our structural model suggests a hydrogen bond between the hydroxyl
group of the aromatic ring of Y8 and the carboxyl group of E496, thus explaining
the critical role of the PxxDY motif tyrosine residue in binding to Eps8 family
SH3. These finding have direct implications also for understanding the atypical
binding specificity of the amino-terminal SH3 of the Nck family proteins.
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Figure 3.
Fig. 3. Calorimetric titration of 12.5 μM Eps8L1 SH3 with
0.25 mM CD3ε peptide (PPVPNPDYEPIR) in 10 mM Tris–HCl buffer
(pH 7.5), 50 mM NaCl, and 25 μM DTT at 25 °C.
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Figure 5.
Fig. 5. Schematic presentation of (a) class I SH3 ligand
binding (e.g., binding of the RPLPPLP peptide to Src SH3;
1QWF).^16 (b) Class II SH3 ligand binding (e.g., binding of
TPQVPLR peptide from HIV-1 Nef to Fyn SH3; 1AVZ).^17 (c) Binding
of CD3ε-derived peptide PPVPNPDY to Eps8L1 SH3 (2ROL) found in
this study.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2008,
382,
167-178)
copyright 2008.
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