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首页> 外文期刊>Journal of Molecular Biology >Structural basis of PxxDY motif recognition in SH3 binding.
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Structural basis of PxxDY motif recognition in SH3 binding.

机译：SH3结合中PxxDY基序识别的结构基础。

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摘要

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.
机译：我们已经确定了与来自CD3epsilon细胞质尾部的PPVPNPDYEPIR肽复合的表皮生长因子受体途径底物8（Eps8）L1 Src同源性3（SH3）域的溶液结构。我们的结构揭示了独特的结构特征，这些特征解释了Eps8家族SH3结构域对包含PxxDY母体而不是规范PxxP配体的配体具有非凡的特异性。 CD3epsilon肽以II类方向结合Eps8L1 SH3，但既不采用聚脯氨酸II螺旋构象，也不与SH3配体结合界面的第一个脯氨酸结合口袋接合。 Eps8L1 SH3的Ile531，而不是通常在SH3结构域中此位置上发现的Tyr或Phe残基，使该疏水口袋更小且对于与常规PxxP肽的结合而言并非最佳。 Eps8L1 SH3的n-Src环中512位带正电荷的精氨酸通过与CD3epsilon肽的D7形成盐桥，在PxxDY基序识别中发挥关键作用。此外，我们的结构模型表明Y8芳香环的羟基与E496的羧基之间存在氢键，从而解释了PxxDY基序酪氨酸残基在与Eps8家族SH3结合中的关键作用。这些发现对于理解Nck家族蛋白的氨基末端SH3的非典型结合特异性也具有直接的含义。

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