Distinct Binding Modes of Two Epitopes in Gab2 that Interact with the SH3C Domain of Grb2
Distinct Binding Modes of Two Epitopes in Gab2 that Interact with the SH3C Domain of Grb2
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DOI：
10.1016/j.str.2009.03.017
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发表时间：
2009-06-10
期刊：
影响因子：
5.7
通讯作者：
Feller, Stephan M.
中科院分区：
文献类型：
--
作者：
Harkiolaki, Maria;Tsirka, Theodora;Feller, Stephan M.
Grb2 和 Gab2 形成复合物，参与正常细胞信号传导和癌症发展。 Grb2SH3C 结构域与 Gab2 的结合对于相互作用至关重要，但分子细节仍不清楚。使用肽阵列和等温滴定量热法，确认并表征了 Gab2 中的两个 Grb2SH3C 结合位点（Gab2a 和 Gab2b）。 Gab2a 与也结合 Grb2SH3C 的 p27Kip1 表位相似。与 Grb2SH3C 复合的两个 Gab2 表位的晶体结构表明，Gab2b 包含 3(10) 螺旋，该螺旋将核心结合基序 RxxK 的精氨酸和赖氨酸置于平行方向。相比之下，Gab2a RxxK 基序嵌入 PPII 螺旋中，其中 Arg 和 Lys 呈交错方向。 Mona/GadsSH3C 与来自推定磷酸酶 HD-PTP 的 RxxxxK 表位的新复合物中也存在类似的相互作用模式。总之，我们的研究揭示了 SH3 结构域的相互作用类型，突出了它们的多功能性。
Grb2 and Gab2 form a complex implicated in normal cell signaling and cancer development. Binding of the Grb2SH3C domain to Gab2 is essential for the interaction, but molecular details remained undefined. Using peptide arrays and isothermal titration calorimetry, two Grb2SH3C binding sites in Gab2 (Gab2a and Gab2b) were confirmed and characterized. Gab2a bears similarity to a p27Kip1 epitope that also binds Grb2SH3C. Crystal structures of both Gab2 epitopes complexed with Grb2SH3C reveal that Gab2b contains a 3(10) helix that positions the arginine and lysine of the core-binding motif RxxK in parallel orientation. In contrast, the Gab2a RxxK motif is embedded in a PPII helix with Arg and Lys in staggered orientation. A similar interaction mode is also present in a new complex of Mona/GadsSH3C with an RxxxxK epitope from the putative phosphatase HD-PTP. In summary, our study reveals interaction types of SH3 domains, highlighting their great versatility.