Tyrosine Phosphorylation of the Lyn Src Homology 2 (SH2) Domain Modulates Its Binding Affinity and Specificity
Tyrosine Phosphorylation of the Lyn Src Homology 2 (SH2) Domain Modulates Its Binding Affinity and Specificity
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DOI：
10.1074/mcp.m114.044404
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发表时间：
2015-03-01
影响因子：
7
通讯作者：
Moran, Michael F.
中科院分区：
文献类型：
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作者：
Jin, Lily L.;Wybenga-Groot, Leanne E.;Moran, Michael F.
Src 同源 2 (SH2) 结构域是模块化蛋白质结构，可结合含有磷酸酪氨酸 (pY) 的多肽，并通过蛋白质-蛋白质相互作用调节细胞功能。蛋白质组学分析表明，Src 家族激酶的 SH2 结构域本身在血液系统癌症中被酪氨酸磷酸化，包括急性髓系白血病、慢性淋巴细胞白血病和多发性骨髓瘤。使用 Src 家族激酶 Lyn SH2 结构域作为模型，我们发现保守 SH2 结构域残基 Y-194 的磷酸化会影响 SH2 结构域与含有 pY 的肽和蛋白质结合的亲和力和特异性。 Lyn SH2 结构域晶体结构的分析支持这样的模型，其中 EF 环上 Y194 的磷酸化调节与 pY+2/+3 位置处的氨基酸侧链接合的结合袋。这些数据表明了另一种调节水平，其中SH2介导的蛋白质-蛋白质相互作用由SH2激酶和磷酸酶调节。
Src homology 2 (SH2) domains are modular protein structures that bind phosphotyrosine (pY)-containing polypeptides and regulate cellular functions through protein-protein interactions. Proteomics analysis showed that the SH2 domains of Src family kinases are themselves tyrosine phosphorylated in blood system cancers, including acute myeloid leukemia, chronic lymphocytic leukemia, and multiple myeloma. Using the Src family kinase Lyn SH2 domain as a model, we found that phosphorylation at the conserved SH2 domain residue Y-194 impacts the affinity and specificity of SH2 domain binding to pY-containing peptides and proteins. Analysis of the Lyn SH2 domain crystal structure supports a model wherein phosphorylation of Y194 on the EF loop modulates the binding pocket that engages amino acid side chains at the pY+2/+3 position. These data indicate another level of regulation wherein SH2-mediated protein-protein interactions are modulated by SH2 kinases and phosphatases.