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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases
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Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases

机译：淋巴特异性酪氨酸磷酸酶Lyp的结构，抑制剂和调控机制，与自身免疫性疾病有关

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摘要

The lymphoid-specific tyrosine phosphatase (Lyp) has generated enormous interest because a single-nucleotide polymorphism in the gene (PTPN22) encoding Lyp produces a gain-of-function mutant phosphatase that is associated with several autoimmune diseases, including type I diabetes, rheumatoid arthritis, Graves disease, and systemic lupus erythematosus. Thus, Lyp represents a potential target for a broad spectrum of autoimmune disorders. Unfortunately, no Lyp inhibitor has been reported. In addition, little is known about the structure and biochemical mechanism that directly regulates Lyp function. Here, we report the identification of a bidentate salicylic acid-based Lyp inhibitor I-C11 with excellent cellular efficacy. Structural and mutational analyses indicate that the inhibitor binds both the active site and a nearby peripheral site unique to Lyp, thereby furnishing a solid foundation upon which inhibitors with therapeutic potency and selectivity can be developed. Moreover, a comparison of the apo- and inhibitor-bound Lyp structures reveals that the Lyp-specific region S~(35)TKYKADK~(42), which harbors a PKC phosphorylation site, could adopt either a loop or helical conformation. We show that Lyp is phosphorylated exclusively at Ser-35 by PKC both in vitro and in vivo. We provide evidence that the status of Ser-35 phosphorylation may dictate the conformational state of the insert region and thus Lyp substrate recognition. We demonstrate that Ser-35 phosphorylation impairs Lyp's ability to inactivate the Src family kinases and down-regulate T cell receptor signaling. Our data establish a mechanism by which PKC could attenuate the cellular function of Lyp, thereby augmenting T cell activation.
机译：淋巴特异性酪氨酸磷酸酶（Lyp）引起了极大的兴趣，因为编码Lyp的基因（PTPN22）中的单核苷酸多态性会产生功能增强的突变型磷酸酶，该酶与几种自身免疫性疾病相关，包括I型糖尿病，类风湿病关节炎，格雷夫斯病和系统性红斑狼疮。因此，Lyp代表了广泛的自身免疫性疾病的潜在靶标。不幸的是，没有Lyp抑制剂的报道。另外，对于直接调节Lyp功能的结构和生化机理知之甚少。在这里，我们报告鉴定具有优异的细胞功效的基于双齿水杨酸的Lyp抑制剂I-C11。结构和突变分析表明，该抑制剂结合了Lyp独有的活性位点和附近的外围位点，从而为可开发具有治疗效力和选择性的抑制剂奠定了坚实的基础。此外，载脂蛋白和抑制剂结合的Lyp结构的比较表明，具有PKC磷酸化位点的Lyp特异性区域S〜（35）TKYKADK〜（42）可以采用环或螺旋构象。我们显示，Lyp在体外和体内都仅在Ser-35处被PKC磷酸化。我们提供的证据表明，Ser-35磷酸化的状态可能决定插入区域的构象状态，进而决定Lyp底物的识别。我们证明Ser 35磷酸化损害Lyp灭活Src家族激酶和下调T细胞受体信号传导的能力。我们的数据建立了一种机制，PKC可以通过这种机制减弱Lyp的细胞功能，从而增强T细胞活化。

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