Biochemical and functional studies of lymphoid-specific tyrosine phosphatase (Lyp) variants S201F and R266W.
Biochemical and functional studies of lymphoid-specific tyrosine phosphatase (Lyp) variants S201F and R266W.
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淋巴特异性酪氨酸磷酸酶 (Lyp) 变体 S201F 和 R266W 的生化和功能研究
DOI：
10.1371/journal.pone.0043631
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Liu J;Chen M;Li R;Yang F;Shi X;Zhu L;Wang HM;Yao W;Liu Q;Meng FG;Sun JP;Pang Q;Yu X
类风湿特异性酪氨酸磷酸酶（Lyp）由于其错义突变R620W在多种自身免疫性疾病中的高风险性而引起了巨大的研究兴趣。虽然R620W最初被表征为功能获得性突变体，但最近的一项研究认为R620W通过T细胞信号传导中的功能丧失导致自身免疫性疾病。在这里，我们研究了两种未表征的Lyp变体S201F和R266W的生化特征和T细胞信号传导功能，以及先前表征的Lyp变体R263Q，其在几种自身免疫性疾病中具有降低的风险，包括系统性红斑狼疮（SLE），溃疡性结肠炎（UC）和类风湿性关节炎（RA）。我们对R263Q多态性的动力学和功能研究基本上再现了以前的发现，即它是一个功能丧失的突变体。另一种变体S201F中度降低Lyp磷酸酶活性，并轻微降低T细胞中的Lyp功能，而R266W严重损害磷酸酶活性，是T细胞信号传导中的功能丧失变体。结合动力学和结构分析表明，R266W变体可能通过干扰Lyp的Q环或WPD环来降低其磷酸酶活性。由于R266W和R263Q都显著改变了它们的磷酸酶活性和T细胞功能，未来的工作可以考虑在更广泛的自身免疫性疾病中评估这些突变体。
The Lymphoid specific tyrosine phosphatase (Lyp) has elicited tremendous research interest due to the high risk of its missense mutation R620W in a wide spectrum of autoimmune diseases. While initially characterized as a gain-of-function mutant, R620W was thought to lead to autoimmune diseases through loss-of-function in T cell signaling by a recent study. Here we investigate the biochemical characters and T cell signaling functions of two uncharacterized Lyp variants S201F and R266W, together with a previously characterized Lyp variant R263Q, which had reduced risk in several autoimmune diseases, including systemic lupus erythematosus (SLE), ulcerative colitis (UC) and rheumatoid arthritis (RA). Our kinetic and functional studies of R263Q polymorphism basically reproduced previous findings that it was a loss-of-function mutant. The other variant S201F reduced Lyp phosphatase activity moderately and decreased Lyp function in T cell slightly, while R266W severely impaired phosphatase activity and was a loss-of-function variant in T cell signaling. A combined kinetic and structure analysis suggests that the R266W variant may decrease its phosphatase activity through perturbing either the Q-loop or the WPD loop of Lyp. As both R266W and R263Q significantly change their phosphatase activity and T cell functions, future work could be considered to evaluate these mutants in a broader spectrum of autoimmune diseases.
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