Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase.
Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase.
复制标题
富含纹状体的蛋白酪氨酸磷酸酶的ERK去磷酸化的分子机制。
DOI：
10.1111/jnc.12463
复制
发表时间：
2014-01
影响因子：
4.7
通讯作者：
Pang Q
中科院分区：
文献类型：
--
作者：
Li R;Xie DD;Dong JH;Li H;Li KS;Su J;Chen LZ;Xu YF;Wang HM;Gong Z;Cui GY;Yu X;Wang K;Yao W;Xin T;Li MY;Xiao KH;An XF;Huo Y;Xu ZG;Sun JP;Pang Q
纹状体富含酪氨酸磷酸酶(STEP)是神经元突触可塑性的重要调节因子，其异常水平或活性与认知功能障碍密切相关。STEP的一个重要下游效应因子和直接底物是细胞外信号调节蛋白激酶(ERK)，它在脊柱稳定和动作电位传递中具有重要功能。抑制磷酸化ERK的STEP活性具有治疗神经元疾病的潜力，但通过STEP去磷酸化ERK的详细机制尚不清楚。因此，我们使用具有不同结构特征的阶跃突变体来检测对pNPP、含磷酸酪氨酸的多肽和全长磷酸化ERK蛋白的阶跃活性。STEP是一种高效的ERK酪氨酸磷酸酶，既需要其N端调控区，又需要其活性部位的关键残基。具体来说，ERK相互作用需要STEP的Kim和KIS。除N-末端KIS区外，位于Kim区的S245、疏水残基L249/L251和碱性残基R242/R243对控制磷酸化ERK的阶跃活性也很重要。进一步的动力学实验揭示了STEP和HePTP之间的细微结构差异，这些差异影响了它们的KIM与ERK的相互作用。此外，STEP通过其活性部位识别磷酸化ERK多肽序列的特定位置，STEP F311与磷酸化ERK V205和T207的接触是关键的相互作用。综上所述，我们的结果不仅为ERK和STEP之间的相互作用提供了信息，而且还将有助于开发针对STEP-ERK识别的特定策略，这可能是一种潜在的神经疾病治疗方法。
Striatal-enriched tyrosine phosphatase (STEP) is an important regulator of neuronal synaptic plasticity, and its abnormal level or activity contributes to cognitive disorders. One crucial downstream effector and direct substrate of STEP is extracellular signal-regulated protein kinase (ERK), which has important functions in spine stabilisation and action potential transmission. The inhibition of STEP activity toward phospho-ERK has the potential to treat neuronal diseases, but the detailed mechanism underlying the dephosphorylation of phospho-ERK by STEP is not known. Therefore, we examined STEP activity toward pNPP, phospho-tyrosine-containing peptides, and the full-length phospho-ERK protein using STEP mutants with different structural features. STEP was found to be a highly efficient ERK tyrosine phosphatase that required both its N-terminal regulatory region and key residues in its active site. Specifically, both KIM and KIS of STEP were required for ERK interaction. In addition to the N-terminal KIS region, S245, hydrophobic residues L249/L251, and basic residues R242/R243 located in the KIM region were important in controlling STEP activity toward phospho-ERK. Further kinetic experiments revealed subtle structural differences between STEP and HePTP that affected the interactions of their KIMs with ERK. Moreover, STEP recognised specific positions of a phospho-ERK peptide sequence through its active site, and the contact of STEP F311 with phospho-ERK V205 and T207 were crucial interactions. Taken together, our results not only provide the information for interactions between ERK and STEP, but will also help in the development of specific strategies to target STEP-ERK recognition, which could serve as a potential therapy for neurological disorders.
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DOI：
10.1126/science.1215802
发表时间：
2012-03-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Liu JJ;Horst R;Katritch V;Stevens RC;Wüthrich K
通讯作者：
Wüthrich K
DOI：
10.1073/pnas.0510506103
发表时间：
2006-04-04
影响因子：
11.1
作者：
Liu, SJ;Sun, JP;Zhang, ZY
通讯作者：
Zhang, ZY
影响因子：
2.9
作者：
Piserchio, Andrea;Francis, Dana M.;Ghose, Ranajeet
通讯作者：
Ghose, Ranajeet
金属依赖性蛋白磷酸酶 1A 充当细胞外信号调节激酶磷酸酶。
影响因子：
5.4
作者：
Li, Rong;Gong, Zheng;Sun, Jin-Peng
通讯作者：
Sun, Jin-Peng
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
影响因子：
3.7
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
通讯作者：
Yu X