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首页> 外文期刊>Biochemistry >Insight into the Binding Properties of MEKK3 PB1 to MEK5 PB1 from Its Solution Structure
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Insight into the Binding Properties of MEKK3 PB1 to MEK5 PB1 from Its Solution Structure

机译：从溶液结构了解MEKK3 PB1与MEK5 PB1的结合特性

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MEKK3 is a mitogen-activated protein kinase kinase kinase that participates in various signaling pathways. One of its functions is to activate the ERK5 signal pathway by phosphorylating and activating MEK5. MEKK3 and MEK5 each harbors a PB1 domain in the N-terminus, and they form a heterodimer via PB1-PB1 domain interaction that was reported to be indispensable to the activation of MEK5. Using NMR spectroscopy, we show here that a prolyl isomerization of the Gln38-Pro39 bond is present in MEKK3 PB1, which is the first case of structural heterogeneity within PB1 domains. We have solved the solution structures of both isomers and found a major difference between them in the Pro39 region. Residues Gly37-Leu40 form a type VIb beta-turn in the cis conformation, whereas no obvious character of beta-turn was observed in the trans conformation. Backbone dynamics studies have unraveled internal motions in the beta3/beta4-turn on a microsecond-millisecond time scale. Further investigation of its binding properties with MEK5 PB1 has demonstrated that MEKK3 PB1 binds MEK5 PB1 tightly with a K_d of about 10~(-8) M. Mutagenesis analysis revealed that residues in the basic cluster of MEKK3 PB1 contributes differently to the PB1- PB1 interaction. Residues Lys 7 and Arg 5 play important roles in the interaction with MEK5 PB1. Taken together, this study provides new insights into structural details of MEKK3 PB1 and its binding properties with MEK5 PB1.
机译：MEKK3是一种有丝分裂原激活的蛋白激酶激酶，参与各种信号传导途径。其功能之一是通过磷酸化和激活MEK5来激活ERK5信号通路。 MEKK3和MEK5各自​​在N端带有一个PB1结构域，它们通过PB1-PB1结构域相互作用形成异二聚体，据报道这对于MEK5的激活是必不可少的。使用核磁共振波谱，我们在这里显示，MEK3 PB1中存在Gln38-Pro39键的脯氨酰异构化，这是PB1域内结构异质性的第一种情况。我们已经解决了两种异构体的溶液结构，发现它们在Pro39区域之间存在主要差异。残基Gly37-Leu40在顺式构象中形成VIb型β-转角，而在反式构象中未观察到明显的β-转角特征。骨干动力学研究以微秒-毫秒的时间尺度揭示了beta3 / beta4圈中的内部运动。对其MEK5 PB1结合特性的进一步研究表明，MEKK3 PB1以约10〜（-8）M的K_d紧密结合MEK5 PB1。诱变分析表明，MEKK3 PB1基本簇中的残基对PB1- PB1的贡献不同相互作用。残基Lys 7和Arg 5在与MEK5 PB1相互作用中起重要作用。两者合计，这项研究提供了对MEKK3 PB1的结构细节及其与MEK5 PB1的结合特性的新见解。

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