A Conserved Allosteric Pathway in Tyrosine Kinase Regulation.
A Conserved Allosteric Pathway in Tyrosine Kinase Regulation.
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DOI：
10.1016/j.str.2019.05.002
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发表时间：
2019-08
期刊：
影响因子：
5.7
通讯作者：
William Marsiglia;Joseph Katigbak;Sijin Zheng;M. Mohammadi;Yingkai Zhang;N. Traaseth
中科院分区：
文献类型：
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作者：
William Marsiglia;Joseph Katigbak;Sijin Zheng;M. Mohammadi;Yingkai Zhang;N. Traaseth
位于激酶铰链处的氢键的自抑制网络（称为“分子制动器”）调节几种受体酪氨酸激酶的活性。人类疾病中制动器突变脱离变构激活激酶的机制尚未完全了解。我们使用了NMR，生物信息学和分子动力学模拟的组合，以表明突变破坏的分子制动触发本地化的构象扰动，传播到活性位点。这需要改变异亮氨酸的相互作用，异亮氨酸是将DFG基序的苯丙氨酸锁定在非活性构象中的三个疏水残基之一。酪氨酸激酶的结构分析提供了证据表明，这种变构控制机制是跨酪氨酸激酶家族共享的。我们还表明，高度激活突变的刹车减少酶的热稳定性，从而解释了为什么这些突变引起较轻的骨骼综合征相比，激活环中的激活突变较少。
An autoinhibitory network of hydrogen bonds located at the kinase hinge (referred to as the "molecular brake") regulates the activity of several receptor tyrosine kinases. The mechanism whereby mutational disengagement of the brake allosterically activates the kinase in human disease is incompletely understood. We used a combination of NMR, bioinformatics, and molecular dynamics simulation to show that mutational disruption of the molecular brake triggers localized conformational perturbations that propagate to the active site. This entails changes in interactions of an isoleucine, one of three hydrophobic residues that lock the phenylalanine of the DFG motif in an inactive conformation. Structural analysis of tyrosine kinases provides evidence that this allosteric control mechanism is shared across the tyrosine kinase family. We also show that highly activating mutations at the brake diminish the enzyme's thermostability, thereby explaining why these mutations cause milder skeletal syndromes compared with less-activating mutations in the activation loop.