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首页> 外文期刊>Journal of Molecular Biology >Membrane Anchoring of Hck Kinase via the Intrinsically Disordered SH4-U and Length Scale Associated with Subcellular Localization
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Membrane Anchoring of Hck Kinase via the Intrinsically Disordered SH4-U and Length Scale Associated with Subcellular Localization

机译：HCK激酶的膜锚固通过本质无序的SH4-U和与亚细胞定位相关的长度尺度

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摘要

Src family kinases (SFKs) are a group of nonreceptor tyrosine kinases that are characterized by their involvement in critical signal transduction pathways. SFKs are often found attached to membranes, but little is known about the conformation of the protein in this environment. Here, solution nuclear magnetic resonance (NMR), neutron reflectometry (NR), and molecular dynamics (MD) simulations were employed to study the membrane interactions of the intrinsically disordered SH4 and Unique domains of the Src family kinase Hck. Through development of a procedure to combine the information from the different techniques, we were able produce a first-of-its-kind atomically detailed structural ensemble of a membrane-bound intrinsically disordered protein. Evaluation of the model demonstrated its consistency with previous work and provided insight into how SFK Unique domains act to differentiate the family members from one another. Fortuitously, the position of the ensemble on the membrane allowed the model to be combined with configurations of the multidomain Hck kinase previously determined from small-angle solution X-ray scattering to produce full-length models of membrane-anchored Hck. The resulting models allowed us to estimate that the kinase active site is positioned about 65 +/- 35 A away from the membrane surface, offering the first estimations of the length scale associated with the concept of SFK subcellular localization. (C) 2019 Elsevier Ltd. All rights reserved.
机译：SRC系列激酶（SFK）是一组非受体酪氨酸激酶，其特征在于它们参与临界信号转导途径。 SFK经常被发现附着在膜上，但关于这种环境中蛋白质的构象知之甚少。这里，采用溶液核磁共振（NMR），中子反射测量（NR）和分子动力学（MD）模拟来研究本质上无序的SH4和SRC系列激酶HCH的独特结构域的膜相互作用。通过开发一种将信息与不同技术组合的程序，我们能够生产膜结合的本质上无序蛋白的一致性原子细节结构集合。该模型的评估证明了其与以前的工作一致性，并深入了解SFK独特的域如何行动如何将家庭成员彼此区分。偶尔，膜上的集合的位置允许模型与先前由小角度溶液X射线散射确定的多麦草HCK激酶的配置组合，以产生全长模型的膜固定HCH。得到的模型使我们估计激酶活性位点远离膜表面约65 +/- 35a，提供与SFK亚细胞定位概念相关的长度尺度的第一估计。 （c）2019 Elsevier Ltd.保留所有权利。

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