Allosteric Boost by TAB1 on the TAK1 Kinase Favorably Sculpts the Thermodynamic Landscape of Activation,Journal of Chemical Information and Modeling

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Allosteric Boost by TAB1 on the TAK1 Kinase Favorably Sculpts the Thermodynamic Landscape of Activation
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2022-11-14 , DOI: 10.1021/acs.jcim.2c00778
Nibedita Ray Chaudhuri ₁ , Shubhra Ghosh Dastidar ₁

Affiliation

The intricate mechanisms of allosteric regulation in kinases are of general interest to the scientific community for potential therapeutic implications. However, the diversity among kinases and their regulatory routes requires a case-by-case study to widen the repertoire of known mechanisms. The present study achieves this by understanding TAK1 kinase activation by TAB1 as a model phenomenon for the first time. Despite the known capacity of TAK1 to switch between its inactive (“DFG-out”) and active-like (“DFG-in”) conformations, the questionable role of TAB1 in offering an energetic favor to this has been addressed here using sequential combination of enhanced sampling methods like targeted molecular dynamics (TMD) and Gaussian accelerated molecular dynamics (GaMD). It reveals how a minimal domain of TAB1 sufficiently acts like a “catalytic gear” by favorably sculpting TAK1’s thermodynamic landscape (potential of mean force in 2D) that accelerates “in”–“out” conformational switching of the conserved DFG motif. Standard molecular dynamics simulations (∼5 μs) reveal that TAB1 fascinatingly exploits the “lever-like” αF helix of TAK1 kinase domain to remotely propel the DFG motif via subtle helical “unfolding–folding” modifications within the kinase activation loop. The presence of two charged residues on terminal poles of αF helix imparts it, with this unique “lever-like” utility, and this turns out to be one important signature of co-evolution between TAK1 and TAB1. The entire mechanism of TAB1’s impact transduction, which is found to be analogous to the moves in the popular “Chinese checker” game, gives a clear proof of the “dynamics-driven allostery” concept in kinases. The findings further benchmark TAK1’s known autophosphorylation capacity. A novel insight into kinase allostery is thus provided, which potentiates investigation of similar capacities in other kinases.

中文翻译：

TAB1 对 TAK1 激酶的变构增强有利于塑造激活的热力学景观

激酶变构调节的复杂机制是科学界普遍关注的潜在治疗意义。然而，激酶及其调节途径之间的多样性需要逐案研究以扩大已知机制的范围。本研究首次将 TAB1 对 TAK1 激酶的激活理解为一种模型现象，从而实现了这一点。尽管已知 TAK1 能够在其非活性（“DFG-out”）和活性样（“DFG-in”）构象之间切换，但 TAB1 在为此提供能量支持方面的可疑作用已在此处使用顺序组合得到解决增强的采样方法，如靶向分子动力学 (TMD) 和高斯加速分子动力学 (GaMD)。它揭示了 TAB1 的最小域如何通过有利地塑造 TAK1 的热力学景观（二维平均力的势能）来充分发挥“催化齿轮”的作用，从而加速保守 DFG 基序的“进”-“出”构象转换。标准分子动力学模拟（~5 μs）表明，TAB1 令人着迷地利用 TAK1 激酶结构域的“杠杆状”αF 螺旋，通过激酶激活环内的细微螺旋“展开-折叠”修饰远程推动 DFG 基序。αF 螺旋末端存在两个带电残基，赋予它这种独特的“类杠杆”效用，事实证明这是 TAK1 和 TAB1 共同进化的一个重要特征。TAB1 的整个冲击传导机制被发现类似于流行的“跳棋”游戏中的动作，清楚地证明了激酶中“动力学驱动的变构”概念。该发现进一步对 TAK1 已知的自磷酸化能力进行了基准测试。因此提供了对激酶变构的新见解，这加强了对其他激酶中类似能力的研究。

更新日期：2022-11-14

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