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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Delineating the folding perturbations and molecular mechanisms of Thr-Ala 642 mutation in Rab-GTPase activating protein Akt substrate of 160kDa and its impact on the aetiology of diabetes
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Delineating the folding perturbations and molecular mechanisms of Thr-Ala 642 mutation in Rab-GTPase activating protein Akt substrate of 160kDa and its impact on the aetiology of diabetes

机译：划定160kda的Rab-GTP酶活化蛋白Akt底物中Thr-Ala 642突变的折叠扰动和分子机制及其对糖尿病患病学的影响

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Diabetes Mellitus is a complex metabolic disorder with one of the highest prevalence rates in the world. The present study probes into the Thr-Ala 642 mutation of Akt substrate of 160 kDa (AS160) which has been implicated in diabetes by the dysregulation of glucose transported vesicle 4 (GLUT4) translocation. Our study provides a possible evidence on structural basis dysfunction of AS160 and how the association of phosphorylated AS160 with 14-3-3, a downstream binding partner regulating GLUT4 translocation got disrupted due to T642A mutation. We initially derived the disease-causing mutation (Thr642Ala) among others through in-silico based statistical analysis. Subsequently, we interpreted the perturbation induced in the structural arrangement and their impaired interaction in core regions. Due to mutation, the key interfacial interactions between AS160-14-3-3 were changing from Thr642-Asp756, Thr642-Asp757, and Thr642-Lys659 for phosphorylated form, to Ala642-Val681 for mutant. Further, for phosphorylated AS160 the hotspot residues observed were Glu-629, Gln-635, His-641, Lys-653 and Arg-842 which changed to Arg-637, His-641 for mutant. Eventually, the molecular dynamics analysis revealed that local region for phosphorylation site of AS160 is reducing the flexibility, whereas mutation is making the region more flexible. Principal component analysis and Free energy landscape analysis together reveals phosphorylated AS160 is occupying less phase space with more stable landscape when compared to mutant. Our study strongly confers the destabilizing effect of the point mutation at a conserved site providing novel insights right down to the residual level of the conformational dysregulation of AS160 implicating deadly disease.
机译：糖尿病是一种复杂的代谢紊乱，是世界上患病率最高的疾病之一。本研究探讨了160 kDa Akt底物（AS160）的Thr-Ala 642突变，该突变与葡萄糖转运囊泡4（GLUT4）易位失调有关。我们的研究为AS160的结构基础功能障碍以及磷酸化AS160与调节GLUT4易位的下游结合伙伴14-3-3的关联如何因T642A突变而中断提供了可能的证据。我们最初通过基于电子的统计分析得出致病突变（Thr642Ala）等。随后，我们解释了结构排列中的扰动及其在核心区域中受损的相互作用。由于突变，AS160-14-3-3之间的关键界面相互作用从磷酸化形式的Thr642-Asp756、Thr642-Asp757和Thr642-Lys659，转变为突变形式的Ala642-Val681。此外，对于磷酸化AS160，观察到的热点残基是Glu-629、Gln-635、His-641、Lys-653和Arg-842，对于突变体，这些残基变为Arg-637、His-641。最终，分子动力学分析显示AS160磷酸化位点的局部区域降低了灵活性，而突变使该区域更加灵活。主成分分析和自由能景观分析表明，与突变体相比，磷酸化AS160占据更少的相空间，景观更稳定。我们的研究有力地证明了一个保守位点的点突变的不稳定效应，为AS160构象失调的残余水平提供了新的见解，该构象失调与致命疾病有关。

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