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Structural Consequences of Mutations to the α-Tocopherol Transfer Protein Associated with the Neurodegenerative Disease Ataxia with Vitamin E Deficiency

机译:维生素E缺乏症与神经退行性疾病共济失调相关的α-生育酚转移蛋白突变的结构后果

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摘要

The α-tocopherol transfer protein (α-TTP) is a liver protein that transfers α-tocopherol (vitamin E) to very-low-density lipoproteins (VLDLs). These VLDLs are then circulated throughout the body to maintain blood α-tocopherol levels. Mutations to the α-TTP gene are associated with ataxia with vitamin E deficiency (AVED), a disease characterized by peripheral nerve degeneration. In this study, molecular dynamics simulations of the E141K and R59W disease-associated mutants were performed. The mutants displayed disruptions in and around the ligand-binding pocket. Structural analysis and ligand docking to the mutant structures predicted a decreased affinity for α-tocopherol. To determine the detailed mechanism of the mutation-related changes, we developed a new tool called ContactWalker that analyzes contact differences between mutant and wild-type proteins and highlights pathways of altered contacts within the mutant proteins. Taken together, our findings are in agreement with experiment and suggest structural explanations for the reduced ability of the mutants to bind and carry α-tocopherol.
机译:α-生育酚转移蛋白(α-TTP)是将α-生育酚(维生素E)转移至极低密度脂蛋白(VLDLs)的肝蛋白。这些VLDL然后在全身循环以维持血液中的α-生育酚水平。 α-TTP基因的突变与维生素E缺乏症(AVED)共济失调有关,该疾病以周围神经变性为特征。在这项研究中,进行了E141K和R59W疾病相关突变体的分子动力学模拟。突变体在配体结合袋中和周围显示出破坏。结构分析和配体对接突变体结构预测对α-生育酚的亲和力降低。为了确定与突变相关的变化的详细机制,我们开发了一种名为ContactWalker的新工具,该工具可以分析突变蛋白与野生型蛋白之间的接触差异,并突出显示突变蛋白内接触改变的途径。两者合计,我们的发现与实验相符,并为突变体结合和携带α-生育酚的能力降低提供了结构解释。

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