{"_":"导致克拉伯病的4种变异的分子动力学模拟。","i":["GALC"]}

摘要(中文译文)

克拉伯病（Krabbe disease），又称球形细胞脑白质营养不良，是一种罕见的溶酶体贮积症，累及中枢和周围神经系统的白质。该病以神经退行性变为特征，其中婴儿型克拉伯病是最常见的形式，通常在出生后第一年内被诊断，且与高发病率和高死亡率相关。该病为常染色体隐性遗传，由基因突变引起，该基因编码溶酶体酶β-半乳糖脑苷脂酶（GALC）。本研究聚焦于检测在克拉伯病患者基因中发现的4种GALC变异体（Gly59Arg、Ser68Phe、Thr278Ile和Ser303Phe）的结构效应。为探究这些突变对蛋白质结构的影响，我们构建了人GALC的结构模型。这些模型作为一系列全原子分子动力学（MD）模拟的基础，用以分析野生型与突变型酶变体的结构稳定性。由于GALC在亚细胞水平定位于溶酶体（pH 4.5至5.5），我们在对应于pH 4.5的质子化状态下进行了MD模拟。我们观察到野生型与各变体之间在蛋白质柔性和分子内相互作用方面存在差异。同样，我们检测到突变对底物结合残基及其邻近区域的影响，尽管突变位点本身并不位于酶的活性位点/结合位点内。总体而言，我们的MD模拟揭示了这些突变如何影响溶酶体中人GALC的结构，并为这些突变为何对酶功能产生影响提供了可能的解释。

Abstract

Krabbe disease, also known as globoid cell leukodystrophy, is a rare lysosomal disorder affecting the white matter of the central and peripheral nervous systems. It is characterized by neurodegeneration, with infantile-onset Krabbe disease as the most common form, typically diagnosed within the first year of life and associated with high morbidity and mortality. This autosomal recessive disease is caused by mutations in the gene, which encodes the lysosomal enzyme β-galactocerebrosidase (GALC). This study focuses on examining the structural effects of 4 GALC variants (Gly59Arg, Ser68Phe, Thr278Ile, and Ser303Phe) found as mutations in the gene of patients with Krabbe disease. To investigate the effects of these mutations on protein structure, structural models of human GALC were built. These models served as the basis for a series of all-atom molecular dynamics (MD) simulations to analyze the structural stability of the wild type and the mutated enzyme variants. Since GALC is subcellularly localized in the lysosome (pH 4.5 to 5.5), MD simulations were performed with protonation states corresponding to pH 4.5. Differences in protein flexibility and intramolecular interactions between the wild type and the variants were observed. Similarly, we detected the effects of the mutations on the substrate-binding residues and their vicinity, although the mutation sites themselves do not lie within the active site/binding site of the enzyme. Overall, our MD simulations shed light on how these mutations affect the structure of human GALC in the lysosome and offer possible explanations as to why these mutations have an effect on enzyme function.

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