探索变色性白质营养不良症中人类 ARSA 金属结合位点的致病突变的影响。

3区 生物学 Q1 Biochemistry, Genetics and Molecular Biology
N Madhana Priya, N Sidharth Kumar, S Udhaya Kumar, G Mohanraj, R Magesh, Hatem Zayed, Karthick Vasudevan, George Priya Doss C
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引用次数: 0

摘要

据观察,变色性白质营养不良症(MLD)是一种溶酶体贮积病,患者体内缺乏芳基硫酸酯酶 A(ARSA)基因。MLD是一种严重的神经退行性疾病,具有常染色体隐性遗传的特点。本研究旨在绘制 ARSA 金属结合位点上最有害突变以及突变位置附近氨基酸的图谱。我们利用一系列计算工具,包括 PredictSNP、MAPP、PhD-SNP、PolyPhen-1、PolyPhen-2、SIFT、SNAP 和 ConSurf,从 UniProt、ClinVar 和 HGMD 中收集到了可能与 MLD 有关的最有害突变。根据致病性、保存、生物物理特征和稳定性分析评估,D29N 和 D30H 这两个突变具有极强的致病性。D29 和 D30 位于 ARSA 的金属相互作用区,会发生翻译后修饰,特别是磷酸化。因此,利用分子动力学模拟(MDS)研究了磷酸化前后金属结合对突变的深入影响。分子动力学模拟结果显示,D29N 和 D30H 突变与原生蛋白的偏差很大,残基的显著波动和紧密度的降低也证实了这一点。这些结构改变表明,这些突变可能会影响蛋白质的功能,为个性化治疗提供了潜在的途径,并为针对严重MLD患者的潜在突变特异性治疗提供了基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Exploring the effect of disease causing mutations in metal binding sites of human ARSA in metachromatic leukodystrophy.

The arylsulfatase A (ARSA) gene is observed to be deficient in patients with metachromatic leukodystrophy (MLD), a type of lysosomal storage disease. MLD is a severe neurodegenerative disorder characterized by an autosomal recessive inheritance pattern. This study aimed to map the most deleterious mutations at the metal binding sites of ARSA and the amino acids in proximity to the mutated positions. We utilized an array of computational tools, including PredictSNP, MAPP, PhD-SNP, PolyPhen-1, PolyPhen-2, SIFT, SNAP, and ConSurf, to identify the most detrimental mutations potentially implicated in MLD collected from UniProt, ClinVar, and HGMD. Two mutations, D29N and D30H, as being extremely deleterious based on assessments of pathogenicity, conservation, biophysical characteristics, and stability analysis. The D29 and D30 are located at the metal-interacting regions of ARSA and found to undergo post-translational modification, specifically phosphorylation. Henceforth, the in-depth effect of metal binding upon mutation was examined using molecular dynamics simulations (MDS) before and after phosphorylation. The MDS results exhibited high deviation for the D29N and D30H mutations in comparison to the native, and the same was confirmed by significant residue fluctuation and reduced compactness. These structural alterations suggest that such mutations may influence protein functionality, offering potential avenues for personalized therapeutic and providing a basis for potential mutation-specific treatments for severe MLD patients.

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来源期刊
Advances in protein chemistry and structural biology
Advances in protein chemistry and structural biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
7.40
自引率
0.00%
发文量
66
审稿时长
>12 weeks
期刊介绍: Published continuously since 1944, The Advances in Protein Chemistry and Structural Biology series has been the essential resource for protein chemists. Each volume brings forth new information about protocols and analysis of proteins. Each thematically organized volume is guest edited by leading experts in a broad range of protein-related topics.
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