Insights into amyotrophic lateral sclerosis linked Pro525Arg mutation in the fused in sarcoma protein through in silico analysis and molecular dynamics simulation

突变体 突变 生物信息学 肌萎缩侧索硬化 野生型 蛋白质结构 生物 化学 生物物理学 细胞生物学 生物化学 医学 基因 病理 疾病
作者
Sompriya Chatterjee,Abbas Salimi,Jin Yong Lee
出处
期刊:Journal of Biomolecular Structure & Dynamics [Informa]
卷期号:39 (16): 5963-5976 被引量:10
标识
DOI:10.1080/07391102.2020.1794967
摘要

A novel heterozygous mutation, Pro525Arg (P525R) in the Fused in Sarcoma (FUS) protein is predominant in young adult females with familial amyotrophic lateral sclerosis (fALS). Investigation of the biophysical characteristics of this mutation through analysis of protein conformation could provide insights into the pathogenic mechanism of amyotrophic lateral sclerosis (ALS). Here, several computational prediction tools were applied to investigate the effect of P525R on the stability, flexibility, and function of FUS. Conservation and biochemical analyses showed that P525 is highly conserved; the mutation of proline to arginine at position 525 in FUS results in a notable increase in molecular weight, number of hydrogen bonds, and loss of hydrophobicity. By performing electrostatic potential, intra-protein interaction, and binding affinity analyses, we found increased electrostatic potential charge in the mutant protein and fewer hydrophobic interactions than the wild-type structure. Binding affinity of the FUS nuclear localization signal (NLS) mutant for transportin (Trn1) was also decreased compared to wild-type. Our molecular dynamics (MD) simulation results highlighted the exchange between hydrophobic and hydrophilic residues from the core to the surface in the mutant structure; also, upon P525R mutation, FUS became less stable, less flexible and more compact and rigid. Overall, this study demonstrated that the Pro525Arg mutation significantly alters the structure and conformation of FUS through loss of nuclear function, thereby likely contributing to its accumulation in the cytoplasm, which has been implicated in the pathogenesis of fALS. Our study can potentially aid in the design of drugs for FUS-associated neurodegenerative diseases.
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