Insights into amyotrophic lateral sclerosis linked Pro525Arg mutation in the fused in sarcoma protein through in silico analysis and molecular dynamics simulation.
Abstract
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 ...Continue Reading
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Intrinsic Origin of Tau Protein Aggregation: Effects of Histidine Tautomerism on Tau267-312 Monomer.
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Amyloid Lateral Sclerosis
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