Effect of Tyrosine to Alanine Mutation on the Dimerization Process of α-Synuclein: A Potential of Mean Force study

Author: Airy Sanjeev and Venkata Satish Kumar Mattaparthi

Journal Name:

Download PDF

Abstract

Aggregation of α-synuclein into well-ordered amyloid fibrils is associated with the pathogenesis of Parkinson’s disease. Several studies have suggested that Tyrosine residues of α-synuclein are involved in the intra and inter-molecular interactions during the fibrillation process. Here we demonstrate the role of tyrosine residues on the inter-molecular interactions during fibrillation process by analyzing the effect of tyrosine to alanine mutation on dimerization process of α-synuclein. We modeled the homo-dimer complex of the three tyrosine mutants: (Y39A; Y133A; Y (125,133,136)A) and Wild type α-synuclein and carried out potential of mean force study to analyze and compare free energy profile. We observed the minimum of separation of monomeric units to be smaller in Y39A and larger in Y133A dimer. Therefore we see Y39A mutation to accelerate the aggregation while Y133A slow down the aggregation. So the methods targeting tyrosine residue at position 133 may be helpful to reduce

Keywords

Aggregation, Parkinson’s disease, mutants, free energy, fibrillation

Conclusion

The involvement of tyrosine residues of α-synuclein in the inter-molecular interactions during the dimerization process was studied. From our study, we can see among the tyrosine mutants, Y133A has the capacity to delay the fibrillation propensity of α-synuclein as it shows a substantially different conformation than the other tyrosine mutants. Among the three mutants (Y133A, Y39A, Y(125,133,136)A) and the WT, we found the inter-molecular interactions to be stronger in case of Y39A and weaker in Y133A.These findings suggest that the aggregation propensity of α-synuclein protein will be higher when it has Y39A mutation and lower when it has Y133A mutation. This is in agreement with the work that has been reported earlier (Ulrih et al., 2008). Therefore we see Y39A mutation to accelerate the α-synuclein aggregation while Y133A slow down the aggregation. So the methods targeting tyrosine residue at position 133 may be focused to reduce the aggregation propensity of α-synuclein.

References

α-Synuclein belongs to the class of Intrinsically Disordered Proteins (Fauvet et al., 2012; Iwai et al., 1995; Weinreb et al., 1996) consisting of 140 amino acids (Bisaglia et al., 2009). The aggregation of α-synuclein into well-ordered fibrils has been associated with the onset of Parkinson’s disease and various other neurodegenerative diseases (Uversky et al., 2009). However, the exact mechanism is still not known. Although the protein-lipid interaction involved in α-synuclein appears to be an important factor for the physio-pathological characteristics of the protein (Bendor et al., 2013; Pirc et al., 2011). The fibrillation of α-synuclein is a nucleation-dependent process which is associated with the transformation of unfolded monomer into oligomers and then to fibrils wherein the cross-β-sheet are formed (Breydo et al., 2012; Fink 2006; Serpell et al., 2000; Uversky et al., 2001). However the increased hydrophobic exposure is associated with the transformed monomeric and o

How to cite this article

Airy Sanjeev and Venkata Satish Kumar Mattaparthi (2017). Effect of Tyrosine to Alanine Mutation on the Dimerization Process of α-Synuclein: A Potential of Mean Force study. Biological Forum – An International Journal 9(1): 100-107.