Ghosh, D.K. and Kumar, Abhishek and Ranjan, Akash (2020) T54R mutation destabilizes the dimer of superoxide dismutase 1T54R by inducing steric clashes at the dimer interface. RSC Advances, 10 (18). pp. 10776-10788. ISSN 2046-2069

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Abstract

Mutations cause abnormalities in protein structure, function and oligomerization. Different mutations in the superoxide dismutase 1 (SOD1) protein cause its misfolding, loss of dimerization and aggravate its aggregation in the amyotrophic lateral sclerosis disease. In this study, we report the mechanistic details of how a threonine-to-arginine mutation at the 54th position (T54R) of SOD1 results in destabilization of the dimer interface of SOD1T54R. Using computational and experimental methods, we show that the T54R mutation increases fluctuation of the mutation-harboring loop (R54-loop) of SOD1T54R. Fluctuation of this loop causes steric clashes that involve arginine-54 (R54) and other residues of SOD1T54R, resulting in loss of inter-subunit contacts at the dimer interface. Since the T54 residue-containing loop is necessary for the dimerization of wild-type SOD1, fluctuation of the R54-loop, steric clashes involving R54 and loss of inter-subunit contacts give rise to the loss of SOD1T54R dimer stability. This correlates to energetically unfavorable tethering of the monomers of SOD1T54R. The outcome is gradual splitting of SOD1T54R dimers into monomers, thereby exposing the previously buried hydrophobic interface residues to the aqueous environment. This event finally leads to aggregation of SOD1T54R. T54R mutation has no effect in altering the relative positions of copper and zinc ion binding residues of SOD1T54R. The native SOD1 structure is stable, and there is no destabilizing effect at its dimer interface. Overall, our study reveals the intricate mechanism of T54R mutation-associated destabilization of the dimer of the SOD1T54R protein.

Item Type:	Article
Subjects:	Computational Biology
Depositing User:	Users 2 not found.
Date Deposited:	10 May 2020 13:38
Last Modified:	10 May 2020 13:38
URI:	http://cdfd.sciencecentral.in/id/eprint/951

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