<b>Abstract</b><br/>Alzheimer's disease (AD) is a progressive disorder that causes brain cells to degenerate and die. AD is one of the common causes of dementia leads to decline in thinking, behavioral and social skills that disrupts a person's ability to function independently. Tau-tubulin kinase1 (TTBK1) is one of crucial disease regulating protein of AD which is majorly responsible for the phosphorylation and accumulation of tau protein at specific Serine/Threonine residues found in paired helicalfilaments, suggesting its role in tauopathy. There are several vital proteins and single amino acid mutations associated with AD, TTBK1 is one kinase among them, thus considered as an important pharmaceutical targets. The literature stronghold provided that the mutation R142Q is associated with multiple important cellular processes of TTBK1 leading to structural destabilization, consequently leading to AD. This study highlighted the destabilizing, damaging and deleterious effect of the mutation R142Q on TTBK1 structure through computational algorithm study and Molecular Dynamics Simulations study. The protein deviation, fluctuations, conformational dynamics, solvent accessibility, hydrogen bonding, and the residue-residue mapping also confirmed the effect of mutant that would cause the most structural damage suggesting overall de-stabilization. The presence of well-defined free energy minima was observed in case of TTBK1-WT when compared to R142Q mutant presenting significant cause of structural deterioration. The overall finding from the study dictated that the presence of R142Q mutation on TTBK1 effectively responsible for the structure instability leading to disruption of its biological functions and the mutation could be used as future diagnostic markers in treating AD.

Structural, functional and dynamic effect of tau tubulin kinase 1 upon R142Q mutation: A neuro-degenerative hotspot

ACS Spring Meeting 2021

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