Abstract
Protein misfolding and aggregation have been associated with several human diseases such as Alzheimer’s, Parkinson’s and familial amyloid polyneuropathy etc. In this study, anti-fibrillation activity of vitamin k3 and its effect on the kinetics of amyloid formation of hen egg white lysozyme (HEWL) and Aβ-42 peptide were investigated. Here, in combination with Thioflavin T (ThT) fluorescence assay, circular dichroism (CD), transmission electron microscopy and cell cytotoxicity assay, we demonstrated that vitamin k3 significantly inhibits fibril formation as well as the inhibitory effect is dose dependent manner. Our experimental studies inferred that vitamin k3 exert its neuro protective effect against amyloid induced cytotoxicity through concerted pathway, modifying the aggregation formation towards formation of nontoxic aggregates. Molecular docking demonstrated that vitamin k3 mediated inhibition of HEWL and Aβ-42 fibrillogenesis may be initiated by interacting with proteolytic resistant and aggregation prone regions respectively. This work would provide an insight into the mechanism of protein aggregation inhibition by vitamin k3; pave the way for discovery of other small molecules that may exert similar effect against amyloid formation and its associated neurodegenerative diseases.
Highlights
Vitamin k3, an anti-inflammatory and anti-cancer agent, is employed for post translational modification of proteins including blood clotting factors
It can be seen from the figure that Thioflavin T (ThT) fluorescence intensity of Hen egg white lysozyme (HEWL) was reduced from 222 to 96 and 50 in presence of 50 and 100 μM of vitamin k3 respectively
Further addition of vitamin k3 to preformed HEWL amyloid fibrils did not lead to decrease in ThT fluorescence intensity, it suggests that vitamin k3 cannot reverse the fibril formation but can only inhibit its formation
Summary
Vitamin k3, an anti-inflammatory and anti-cancer agent, is employed for post translational modification of proteins including blood clotting factors. Similar behaviour to vitamin k makes it a good choice as a health supplement and component of multivitamin drugs[22,23,24]. Mechanism of action of vitamin k3 has been investigated on HEWL and Aβ-42 amyloid fibrillogenesis process by exploiting various complementary techniques. To assess the effect of vitamin k3 on the growth phase of amyloid, aggregation kinetics study was performed by ThT binding assay. Morphology of aggregates was studied by using transmission electron microscopy. Interaction mode of vitamin k3 with HEWL and Aβ-42 was studied using molecular docking. Cell viability (MTT) assay was accomplished by using SH-SY5Y cell lines
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