COMPUTATIONAL ANALYSIS OF POST TRANSLATIONAL MODIFICATIONS IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE

Abstract

Aim: Post-translational modifications like acetylation and ubiquitination share a common feature that they both act on lysine residue. Acetylation is responsible for transcriptional deregulation which further leads to mitochondrial dysfunction, autophagic pathway problems and DNA damage which ultimately leads to cell death. On the other hand, ubiquitination aids in degrading the accumulated toxic proteins. Thus, we aim to investigate the potential acetylation and ubiquitination sites in YWHAZ which is responsible for the pathogenesis of AD. Moreover, we aim to identify the impact of these PTMs on the structural features of YWHAZ and also the influence of putative lysine mutation on disease susceptibility. Lastly, we also aim to identify possible drugs and their impact on YWHAZ protein. Result: Herein, we found 13 downregulated genes and 35 upregulated genes between AD and healthy conditions. Further, protein-protein interaction (PPI) network and PTMs integration helped us identify HUB genes namely, YWHAZ, ATP5B, MRPS16, MRPL15, NEDD8, KLHL22, COPS8, ITGB1, PTFAR, and LAMTOR2 with 20 potential lysine modified sites. Moreover, 43% of PTM sites in NEDD8, YWHAZ, ITGB1 and ATP5F1B fall in coiled and none of the four regulatory proteins had any ordered region. Added, 7 common putative lysine sites, K3, K9, K27, K68, K85, K115 and K138 of YWHAZ are crosstalk hotspots for acetylation and ubiquitination. Conclusion: The loss of acetylated hotspots results in more loss of ubiquitination function than gain of function.