Impaired insulin signaling has been thought of as important step in both Alzheimer�s disease (AD) and type 2 diabetes mellitus\n(T2DM). Posttranslational modifications (PTMs) regulate functions and interaction of insulin with insulin receptors substrates\n(IRSs) and activate insulin signaling downstream pathways via autophosphorylation on several tyrosine (TYR) residues on IRSs.\nTwo important insulin receptor substrates 1 and 2 are widely expressed in human, and alternative phosphorylation on their serine\n(Ser) and threonine (Thr) residues has been known to block the Tyr phosphorylation of IRSs, thus inhibiting insulin signaling and\npromoting insulin resistance. Like phosphorylation, O-glycosylation modification is important PTMand inhibits phosphorylation\non same or neighboring Ser/Thr residues, often called Yin Yang sites. Both IRS-1 and IRS-2 have been shown to be O-glycosylated;\nhowever exact sites are not determined yet. In this study, by using neuronal network based prediction methods, we found more\nthan 50 Ser/Thr residues that have potential to be O-glycosylated and may act as possible sites as well. Moreover, alternative\nphosphorylation and O-glycosylation on IRS-1 Ser-312, 984, 1037, and 1101 may act as possible therapeutic targets to minimize\nthe risk of AD and T2DM.
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