<P> Compared to the protein phosphorylation of prokaryotes, the studies done in the protein phosphorylation in eukaryotes of yeast and human cells have been more extensive . It is known that eukaryotes rely on the phosphorylation of the hydroxyl group on the side chains of serine, threonine, and tyrosine . These bases are the main regulatory post-translational modifications in eukaryotic cells but the protein phosphorylation of prokaryotes are less intensely studied . While serine, threonine, and tyrosine are phosphorylated in eukaryotes, histidine and aspartate is phosphorylated in prokaryotes . In bacteria, histidine phosphorylation occurs in the phosphoenolpyruvate - dependent phosphotransferase systems (PTSs), which are involved in the process of internalization as well as the phosphorylation of sugars . </P> <P> Protein phosphorylation by protein kinase was first obtained by E. coli and Salmonella typhimurium and has since been demonstrated in many other bacterial cells . It was found that bacteria use histidine and aspartate phosphorylation as a model for bacterial signaling transduction but in the last few years there has been evidence that has shown that serine, threonine, and tyrosine phosphorylation are also present in bacteria . It was shown that bacteria carry kinases and phosphatases similar to that of their eukaryotic equivalent but they have also developed unique kinases and phosphatases not found in eukaryotes . </P> <P> Abnormal protein phosphorylation has been implicated in a number of diseases, such as Alzheimer's disease, Parkinson's disease, and other degenerative disorders . </P> <P> Tau protein belongs to a group of Microtubule Associated Proteins (MAPs) which, among several things, help stabilize microtubules in cells, including neurons . Association and stabilizing activity of tau protein depends on its phosphorylated state . In Alzheimer's disease, due to misfoldings and abnormal conformational changes in tau protein structure, it is rendered ineffective at binding to microtubules and thus unable to keep the neural cytoskeletal structure organized during neural processes; in fact abnormal tau inhibits and disrupts microtubule organization and disengages normal tau from microtubules into cytosolic phase . The misfoldings lead to the abnormal aggregation into fibrillary tangles inside the neurons, the hallmark of Alzheimer's disease . There is an adequate amount that the tau protein needs to be phosphorylated to function, but hyperphosphorylation of tau protein is thought to be one of the major influences on its incapacity to associate . Kinases PP1, PP2A, PP2B, and PP2C dephosphorylate tau protein in vitro, and their activities have found to be reduced in areas of the brain in Alzheimer patients . Tau phosphoprotein is three to fourfold hyperphosphorylated in an Alzheimer patient compared to an aged non-afflicted individual . Alzheimer disease tau seems to remove MAP1 and MAP2 (two other major associated proteins) from microtubules and this deleterious effect is reversed when dephosphorylation is performed, evidencing hyperphosphorylation as the sole cause of the crippling activity . </P>

The multiple roles of histidine in protein interactions