Phosphomimetics are amino acid substitutions that mimic a phosphorylated protein, thereby activating (or deactivating) the protein. Within cells, proteins are commonly modified at serine, tyrosine and threonine amino acids by adding a phosphate group. Phosphorylation is a common mode of activating or deactivating a protein as a form of regulation. However some non-phosphorylated amino acids appear chemically similar to phosphorylated amino acids. Therefore, by replacing an amino acid, the protein may maintain a higher level of activity. For example, aspartic acid is chemically similar to phospho-serine. Therefore, when an aspartic acid replaces a serine, it is a phosphomimetic of phospho-serine and can make the protein always in its phosphorylated form.
This chemical similarity can be exploited in cancer, where a protein may mutate into an "always on" (constitutively active) state. A mutation may occur to replace a tyrosine (which needs to be phosphorylated in order to activate the protein) with an aspartic acid (which would not need to be phosphorylated). In a laboratory setting, the use of recombinant proteins to artificially introduce phosphomimetics is a common tool for studying phosphorylation and protein activation. For example, the IRF3 protein must be phosphorylated for its normal activity (transcription of its target genes, like IFNβ), but when serine amino acid residues were mutated to aspartic acid, the activity increased 90-fold. Phosphomimetics are commonly used in a gain of function experiment with respect to phosphorylation. For example, aspartate mutants were successfully used to probe the biological function of the phosphorylation of a threonine residue of a ribosomal protein both in vivo and in vitro to investigate a gain-of-function mutation on a kinase that is related to Parkinson's disease. Phosphomimetics were also used to investigate the therapeutic potential of proteins or peptides. For example, phosphomimetic mutants (using glutamate to mimic serine phosphorylation) have been used to demonstrate that the phosphorylated glycoprotein may have stronger anti-melanoma effects that the wildtype protein. This approach is in particularly useful as up to three serine residues can be phosphoylated on the said protein, and hence phosphomimetic mutants are useful to probe the function of the individual phosphorylation.
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