Phosphomimetics are

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

substitutions that mimic a phosphorylated protein, thereby activating (or deactivating) the protein. Within cells, proteins are commonly modified at

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − for ...

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

and

threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...

amino acids by adding a

phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phosph ...

group.

Phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

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 Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α- amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pr ...

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. Phosphonate-based compounds have been used as phosphotyrosine analogues, as they are less enzyme labile and are physiologically more stable.

Applications

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 Interferon regulatory factor 3, also known as IRF3, is an interferon regulatory factor. Function IRF3 is a member of the interferon regulatory transcription factor (IRF) family. IRF3 was originally discovered as a homolog of IRF1 and IRF2. I ...

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 Gain-of-function research (GoF research or GoFR) is medical research that genetically alters an organism in a way that may enhance the biological functions of gene products. This may include an altered pathogenesis, transmissibility, or host ran ...

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 A ribosomal protein (r-protein or rProtein) is any of the proteins that, in conjunction with rRNA, make up the ribosomal subunits involved in the cellular process of translation. ''E. coli'', other bacteria and Archaea have a 30S small subunit ...

both ''in vivo'' and ''in vitro'' to investigate a gain-of-function mutation on a kinase that is related to

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

. 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 Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as g ...

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.

References

Biochemistry {{protein-stub