Why nature chose phosphate to modify proteins

Abstract

The advantageous chemical properties of the phosphate ester linkage were exploited early in evolution to generate the phosphate diester linkages that join neighbouring bases in RNA and DNA (Westheimer 1987 Science 235, 1173-1178). Following the fixation of the genetic code, another use for phosphate ester modification was found, namely reversible phosphorylation of the three hydroxyamino acids, serine, threonine and tyrosine, in proteins. During the course of evolution, phosphorylation emerged as one of the most prominent types of post-translational modification, because of its versatility and ready reversibility. Phosphoamino acids generated by protein phosphorylation act as new chemical entities that do not resemble any natural amino acid, and thereby provide a means of diversifying the chemical nature of protein surfaces. A protein-linked phosphate group can form hydrogen bonds or salt bridges either intra- or intermolecularly, creating stronger hydrogen bonds with arginine than either aspartate or glutamate. The unique size of the ionic shell and charge properties of covalently attached phosphate allow specific and inducible recognition of phosphoproteins by phosphospecific-binding domains in other proteins, thus promoting inducible protein-protein interaction. In this manner, phosphorylation serves as a switch that allows signal transduction networks to transmit signals in response to extracellular stimuli.