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.Keywords: phosphate; ester; protein; phosphorylation; kinase; evolution PHOSPHATE ESTERS HAVE ADVANTAGEOUS CHEMICAL PROPERTIES FOR THE EVOLUTION OF LIFEPhosphate-containing molecules are essential constituents of all living cells. What then are the special properties of phosphate that led to its selection as a key building block during the evolution of self-replicating life forms? Phosphorus is a Group 15 element, and therefore has five electrons in its outer shell. By donating its electrons, phosphorus can form five covalent bonds; for example, by combining with four oxygen atoms, phosphorus forms orthophosphate, PO 3À 4 . Phosphate has three pKas (2.2, 7.2 (5.8 as an ester) and 12.4) and is highly soluble in water, forming a large hydrated ionic shell. Phosphate is chemically versatile and can form mono-, di-and tri-esters with alkyl and aryl hydroxyl groups, as well as acid anhydrides. In addition, phosphorus can form P-N (phosphoramidate), P-S (phosphorothioate) and P-C (phosphonate) linkages.Phosphate salts are very abundant on the Earth, and, owing to their water solubility, were readily available during the evolution of life. The ability of phosphate to form esters and anhydrides that are stable at ambient temperatures in water made it ideal for the generation of biological molecules. Phosphate esters and anhydrides predominate in living organisms, but phosphoramidates, phosphorothioates and phosphonates are all found in nature. Phosphate esters are readily formed under physiological conditions using adenosine triphosphate (ATP), a phosphate anhydride, as a phosphate donor and an enzyme catalyst. On...

Eukaryotic Phosphate Homeostasis: The Inositol Pyrophosphate Perspective

“…Furthermore, being negatively charged at physiological pH provides phosphate with signalling properties, including the attachment of a phosphate group to a specific amino acid, thereby altering the overall charge of the protein and affecting its functions [2]. In fulfilling these varied roles, phosphate moieties circulate between organic molecules, generally being passed along via phosphotransfer reactions involving nucleotide triphosphates.…”

Advances in development of new tools for the study of phosphohistidine

“…70 Hultquist's phosphoryl transfer experiments can be used as a plausible explanation for the accumulation of τ-pHis with the decrease in π-and bis-pHis over time (Scheme 3). Phosphoryl transfer reactions (1)(2)(3)(4)(5)(6)(7)(8) suggest that the phosphoryl group of pHis can be donated to the imidazole nitrogen of His or α-N-acetyl-His. Comparison of (1) and (5), with (7) and (8) suggests that π-pHis has the more labile phosphorus nitrogen (P-N) bond compared with τ-pHis.…”

“…Hence, it should be of no surprise that phosphorylation affects protein conformation, protein-protein interactions, biochemical pathways and its dysregulation is connected to many disease states. 2 There are nine known phosphorylated amino-acid residues Ser, Thr, Tyr, histidine (His), lysine (Lys), arginine (Arg), aspartic acid (Asp), glutamic acid (Glu) and cysteine (Cys). 2 The hydroxy O-linked phospho-residues, phosphoserine (pSer), phosphothreonine (pThr) and phosphotyrosine (pTyr) have been extensively studied, most probably due to their relative stability in acidic conditions routinely used for analysis.…”

“…2 There are nine known phosphorylated amino-acid residues Ser, Thr, Tyr, histidine (His), lysine (Lys), arginine (Arg), aspartic acid (Asp), glutamic acid (Glu) and cysteine (Cys). 2 The hydroxy O-linked phospho-residues, phosphoserine (pSer), phosphothreonine (pThr) and phosphotyrosine (pTyr) have been extensively studied, most probably due to their relative stability in acidic conditions routinely used for analysis. Hence, the relatively acid labile N-linked phosphoramidate, carboxy O-linked acyl phosphate and S-linked phosphorothiolate amino-acid residues (His, Lys, Arg; Asp, Glu; Cys, respectively) have been largely overlooked and less frequently reported.…”

DNA Replication Stress Phosphoproteome Profiles Reveal Novel Functional Phosphorylation Sites on Xrs2 in Saccharomyces cerevisiae

“…A common approach is to generate phospho-mimicking (aspartic or glutamic acid) amino acid substitutions of the site of interest and to determine if the observed phenotypes are reversed or neutralized. However, since the chemical environment introduced by phosphorylation is not completely equivalent to that of negatively charged residues, the failure rate of such studies is high, and the behavior of phosphomimetic mutations can be hard to interpret (Hunter 2012;Dephoure et al 2013). In our studies, none of the phospho-mutants showed growth defects under normal conditions (in contrast to the full ORF deletion mutants, which exhibited mild-tosignificant growth defects) (Figure 2A), suggesting that the engineered phosphosite substitutions behave similarly to wild type.…”