Phosphorylation on unusual amino acids

Cysteine Phosphorylation

In E. coli and other bacteria, the glucose transporter complex phosphorylates glucose while transporting it. This involves an extended phosphotransfer relay with several subunits of the phosphotransferase (PTS) system (1).

• 1. The EI enzyme receives a phosphate from phosphoenolpyruvate, and transfers it to a phosphoacyl carrier protein (HPr)
• 2. The IIAGlc subunit transfers a phosphate from Hpr to a cysteine (C520 in E. coli) of the IIBCGlc subunit
• 3. IIBCGlc then transports and phosphorylates the glucose.

In eukaryotes, the active site Cysteine of PTP phosphatases forms a phospho-cysteine intermediate during catalysis (2,3). In addition, one phosphoproteome study reported phosphorylation of Cys63 of sarcomeric mitochondrial creatine kinase, a partially conserved residue of unknown function (4).

References:

1. Cysteine phosphorylation of the glucose transporter of Escherichia coli. M Meins, P Jenö, D Müller, W J Richter, J P Rosenbusch and B Erni (1993). J. Biol. Chem, 268, 11604-11609.

2. Dixon, JE, Guan, KL. Evidence for protein-tyrosine-phosphatase catalysis proceeding via a cysteine-phosphate intermediate. J. Biol. Chem., 266, 17026-17030.

3.Pannifer, ADB, Flint, AJ, Tonks, NK, Barford, D. Visualization of the Cysteinyl-phosphate Intermediate of a Protein-tyrosine Phosphatase by X-ray Crystallography. . The Journal of Biological Chemistry, 273, 10454-10462. doi: 10.1074/jbc.273.17.10454

4. Feng J, Zhu M, Schaub MC, Gehrig P, Roschitzki B, Lucchinetti E, Zaugg M. (2009) Phosphoproteome analysis of isoflurane-protected heart mitochondria: phosphorylation of adenine nucleotide translocator-1 on Tyr194 regulates mitochondrial function. Cardiovasc Res. 80:20-9.

Histidine Phosphorylation

Histidine Kinases, found in bacteria, plants, and lower eukaryotes, autophosphorylate on a histidine, before transferring this labile phosphate to an aspartate on a substrate protein. The only human members of this family, the pyruvate dehydrogenase kinases, seem to have changed their specificity to be serine autokinases.

Nucleoside diphosphate kinases can also phosphorylate histidine with one well validated case in humans. A mitochondrial phosphoproteome study also found phosphorylation on His292 of pyruvate dehydrogenase E1 alpha subunit (Ser293 is also highly phosphorylated in many studies - could HisP be misinterpreted as SerP based on peptide mass?) (1). H292 mutations abolish PDH function (A. Seyda and B.H. Robinson, Functional expression of four PDH-E(1)alpha recombinant histidine mutants in a human fibroblast cell line with zero endogenous PDH complex activity. Biochem. Biophys. Res. Commun. 270 (2000), pp. 1068–1073) [This might be H263 in the original paper, maybe that's the mature form. This quotes the function of this site: "In 1993 a model for the thiamine pyrophosphate- binding site of human pyruvate dehydrogenase E was 1 proposed. This model was constructed based on homol- ogies between the published X-ray crystal structure of a TPP-binding enzyme transketolase (from Hanensula polymorpha) and E1 from human, S. stearothermophi- lus, E. coli, as well as S. cerevisiae pyruvate decarbox- ylase (17). According to this model, two histidine resi- dues, H84 and H263, are required for pyrophosphate coordination through hydrogen bonding").

References:

1. Feng J, Zhu M, Schaub MC, Gehrig P, Roschitzki B, Lucchinetti E, Zaugg M. (2009) Phosphoproteome analysis of isoflurane-protected heart mitochondria: phosphorylation of adenine nucleotide translocator-1 on Tyr194 regulates mitochondrial function. Cardiovasc Res. 80:20-9.

Aspartate Phosphorylation

Aspartate is the substrate of activated histdine kinases

Lysine and Arginine Phosphorylation

These are reported to be phosphorylated on histones and other proteins.

Glutamate Phosphorylation

One unreferenced note on phosphosite, following up.