Phosphorylation on unusual amino acids
Contents
Histidine Phosphorylation
Histidine Kinases autophosphorylate on a histidine, before transferring this labile phosphate to an aspartate on a substrate protein. They are frequently receptor proteins, and usually phosphorylate a specific regulator domain. They are widespread in bacteria and eukaryotes, but in animals, the only members of this fold family are the mitochondrial pyruvate dehydrogenase kinases, which 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 proposed. This model was constructed based on homologies between the published X-ray crystal structure of a TPP-binding enzyme transketolase (from Hanensula polymorpha) and E1 from human, S. stearothermophilus, E. coli, as well as S. cerevisiae pyruvate decarboxylase (17). According to this model, two histidine residues, 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. In humans, aldolase C is known to by phosphorylated on Asp319 by the nucleoside diphosphate kinase NDPK-A (nm23, NME1) (1). In two component signaling, found in bacteria, plants and lower eukaryotes, the response regulator domain is phosphorylated on Asp by the histidine kinase domain.
References
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. . J. Biol. Chem., 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.
Lysine and Arginine Phosphorylation
Phosphorylation of the nitrogens of Lys and Arg has been reported in mammals, by biochemical methods, but the kinases involved have not been purified (1). Like histitine, phosphorylated lys and arg are labile and difficult to purify, and may be much more common than the published evidence suggests. Histones have been reported to be phosphorylated on both lys and arg, though the biological relevance is not certain.
A specific Arginine kinase has been isolated in Bacillus subtilis (2). McsB was previously described as a tyrosine kinase (3), but found to phosphorylate arginine residues in it's binding partner, CtsR and peptides in vitro. The protein is related to arginine and creatine kinases, which also have homologs in eukaryotes.
References
1. Matthews, HR (1995) Protein Kinases and Phosphatases that Act on Histidine, Lysine, or Arginine Residues in Eukaryotic Proteins: a possible regulator of the mitogen-activated protein kinase cascade. Pharmac. ther. 67:323-50
2. Fuhrman, J et al (2009). McsB Is a Protein Arginine Kinase That Phosphorylates and Inhibits the Heat-Shock egulator CtsR. Science 324:1323-7
3. Awaiting ref.
