Volume 14 Supplement 14
Circles within circles: crosstalk between protein Ser/Thr/Tyr-phosphorylation and Met oxidation
© Prasad Rao et al.; licensee BioMed Central Ltd. 2013
Published: 9 October 2013
Reversible posttranslational protein modifications such as phosphorylation of Ser/Thr/Tyr and Met oxidation are critical for both metabolic regulation and cellular signalling. Although these modifications are typically studied individually, herein we describe the potential for cross-talk and hierarchical regulation.
The proximity of Met to Ser/Thr/Tyr within the proteome has not previously been addressed. In order to consider the possibility of a generalized interaction, we performed a trans-kingdom sequence analysis of known phosphorylation sites in proteins from bacteria, fungi, plants, and animals. The proportion of phosphorylation sites that include a Met within a 13-residue window centered upon Ser/Thr/Tyr is significantly less than the occurrence of Met in proximity to all Ser/Thr/Tyr residues. Met residues are present at all positions (-6 to +6, inclusive) within the 13-residue window that we have considered. Detailed analysis of sequences from eight disparate plant taxa revealed that many conserved phosphorylation sites have a Met residue in the proximity. Results from GO enrichment analysis indicated that the potential for phosphorylation and Met oxidation crosstalk is most prevalent in kinases and proteins involved in signalling.
The large proportion of known phosphorylation sites with Met in the proximity fulfils the necessary condition for cross-talk. Kinases/signalling proteins are enriched for Met around phosphorylation sites. These proteins/sites are likely candidates for cross-talk between oxidative signalling and reversible phosphorylation.
KeywordsMethionine methionine sulfoxide oxidation protein phosphorylation regulation reversible posttranslational modifications signalling
The proteome includes the combination of at least three components; genome-encoded proteins, the products of alternative initiation and splicing, and of posttranslational modifications (PTM). This combination is orders of magnitude larger than could be solely genome-encoded . The diversity of PTM is extraordinarily large; to date as many as 435 different PTMs are known [2–5]. They can be reversible (e.g., acetylation) or irreversible (e.g., proteolytic cleavage), enzyme catalysed (e.g., kinase-mediated phosphorylation) or the result direct chemical reaction (e.g., oxidation), and individual or combinatorial [6, 7]. In toto, these factors comprise a well-adapted basis for signalling, regulation, targeting, and interaction, all at least potentially in the absence of de novo protein synthesis [3, 8].
Among PTM, reversible phosphorylation has been the most extensively studied [9–11]. This is in part because reversible phosphorylation is a component of both cellular signalling [8, 12] and direct regulatory control of protein function [13–15]. Protein phosphorylation can be stoichiometric at an individual site, or combinatorial and sequential/hierarchical at multiple sites [16, 17]. During the 'genomic era,' an enormous number of different protein kinases and phospho-protein (P-protein) phosphatases were identified, and reversible protein phosphorylation has been shown to be involved in regulating many fundamental cellular processes. It has been reported that the combination of genes encoding protein kinases and P-protein phosphatases constitute between 2 and 4% of the total number of genes in a typical eukaryotic genome . Saccharomyces cerevisiae has genes for 113 protein kinases while the Homo sapiens has 518 such genes . The genome of the reference dicot plant Arabidopsis thaliana includes genes encoding 1055 protein kinases  and 112 P-protein phosphatase catalytic subunits . Clearly, this PTM is ubiquitous across all branches of the tree of life .
Reactive oxygen species (ROS) are an inevitable consequence of aerobic metabolism [22–24]. High levels of ROS cause oxidative damage to proteins, which is lethal unless repaired or reversed [25, 26]. In contrast, low levels of ROS have evolved functional roles in many aspects of cellular signalling [27–29]. The reversible chemical oxidation of Met to methionine sulfoxide (MetSO) spans the two extremes in response to ROS. Oxidation of Met to MetSO can damage/inactivate proteins, but because this PTM is enzymatically reversible [30, 31] it can participate in the types of regulation  and signalling [33, 34] typified by reversible phosphorylation. Met oxidation is a particularly important component of cellular responses to oxidative stress [35, 36].
In addition to Ser/Thr/Tyr phosphorylation and Met oxidation, other common reversible PTMs include Ser/Thr O-glycosylation , Lys/Arg methylation , and Lys acetylation . There are examples of each directly regulating protein activities as well as playing roles in cellular signalling [40–43]. While a single PTM can modulate protein function, combinatorial and sequential/hierarchical interplay among two or more types of PTM can integrate signals from multiple pathways [6, 44, 45]. Dynamic interactions among PTM can take place at the same target residue [5, 46], or there can be cross-talk between or among multiple residues [47, 48]. In some instances the PTM of a specific residue can require a prior (primed) PTM at another site [6, 17, 49].
It was recently suggested that reversible Met oxidation might serve as a rheostat to control proximal Ser/Thr/Tyr phosphorylation [50, 51], and that this could be a mechanism for integrating information from both metabolic and ROS-based signalling pathways [52, 53]. However, it is not known how often phosphorylation sites contain Met residues in their proximity. It is important to identify candidate proteins with coupled Met oxidation and phosphorylation sites. The results described herein are from a study undertaken to test the possibility that phosphorylation and Met oxidation crosstalk has a broad occurrence.
Proteome sequences and phosphorylation sites
In order to consider our analysis of potential crosstalk in as broad a context as possible we have employed a data-mining strategy. Selected reference proteome or complete proteome sequences were downloaded from Uniprot , NCBI , or TAIR . Experimentally confirmed phosphorylation (Ser/Thr/Tyr) site information was obtained from multiple databases [21, 57]. Plant-specific phosphorylation site data was obtained from P3DB . Our aim was to explore the proportion of phosphorylated (and potentially phosphorylatable) sites that contain a Met residue within 13 residue window in different taxa. We used sequences and sites from several species of plants, yeast, animals, bacteria, and archaea (Additional file 1). Because Met oxidation is an aerobic process, we also included species that have an anaerobic metabolism/lifestyle such as Bacteroides fragilis, Clostridium botulinum, and Ascaris suum.
Phosphorylation site predictions
Phosphorylation sites were predicted for complete proteomes using Musite , NetPhosBac , or Disphos . Predictions were based on taxa-specific Ser/Thr/Tyr models at 95% specificity for the respective proteomes. Predictions were made to compare the differences, if any, between the proportion of Met residues in the vicinity of experimentally known phosphorylation sites and predicted phosphorylation sites.
The proportion of Ser/Thr/Tyr sites that include at least one Met-residue in a window ranging up to 21-residues was scanned. As most known phosphorylation motifs are less than 13-residues in length , a 13-residue window (six residues either side of the phosphorylation site) was selected for our analyses. Amino acid frequencies for individual proteomes were computed. Amino-terminal Met-residues were discounted in both calculations of Met frequency and sequence-distribution analyses. The hydropathy score for each site (Ser/Thr/Tyr centered in a 13-residue window; the phosphorylation site itself was not included) was calculated using the Kyte-Doolittle scale [57, 63].
In order to evaluate the extent of conservation of phosphorylation sites that contain a Met, and to identify candidate proteins for Phos-Met oxidation crosstalk in plants, a PSI-BLAST search was conducted for Arabidopsis thaliana, Glycine max, and Oryza sativa proteins that include a Met-residue within the 13-residue phosphorylation-site window. Proteins from these three taxa account for ~90% of known phosphorylation sites in plants. The results were used to identify related sequences in five additional proteomes (Pinus taeda, Selaginella moellendorffii, Physcomitrella patens, Chlamydomonas reinhardtii, and Cyanidioschyzon merolae), using a significance E-value cutoff of 0.00001. The total number of phosphorylation sites with Met-conservation was then calculated among the eight disparate taxa. Additionally, the proportion of hydrophobic residues (Met/Leu/Ile/Val/Phe/) was enumerated for each phosphorylation site.
Gene ontology enrichment analysis
A gene ontology (GO) term-enrichment analysis was performed for proteins that contain at least one known phosphorylation site including a Met within our specified ± 6-residue window, using the agriGO webserver  for A. thaliana or the g:Profiler webserver  for S. cerevisiae and H. sapiens. A hypergeometric test (with Bonferroni correction for multiple comparisons) was used to select significantly enriched (p < 0.05) terms [64, 65]. A log2 ratio of numbers of each significantly enriched GO term in the test set (phosphoproteins that have Met residues in the vicinity of phosphorylation site) to background set (all phosphoproteins) was calculated. All data analyses were performed using Python ver. 2.7. A Z-test was used to calculate the difference between two group proportions; p < 0.05 was considered significant.
The patterns are somewhat more complex when comparing the distribution of other members of the hydrophobic amino acid homology group (Leu, Ile, Val, and Phe) within the ± 6 residue window used to evaluate Met distribution (Additional file 2). With few exceptions, plant, yeast, and animal proteins have a lower occurrence of a hydrophobic residue within the ± 6 residue window centered on a P-Ser/Thr/Tyr residue. The exceptions include yeast position +1, and mammalian positions -1 and +3 from a P-Tyr residue (Additional file 2). Overall distribution of hydrophobic residues in the ± 6 window of prokaryotic and archaeal proteins is quite uneven, but it must be considered that the total number of phosphorylation sites in these proteins is much lower than in eukaryotic proteins (e.g., E. coli has been reported to have only 32 P-Tyr-containing proteins and two tyrosine-kinases .
Two unrelated plant enzymes, cytoplasmic nitrate reductase , and mitochondrial pyruvate dehydrogenase , have a Met residue proximal to a regulatory phosphorylation site, and in both cases oxidation of this Met to MetSO inhibits phosphorylation. It has been suggested that the redox status of these Met residues allows the enzymes to monitor oxidative stress, and crosstalk between these two PTMs can serve to fine-tune activity/metabolism [52, 53]. The study described herein was undertaken to evaluate how widespread the potential is for this sort of regulation by crosstalk between PTMs.
A 13-amino acid motif centered on the phosphorylatable Ser/Thr/Tyr-residue is apparently adequate for recognition by protein kinases [62, 67]. Multiple distinct factors likely contributed to evolution of this motif, including the occurrence of each of the amino acids [68, 69] and the constraints inherent to protein structure .
Given that thousands of phosphorylation sites are known in proteomes spanning taxa , the presence of Met in ~14% of these sites (Figure 2, Additional file 1) translates into a number of potential sites and proteins for phosphorylation and Met-oxidation crosstalk. Many phosphorylation motifs contain hydrophobic residues (Met/Val/Ile/Leu/Phe). This presumably reflects some essential aspect of protein structure or folding. However, Met is less abundant than the other hydrophobic residues , and is less likely to accommodate a structural requirement . Furthermore, biosynthesis of Met is more energetically expensive than other members of the hydrophobic group [69, 71, 73]. Considering all these constraints, the presence of Met in the phosphorylation motif would need to be of some evolutionary benefit otherwise it would have been lost during subsequent optimizing of the regulatory network . We propose that the benefit might have been acquisition of the ability to monitor ROS status by reversible Met oxidation, a capability not available with other hydrophobic residues . Even non-surface exposed Met residues are susceptible to oxidation because of local polypeptide flexibility .
Met residue in the neighbourhood of phosphorylation sites can have two distinct roles (Figure 7). It could have a solely structural role in which Met acts as a hydrophobic residue in a kinase recognition motif. If Met is replaced by other hydrophobic (VILF) residues in related species, then it is likely to have a structural role. On the other hand, Met could play a regulatory role if it is conserved near phosphorylation site in a protein from diverse species . We identified a large number of plant proteins and phosphorylation sites including Met that are highly conserved (Figure 5, Figure 7 and Additional file 3). These proteins are potential candidates wherein Met oxidation may be involved in coupling oxidative signals with phosphorylation and regulation of protein function.
This proposed evolutionary acquisition of Met/MetSO as a mechanism for fine-control of phosphorylation status might be addressed by comparison of phosphorylation sites in proteins from aerobic microorganisms with those from closely-related but obligate anaerobes. If Met oxidation exerts an influence (selection) on phosphorylation then it would be predicted that one group would have a significantly different proportion of (potential) phosphorylation sites including a Met residue. At least superficially this is not the case. In the very limited data available to us, aerobes (e.g., Escherichia coli and Staphylococcus aurius) and anaerobes (e.g., Bacillus fragilis and Clostridium botulinum) have a similar proportion of sites with Met (Additional file 1). It would be particularly interesting to evaluate the P-proteome of an organism such as the nematode Ascaris suum which has both aerobic and anaerobic components of its' life-cycle. Unfortunately, no P-proteomic data are currently available.
While the regulatory importance of protein PTM has been long known, it has only been more recently that roles for multiple and interacting PTM's have been appreciated . Examples range from interaction between multiple instances of the same PTM at different sites (e.g., prior or priming phosphorylation of site A is necessary for subsequent phosphorylation of site B [14–17]), through hierarchical responses to multiple PTM of the same site [5, 37, 46], or differential responses to multiple different PTM at different sites , and ultimately to crosstalk among different PTM at different sites . A protein with 10 instances of a single PTM could give rise to 1024 (2n) different molecular species, but if there are two types of PTM there is the potential to generate 59049 (3n) species . The enormity of this molecular diversity would generate a gradient in response that will allow an exquisitely fine control over metabolic activity, signalling, and cellular function .
Our initial interest in crosstalk between Ser/Thr/Tyr-phosphorylation and Met oxidation was stimulated by observations that two important metabolic enzymes could be responsive to cellular redox signalling through this mechanism [50–52]. While this study was underway, it came to our attention that there have been additional reports of what now appears to be crosstalk between phosphorylation and Met oxidation. Decreased phosphorylation is correlated with increased Met oxidation of α-synuclein in MetSO knockdown mutants of both yeast and mice [80, 81]. Site-specific oxidation of Met in calmodulin was shown to affect its structure, and thus its interaction with Ca2+/calmodulin-dependent protein kinase II and subsequent downstream signalling . There is also an analogous example  where activity of a protein P-Tyr-phosphatase is regulated by reversible Cys-oxidation. Finally, there is the intriguing recent report that Met oxidation in A. thaliana is responsive to cGMP .
Results from GO analysis indicated that the occurrence of Met near phosphorylation sites could be more prevalent in proteins related to signalling such as kinases and stress related proteins, and could be common to all three taxa - plants, yeast, and animals (Figure 4 and 6). Many phosphorylation motifs - kinase recognition signatures - contain hydrophobic Met residue [57, 62]. Oxidation of Met to MetSO causes a shift from hydrophobic to hydrophilic in nature, and would thus likely disrupt kinase recognition . So it is potentially useful for kinases and stress signalling proteins to have evolutionary selection for Met near phosphorylation sites for potential crosstalk. This would allow direct communication of oxidative signals to other mainstream processes.
Our study identified a large number of phosphorylation sites which include a vicinal Met residue. The proteins containing these sites can potentially function as redox-sensors capable of transducing input from ROS signalling to regulation of phosphorylation. These observations should stimulate further research on PTM crosstalk and control of protein function in response to oxidative signalling.
This work was supported in part by National Science Foundation-Plant Genome Research Program Grant DBI-0604439 to J.J.T.
Publication costs for this article were funded by the United Stated Department of Agriculture, Agricultural Research Service, Project number 3622-21000-032-00D.
This article has been published as part of BMC Bioinformatics Volume 14 Supplement 14, 2013: Proceedings of the Tenth Annual MCBIOS Conference. Discovery in a sea of data. The full contents of the supplement are available online at http://www.biomedcentral.com/bmcbioinformatics/supplements/14/S14.
- Prabakaran S, Lippens G, Steen H, Gunawardena J: Post-translational modification: nature's escape from genetic imprisonment and the basis for dynamic information encoding. Wiley Interdiscip Rev Syst Biol Med. 2012, 4: 565-583. 10.1002/wsbm.1185.PubMed CentralView ArticlePubMedGoogle Scholar
- Mann M, Jensen ON: Proteomic analysis of post-translational modifications. Nature Biotechnol. 2003, 21: 255-261. 10.1038/nbt0303-255.View ArticleGoogle Scholar
- Walsh CT, Garneau-Tsodikova S, Gatto GJ: Protein posttranslational modifications: The chemistry of proteome diversifications. Angew Chem Int Ed Engl. 2005, 44: 7342-7372. 10.1002/anie.200501023.View ArticlePubMedGoogle Scholar
- Khoury GA, Baliban RC, Floudasa CA: Proteome-wide post-translational modification statistics: Frequency analysis and curation of the swiss-prot database. Sci Rep. 2011, 1: 90.PubMed CentralView ArticleGoogle Scholar
- Minguez P, Parca L, Diella F, Mende DR, Kumar R, Helmer-Citterich M, Gavin AC, van Noort V, Bork P: Deciphering a global network of functionally associated post-translational modifications. Molec Syst Biol. 2012, 8: 599.View ArticleGoogle Scholar
- Hunter T: The age of crosstalk: Phosphorylation, ubiquitination and beyond. Mol Cell. 2007, 28: 730-738. 10.1016/j.molcel.2007.11.019.View ArticlePubMedGoogle Scholar
- Beltrao P, Albanèse V, Kenner LR, Swaney DL, Burlingame A, Villén J, Lim WA, Fraser JS, Frydman J, Krogan NJ: Systematic functional prioritization of protein posttranslational modifications. Cell. 2012, 150: 413-425. 10.1016/j.cell.2012.05.036.PubMed CentralView ArticlePubMedGoogle Scholar
- Deribe YL, Pawson T, Dikic I: Post-translational modifications in signal integration. Nature Struct Mol Biol. 2010, 17: 666-672. 10.1038/nsmb.1842.View ArticleGoogle Scholar
- Loroch S, Dickhut C, Zahedi RP, Sickmann A: Phosphoproteomics - More than meets the eye. Electrophoresis. 2013, doi: 10.1002/elps.201200710.,Google Scholar
- Havelund JF, Thelen JJ, Møller IM: Biochemistry, proteomics, and phosphoproteomics of plant mitochondria from non-photosynthetic cells. Front Plant Sci. 2013, 4: 51.PubMed CentralView ArticlePubMedGoogle Scholar
- Mijakovic I, Macek B: Impact of phosphoproteomics on studies of bacterial physiology. FEMS Microbiol Rev. 2012, 36: 877-892. 10.1111/j.1574-6976.2011.00314.x.View ArticlePubMedGoogle Scholar
- Rogne M, Taskén K: Cell signalling analyses in the functional genomics era. Nature Biotechnol. 2013, 30: 333-338.Google Scholar
- Furuya E, Yokoyama M, Uyeda K: Regulation of fructose-6-phosphate 2-kinase by phosphorylation and dephosphorylation: possible mechanism for coordinated control of glycolysis and glycogenolysis. Proc Natl Acad Sci USA. 1982, 79: 325-329. 10.1073/pnas.79.2.325.PubMed CentralView ArticlePubMedGoogle Scholar
- Dexter JP, Gunawardena J: Dimerization and bifunctionality confer robustness to the isocitrate dehydrogenase regulatory system in Escherichia coli. J Biol Chem. 2013, 288: 5770-5778. 10.1074/jbc.M112.339226.PubMed CentralView ArticlePubMedGoogle Scholar
- Oliveira AP, Ludwig C, Picotti P, Kogadeeva M, Aebersold R, Sauer U: Regulation of yeast central metabolism by enzyme phosphorylation. Mol Syst Biol. 2012, 8: 623.PubMed CentralView ArticlePubMedGoogle Scholar
- Just S, Illing S, Trester-Zedlitz M, Lau EK, Kotowski SJ, Miess E, Mann A, Doll C, Trinidad JC, Burlingame AL, von Zastrow M, Schulz S: Differentiation of opioid drug effects by hierarchical multi-site phosphorylation. Mol Pharmacol. 2013, 83: 633-639. 10.1124/mol.112.082875.PubMed CentralView ArticlePubMedGoogle Scholar
- Ahsan N, Huang Y, Tovar-Mendez A, Swatek KN, Zhang J, Miernyk JA, Xu D, Thelen JJ: A versatile mass spectrometry-based method to both identify kinase client-relationships and characterize signaling network topology. J Proteome Res. 2013, 12: 937-948. 10.1021/pr3009995.PubMed CentralView ArticlePubMedGoogle Scholar
- Moorhead GBG, De Wever V, Templeton G, Kerk D: Evolution of protein phosphatases in plants and animals. Biochem J. 2002, 417: 401-409.View ArticleGoogle Scholar
- Niedner RH, Buzko OV, Haste NM, Taylor A, Gribskov M, Taylor SS: Protein kinase resource: an integrated environment for phosphorylation research. Proteins. 2006, 78-86. 63Google Scholar
- Kerk D, Bulgrien J, Smith DW, Barsam B, Veretnik S, Gribskov M: The complement of protein phosphatase catalytic subunits encoded in the genome of Arabidopsis. Plant Physiol. 2002, 129: 908-925. 10.1104/pp.004002.PubMed CentralView ArticlePubMedGoogle Scholar
- Aivaliotis M, Macek B, Gnad F, Reichelt P, Mann M, Oesterhelt D: Ser/Thr/Tyr protein phosphorylation in the archaeon Halobacterium salinarum - A representative of the third domain of life. PLoS ONE. 2009, 4: e4777-10.1371/journal.pone.0004777.PubMed CentralView ArticlePubMedGoogle Scholar
- Hatanaka E, Dermargos A, Hirata AE, Vinolo MA, Carpinelli AR, Newsholme P, Armelin HA, Curi R: Oleic, linoleic and linolenic acids increase ROS production by fibroblasts via NADPH oxidase activation. PLoS One. 2013, 8: e58626-10.1371/journal.pone.0058626.PubMed CentralView ArticlePubMedGoogle Scholar
- Grivennikova VG, Vinogradov AD: Partitioning of superoxide and hydrogen peroxide production by mitochondrial respiratory complex I. Biochim Biophys Acta. 2013, 1827: 446-454. 10.1016/j.bbabio.2013.01.002.View ArticlePubMedGoogle Scholar
- Panieri E, Gogvadze V, Norberg E, Venkatesh R, Orrenius S, Zhivotovsky B: Reactive oxygen species generated in different compartments induce cell death, survival, or senescence. Free Radic Biol Med. 2013, 57: 176-187.View ArticlePubMedGoogle Scholar
- Møller IM, Jensen PE, Hansson A: Oxidative modifications to cellular components in plants. Annu Rev Plant Biol. 2007, 58: 459-481. 10.1146/annurev.arplant.58.032806.103946.View ArticlePubMedGoogle Scholar
- Höhn A, König J, Grune T: Protein oxidation in aging and the removal of oxidized proteins. J Proteomics. 2013, doi:pii: S1874-3919(13)00021-3.,Google Scholar
- Møller IM, Sweetlove LJ: ROS signalling--specificity is required. Trends Plant Sci. 2010, 15: 370-374. 10.1016/j.tplants.2010.04.008.View ArticlePubMedGoogle Scholar
- Aiken CT, Kaake RM, Wang X, Huang L: Oxidative stress-mediated regulation of proteasome complexes. Mol Cell Proteomics. 2011, 10: R110-006924.PubMed CentralView ArticlePubMedGoogle Scholar
- Wang P, Du Y, Zhao X, Miao Y, Song CP: The MPK6-ERF6-ROS-responsive cis-acting Element7/GCC box complex modulates oxidative gene transcription and the oxidative response in Arabidopsis. Plant Physiol. 2013, 161: 1392-1408. 10.1104/pp.112.210724.PubMed CentralView ArticlePubMedGoogle Scholar
- Boschi-Muller S, Olry A, Antoine M, Branlant G: The enzymology and biochemistry of methionine sulfoxide reductases. Biochim Biophys Acta. 2005, 1703: 231-238. 10.1016/j.bbapap.2004.09.016.View ArticlePubMedGoogle Scholar
- Boschi-Muller S, Gand A, Branlant G: The methionine sulfoxide reductases: Catalysis and substrate specificities. Arch Biochem Biophys. 2008, 474: 266-273. 10.1016/j.abb.2008.02.007.View ArticlePubMedGoogle Scholar
- Stadtman ER, Moskovitz J, Levine RL: Oxidation of methionine residues of proteins: biological consequences. Antioxid Redox Signal. 2003, 5: 577-582. 10.1089/152308603770310239.View ArticlePubMedGoogle Scholar
- Carruthers NJ, Stemmer PM: Methionine oxidation in the calmodulin-binding domain of calcineurin disrupts calmodulin binding and calcineurin activation. Biochemistry. 2008, 47: 3085-3095. 10.1021/bi702044x.PubMed CentralView ArticlePubMedGoogle Scholar
- Bigelow DJ, Squier TC: Thioredoxin-dependent redox regulation of cellular signaling and stress response through reversible oxidation of methionines. Mol Biosyst. 2011, 7: 2101-2109. 10.1039/c1mb05081h.View ArticlePubMedGoogle Scholar
- Erickson JR, Joiner ML, Guan X, Kutschke W, Yang J, Oddis CV, Bartlett RK: A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation. Cell. 2008, 133: 462-474. 10.1016/j.cell.2008.02.048.PubMed CentralView ArticlePubMedGoogle Scholar
- Bigelow DJ, Squier TC: Redox modulation of cellular signaling and metabolism through reversible oxidation of methionine sensors in calcium regulatory proteins. Biochim Biophys Acta. 2005, 1703: 121-134. 10.1016/j.bbapap.2004.09.012.View ArticlePubMedGoogle Scholar
- Zauner G, Kozak RP, Gardner RA, Fernandes DL, Deelder AM, Wuhrer M: Protein O-glycosylation analysis. Biol Chem. 2012, 393: 687-708.View ArticlePubMedGoogle Scholar
- Erce MA, Pang CN, Hart-Smith G, Wilkins MR: The methylproteome and the intracellular methylation network. Proteomics. 2012, 12: 564-586. 10.1002/pmic.201100397.View ArticlePubMedGoogle Scholar
- Zhang K, Tian S, Fan E: Protein lysine acetylation analysis: current MS-based proteomic technologies. Analyst. 2013, 138: 1628-1636. 10.1039/c3an36837h.View ArticlePubMedGoogle Scholar
- Theillet FX, Smet-Nocca C, Liokatis S, Thongwichian R, Kosten J, Yoon MK, Kriwacki RW: Cell signaling, post-translational protein modifications and NMR spectroscopy. J Biomol NMR. 2012, 54: 217-236. 10.1007/s10858-012-9674-x.View ArticlePubMedGoogle Scholar
- Shi SP, Qiu JD, Sun XY, Suo SB, Huang SY, Liang RP: PMeS: prediction of methylation sites based on enhanced feature encoding scheme. PLoS One. 2012, 7: e38772-10.1371/journal.pone.0038772.PubMed CentralView ArticlePubMedGoogle Scholar
- Donlin LT, Andresen C, Just S, Rudensky E, Pappas CT, Kruger M, Jacobs EY: Smyd2 controls cytoplasmic lysine methylation of Hsp90 and myofilament organization. Genes Dev. 2012, 26: 114-119. 10.1101/gad.177758.111.PubMed CentralView ArticlePubMedGoogle Scholar
- Gill DJ, Clausen H, Bard F: Location, location, location: new insights into O-GalNAc protein glycosylation. Trends Cell Biol. 2011, 21: 149-158. 10.1016/j.tcb.2010.11.004.View ArticlePubMedGoogle Scholar
- Young NL, Plazas-Mayorca MD, Garcia BA: Systems-wide proteomic characterization of combinatorial post-translational modification patterns. Expert Rev Proteomics. 2010, 7: 79-92. 10.1586/epr.09.100.View ArticlePubMedGoogle Scholar
- Hart GW, Slawson C, Ramirez-Correa G, Lagerlof O: Cross talk between O-GlcNAcylation and phosphorylation: Roles in signaling, transcription, and chronic disease. Annu Rev Biochem. 2011, 80: 825-858. 10.1146/annurev-biochem-060608-102511.PubMed CentralView ArticlePubMedGoogle Scholar
- Hart GW, Housley MP, Slawson C: Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature. 2007, 446: 1017-1022. 10.1038/nature05815.View ArticlePubMedGoogle Scholar
- Lu Z, Cheng Z, Zhao Y, Volchenboum SL: Bioinformatic analysis and post-translational modification crosstalk prediction of lysine acetylation. PLoS One. 2011, 6: e28228-10.1371/journal.pone.0028228.PubMed CentralView ArticlePubMedGoogle Scholar
- van Noort V, Seebacher J, Bader S, Mohammed S, Vonkova I, Betts MJ, Kühner S: Cross-talk between phosphorylation and lysine acetylation in a genome-reduced bacterium. Mol Syst Biol. 2012, 8: 571.PubMed CentralView ArticlePubMedGoogle Scholar
- Sharfi H, Eldar-Finkelman H: Sequential phosphorylation of insulin receptor substrate-2 by glycogen synthase kinase-3 and c-Jun NH2-terminal kinase plays a role in hepatic insulin signaling. Am J Physiol Endocrinol Metab. 2008, 294: E307-315.View ArticlePubMedGoogle Scholar
- Hardin SC, Larue CT, Oh MH, Jain V, Huber SC: Coupling oxidative signals to protein phosphorylation via methionine oxidation in Arabidopsis. Biochem J. 2009, 422: 305-312. 10.1042/BJ20090764.PubMed CentralView ArticlePubMedGoogle Scholar
- Miernyk JA, Johnston ML, Huber SC, Tovar-Méndez A, Hoyos E, Randall DD: Oxidation of an adjacent methionine residue inhibits regulatory seryl-phosphorylation of pyruvate dehydrogenase. Proteomics Insights. 2009, 2: 15-22.Google Scholar
- Emes MJ: Oxidation of methionine residues: the missing link between stress and signalling responses in plants. Biochem J. 2009, 422: e1-2. 10.1042/BJ20091063.View ArticlePubMedGoogle Scholar
- Zhang X-H: Regulation of protein function by residue oxidation. Proteomics Insights. 2010, 3: 17-24.View ArticleGoogle Scholar
- Uniprot. [http://www.uniprot.org/]
- NCBI. [http://www.ncbi.nlm.nih.gov/]
- TAIR. [http://www.arabidopsis.org/]
- Rao RSP, Møller IM: Large-scale analysis of phosphorylation site occupancy in eukaryotic proteins. Biochim Biophys Acta. 2012, 1824: 405-412. 10.1016/j.bbapap.2011.12.001.View ArticlePubMedGoogle Scholar
- P3DB. [http://www.p3db.org/]
- Gao J, Thelen JJ, Dunker AK, Xu D: Musite, a tool for global prediction of general and kinase-specific phosphorylation sites. Mol Cell Proteomics. 2010, 9: 2586-2600. 10.1074/mcp.M110.001388.PubMed CentralView ArticlePubMedGoogle Scholar
- Miller ML, Soufi B, Jers C, Blom N, Macek B, Mijakovic I: NetPhosBac - A predictor for Ser/Thr phosphorylation sites in bacterial proteins. Proteomics. 2009, 9: 116-125. 10.1002/pmic.200800285.View ArticlePubMedGoogle Scholar
- Iakoucheva LM, Radivojac P, Brown CJ, O'Connor TR, Sikes JG, Obradovic Z, Dunker AK: The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res. 2004, 32: 1037-1049. 10.1093/nar/gkh253.PubMed CentralView ArticlePubMedGoogle Scholar
- Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP: Large-scale characterization of HeLa cell nuclear phosphoproteins. Proc Natl Acad Sci USA. 2004, 101: 12130-12135. 10.1073/pnas.0404720101.PubMed CentralView ArticlePubMedGoogle Scholar
- Kyte J, Doolittle RF: A simple method for displaying the hydropathic character of a protein. J Mol Biol. 1982, 157: 105-132. 10.1016/0022-2836(82)90515-0.View ArticlePubMedGoogle Scholar
- Du Z, Zhou X, Ling Y, Zhang Z, Su Z: AgriGO: A GO analysis toolkit for the agricultural community. Nucleic Acids Res. 2010, 38: W64-70. 10.1093/nar/gkq310.PubMed CentralView ArticlePubMedGoogle Scholar
- Reimand J, Kull M, Peterson H, Hansen J, Vilo J: g:Profiler - a web-based toolset for functional profiling of gene lists from large-scale experiments. Nucleic Acids Res. 2007, 35: W193-200. 10.1093/nar/gkm226.PubMed CentralView ArticlePubMedGoogle Scholar
- Mijakovic I: Protein phosphorylation in bacteria. Microbe. 5: 21-25.Google Scholar
- Mok J, Kim PM, Lam HYK, Piccirillo S, Zhou X, Jeschke GR, Sheridan DL: Deciphering protein kinase specificity through large-scale analysis of yeast phosphorylation site motifs. Science Signaling. 2010, 3: ra12-10.1126/scisignal.2000482.PubMed CentralView ArticlePubMedGoogle Scholar
- Grantham R: Amino acid difference formula to help explain protein evolution. Science. 1974, 185: 862-864. 10.1126/science.185.4154.862.View ArticlePubMedGoogle Scholar
- Akashi H, Gojobori T: Metabolic efficiency and amino acid composition in the proteomes of Escherichia coli and Bacillus subtilis. Proc Natl Acad Sci USA. 2002, 99: 3695-3700. 10.1073/pnas.062526999.PubMed CentralView ArticlePubMedGoogle Scholar
- Siltberg-Liberles J, Grahnen JA, Liberles DA: The evolution of protein structures and structural ensembles under functional constraint. Genes. 2011, 2: 748-762. 10.3390/genes2040748.PubMed CentralView ArticlePubMedGoogle Scholar
- Raiford DW, Heizer EM, Miller RV, Akashi H, Raymer ML, Krane DE: Do amino acid biosynthetic costs constrain protein evolution in Saccharomyces cerevisiae?. J Mol Evol. 2008, 67: 621-630. 10.1007/s00239-008-9162-9.View ArticlePubMedGoogle Scholar
- Jha AN, Vishveshwara S, Banavar JR: Amino acid interaction preferences in proteins. Protein Sci. 2010, 19: 603-616. 10.1002/pro.339.View ArticlePubMedGoogle Scholar
- Barton MD, Delneri D, Oliver SG, Rattray M, Bergman CM: Evolutionary systems biology of amino acid biosynthetic cost in yeast. PLoS ONE. 2010, 5: e11935-10.1371/journal.pone.0011935.PubMed CentralView ArticlePubMedGoogle Scholar
- Tan CS, Pasculescu A, Lim WA, Pawson T, Bader GD, Linding R: Positive selection of tyrosine loss in metazoan evolution. Science. 2009, 325: 1686-1688. 10.1126/science.1174301.PubMed CentralView ArticlePubMedGoogle Scholar
- Møller IM, Rogowska-Wrzesinska A, Rao RS: Protein carbonylation and metal-catalyzed protein oxidation in a cellular perspective. J Proteomics. 2011, 74: 2228-2242. 10.1016/j.jprot.2011.05.004.View ArticlePubMedGoogle Scholar
- Xu K, Uversky VN, Xue B: Local flexibility facilitates oxidization of buried methionine residues. Protein Pept Lett. 2012, 19: 688-697. 10.2174/092986612800494084.View ArticlePubMedGoogle Scholar
- Woodsmith J, Kamburov A, Stelzl U: Dual coordination of post translational modifications in human protein networks. PLoS Comput Biol. 2013, 9: e1002933-10.1371/journal.pcbi.1002933.PubMed CentralView ArticlePubMedGoogle Scholar
- Wellen KE, Thompson CB: A two-way street: Reciprocal regulation of metabolism and signalling. Nature Rev Mol Cell Biol. 2012, 13: 270-276.Google Scholar
- Yang X-J, Seto E: Lysine acetylation: Codified crosstalk with other posttranslational modifications. Mol Cell. 2008, 31: 449-461. 10.1016/j.molcel.2008.07.002.PubMed CentralView ArticlePubMedGoogle Scholar
- Oien DB, Carrasco GA, Moskovitz J: Decreased phosphorylation and increased methionine oxidation of α-synuclein in the methionine sulfoxide reductase A knockout mouse. J Amino Acids. 2011, 2011: 721094.PubMed CentralView ArticlePubMedGoogle Scholar
- Oien DB, Shinogle HE, Moore DS, Moskovitz J: Clearance and phosphorylation of alpha-synuclein are inhibited in methionine sulfoxide reductase A null yeast cells. J Mol Neurosci. 2009, 39: 323-332. 10.1007/s12031-009-9274-8.PubMed CentralView ArticlePubMedGoogle Scholar
- Snijder J, Rose RJ, Raijmakers R, Heck AJ: Site-specific methionine oxidation in calmodulin affects structural integrity and interaction with Ca2+/calmodulin-dependent protein kinase II. J Struct Biol. 174: 187-195.Google Scholar
- Xu S, Ding H, Su F, Zhang A, Jiang M, Ostman A, Frijhoff J: Regulation of protein tyrosine phosphatases by reversible oxidation. J Biochem. 2011, 150: 345-356. 10.1093/jb/mvr104.View ArticleGoogle Scholar
- Marondedze C, Turek I, Parrott B, Thomas L, Jankovic B, Lilley KS, Gehring C: Structural and functional characteristics of cGMP-dependent methionine oxidation in Arabidopsis thaliana proteins. Cell Commun Signal. 2013, 11: 1-10.1186/1478-811X-11-1.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.