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The Methods Employed in Mass Spectrometric Analysis of Posttranslational Modifications (PTMs) and Protein–Protein Interactions (PPIs)

  • Rama R. Yakubu
  • Edward Nieves
  • Louis M. WeissEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1140)

Abstract

Mass Spectrometry (MS) has revolutionized the way we study biomolecules, especially proteins, their interactions and posttranslational modifications (PTM). As such MS has established itself as the leading tool for the analysis of PTMs mainly because this approach is highly sensitive, amenable to high throughput and is capable of assigning PTMs to specific sites in the amino acid sequence of proteins and peptides. Along with the advances in MS methodology there have been improvements in biochemical, genetic and cell biological approaches to mapping the interactome which are discussed with consideration for both the practical and technical considerations of these techniques. The interactome of a species is generally understood to represent the sum of all potential protein-protein interactions. There are still a number of barriers to the elucidation of the human interactome or any other species as physical contact between protein pairs that occur by selective molecular docking in a particular spatiotemporal biological context are not easily captured and measured.

PTMs massively increase the complexity of organismal proteomes and play a role in almost all aspects of cell biology, allowing for fine-tuning of protein structure, function and localization. There are an estimated 300 PTMS with a predicted 5% of the eukaryotic genome coding for enzymes involved in protein modification, however we have not yet been able to reliably map PTM proteomes due to limitations in sample preparation, analytical techniques, data analysis, and the substoichiometric and transient nature of some PTMs. Improvements in proteomic and mass spectrometry methods, as well as sample preparation, have been exploited in a large number of proteome-wide surveys of PTMs in many different organisms. Here we focus on previously published global PTM proteome studies in the Apicomplexan parasites T. gondii and P. falciparum which offer numerous insights into the abundance and function of each of the studied PTM in the Apicomplexa. Integration of these datasets provide a more complete picture of the relative importance of PTM and crosstalk between them and how together PTM globally change the cellular biology of the Apicomplexan protozoa. A multitude of techniques used to investigate PTMs, mostly techniques in MS-based proteomics, are discussed for their ability to uncover relevant biological function.

Keywords

Mass spectrometry Posttranslational modifications Protein-protein interactions In-silico databases Toxoplasma gondii Posttranslational crosstalk Experimental techniques Cell cycle 

References

  1. 1.
    Brauch, H., Kishida, T., Glavac, D., Chen, F., Pausch, F., Hofler, H., et al. (1995). Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: Evidence for a founder effect. Human Genetics, 95(5), 551–556.PubMedGoogle Scholar
  2. 2.
    Ohh, M., Park, C. W., Ivan, M., Hoffman, M. A., Kim, T. Y., Huang, L. E., et al. (2000). Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nature Cell Biology, 2(7), 423–427.PubMedGoogle Scholar
  3. 3.
    De Las Rivas, J., & Fontanillo, C. (2010). Protein-protein interactions essentials: Key concepts to building and analyzing interactome networks. PLoS Computational Biology, 6(6), e1000807.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Khare, S. D., & Fleishman, S. J. (2013). Emerging themes in the computational design of novel enzymes and protein-protein interfaces. FEBS Letters, 587(8), 1147–1154.PubMedGoogle Scholar
  5. 5.
    Huang, P. S., Love, J. J., & Mayo, S. L. (2007). A de novo designed protein protein interface. Protein Science, 16(12), 2770–2774.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Goncearenco, A., Shoemaker, B. A., Zhang, D., Sarychev, A., & Panchenko, A. R. (2014). Coverage of protein domain families with structural protein-protein interactions: Current progress and future trends. Progress in Biophysics and Molecular Biology, 116(2–3), 187–193.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Dutta, S., Burkhardt, K., Young, J., Swaminathan, G. J., Matsuura, T., Henrick, K., et al. (2009). Data deposition and annotation at the worldwide protein data bank. Molecular Biotechnology, 42(1), 1–13.PubMedGoogle Scholar
  8. 8.
    Venkatesan, K., Rual, J. F., Vazquez, A., Stelzl, U., Lemmens, I., Hirozane-Kishikawa, T., et al. (2009). An empirical framework for binary interactome mapping. Nature Methods, 6(1), 83–90.PubMedGoogle Scholar
  9. 9.
    Stumpf, M. P., Thorne, T., de Silva, E., Stewart, R., An, H. J., Lappe, M., et al. (2008). Estimating the size of the human interactome. Proceedings of the National Academy of Sciences of the United States of America, 105(19), 6959–6964.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Liu, C. H., Chen, T. C., Chau, G. Y., Jan, Y. H., Chen, C. H., Hsu, C. N., et al. (2013). Analysis of protein-protein interactions in cross-talk pathways reveals CRKL protein as a novel prognostic marker in hepatocellular carcinoma. Molecular & Cellular Proteomics, 12(5), 1335–1349.Google Scholar
  11. 11.
    Kestler, H. A., & Kuhl, M. (2008). From individual Wnt pathways towards a Wnt signalling network. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 363(1495), 1333–1347.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Sorkin, A., & von Zastrow, M. (2009). Endocytosis and signalling: Intertwining molecular networks. Nature Reviews. Molecular Cell Biology, 10(9), 609–622.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Rual, J.-F., Venkatesan, K., Hao, T., Hirozane-Kishikawa, T., Dricot, A., Li, N., et al. (2005). Towards a proteome-scale map of the human protein–protein interaction network. Nature, 437(7062), 1173–1178.PubMedGoogle Scholar
  14. 14.
    Stelzl, U., Worm, U., Lalowski, M., Haenig, C., Brembeck, F. H., Goehler, H., et al. (2005). A human protein-protein interaction network: A resource for annotating the proteome. Cell, 122(6), 957–968.PubMedGoogle Scholar
  15. 15.
    Ewing, R. M., Chu, P., Elisma, F., Li, H., Taylor, P., Climie, S., et al. (2007). Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular Systems Biology, 3, 89.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Hubner, N. C., Bird, A. W., Cox, J., Splettstoesser, B., Bandilla, P., Poser, I., et al. (2010). Quantitative proteomics combined with BAC TransgeneOmics reveals in vivo protein interactions. The Journal of Cell Biology, 189(4), 739–754.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Stelzl, U., & Wanker, E. (2006). The value of high quality protein–protein interaction networks for systems biology. Current Opinion in Chemical Biology, 10(6), 551–558.PubMedGoogle Scholar
  18. 18.
    Ramirez, F., Schlicker, A., Assenov, Y., Lengauer, T., & Albrecht, M. (2007). Computational analysis of human protein interaction networks. Proteomics, 7(15), 2541–2552.PubMedGoogle Scholar
  19. 19.
    Keskin, O., Tuncbag, N., & Gursoy, A. (2016). Predicting protein-protein interactions from the molecular to the proteome level. Chemical Reviews, 116(8), 4884–4909.PubMedGoogle Scholar
  20. 20.
    Ngounou Wetie, A. G., Sokolowska, I., Woods, A. G., Roy, U., Loo, J. A., & Darie, C. C. (2013). Investigation of stable and transient protein-protein interactions: Past, present, and future. Proteomics, 13(3–4), 538–557.PubMedGoogle Scholar
  21. 21.
    Ngounou Wetie, A. G., Sokolowska, I., Woods, A. G., Roy, U., Deinhardt, K., & Darie, C. C. (2014). Protein-protein interactions: Switch from classical methods to proteomics and bioinformatics-based approaches. Cellular and Molecular Life Sciences, 71(2), 205–228.PubMedGoogle Scholar
  22. 22.
    Berggard, T., Linse, S., & James, P. (2007). Methods for the detection and analysis of protein-protein interactions. Proteomics, 7(16), 2833–2842.PubMedGoogle Scholar
  23. 23.
    Nooren, I. M., & Thornton, J. M. (2003). Diversity of protein-protein interactions. The EMBO Journal, 22(14), 3486–3492.PubMedCentralGoogle Scholar
  24. 24.
    Prieto, C., & De Las Rivas, J. (2010). Structural domain-domain interactions: Assessment and comparison with protein-protein interaction data to improve the interactome. Proteins, 78(1), 109–117.PubMedGoogle Scholar
  25. 25.
    Snider, J., Kotlyar, M., Saraon, P., Yao, Z., Jurisica, I., & Stagljar, I. (2015). Fundamentals of protein interaction network mapping. Molecular Systems Biology, 11(12), 848.PubMedCentralGoogle Scholar
  26. 26.
    Berlow, R. B., Dyson, H. J., & Wright, P. E. (2015). Functional advantages of dynamic protein disorder. FEBS Letters, 589(19 Pt A), 2433–2440.PubMedCentralGoogle Scholar
  27. 27.
    Fields, S., & Song, O. (1989). A novel genetic system to detect protein-protein interactions. Nature, 340(6230), 245–246.PubMedGoogle Scholar
  28. 28.
    Hamdi, A., & Colas, P. (2012). Yeast two-hybrid methods and their applications in drug discovery. Trends in Pharmacological Sciences, 33(2), 109–118.PubMedGoogle Scholar
  29. 29.
    Ferro, E., & Trabalzini, L. (2013). The yeast two-hybrid and related methods as powerful tools to study plant cell signalling. Plant Molecular Biology, 83(4–5), 287–301.PubMedGoogle Scholar
  30. 30.
    Uetz, P., Giot, L., Cagney, G., Mansfield, T. A., Judson, R. S., Knight, J. R., et al. (2000). A comprehensive analysis of protein-protein interactions in Saccharomyces cerevisiae. Nature, 403(6770), 623–627.PubMedGoogle Scholar
  31. 31.
    Ito, T., Chiba, T., Ozawa, R., Yoshida, M., Hattori, M., & Sakaki, Y. (2001). A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proceedings of the National Academy of Sciences of the United States of America, 98(8), 4569–4574.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Sprinzak, E., Sattath, S., & Margalit, H. (2003). How reliable are experimental protein–protein interaction data? Journal of Molecular Biology, 327(5), 919–923.PubMedGoogle Scholar
  33. 33.
    Overington, J. P., Al-Lazikani, B., & Hopkins, A. L. (2006). How many drug targets are there? Nature Reviews. Drug Discovery, 5(12), 993–996.PubMedGoogle Scholar
  34. 34.
    Zhang, Y., Gao, P., & Yuan, J. S. (2010). Plant protein-protein interaction network and interactome. Current Genomics, 11(1), 40–46.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Gisler, S. M., Kittanakom, S., Fuster, D., Wong, V., Bertic, M., Radanovic, T., et al. (2008). Monitoring protein-protein interactions between the mammalian integral membrane transporters and PDZ-interacting partners using a modified split-ubiquitin membrane yeast two-hybrid system. Molecular & Cellular Proteomics, 7(7), 1362–1377.Google Scholar
  36. 36.
    Snider, J., Kittanakom, S., Damjanovic, D., Curak, J., Wong, V., & Stagljar, I. (2010). Detecting interactions with membrane proteins using a membrane two-hybrid assay in yeast. Nature Protocols, 5(7), 1281–1293.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Petschnigg, J., Snider, J., & Stagljar, I. (2011). Interactive proteomics research technologies: Recent applications and advances. Current Opinion in Biotechnology, 22(1), 50–58.PubMedGoogle Scholar
  38. 38.
    Paumi, C. M., Menendez, J., Arnoldo, A., Engels, K., Iyer, K. R., Thaminy, S., et al. (2007). Mapping protein-protein interactions for the yeast ABC transporter Ycf1p by integrated split-ubiquitin membrane yeast two-hybrid analysis. Molecular Cell, 26(1), 15–25.PubMedGoogle Scholar
  39. 39.
    Deribe, Y. L., Wild, P., Chandrashaker, A., Curak, J., Schmidt, M. H. H., Kalaidzidis, Y., et al. (2009). Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6. Science Signaling, 2(102), ra84.PubMedGoogle Scholar
  40. 40.
    Snider, J., Hanif, A., Lee, M. E., Jin, K., Yu, A. R., Graham, C., et al. (2013). Mapping the functional yeast ABC transporter interactome. Nature Chemical Biology, 9(9), 565–572.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Broder, Y. C., Katz, S., & Aronheim, A. (1998). The ras recruitment system, a novel approach to the study of protein-protein interactions. Current Biology, 8(20), 1121–1124.PubMedGoogle Scholar
  42. 42.
    Egea-Cortines, M., Saedler, H., & Sommer, H. (1999). Ternary complex formation between the MADS-box proteins SQUAMOSA, DEFICIENS and GLOBOSA is involved in the control of floral architecture in Antirrhinum majus. The EMBO Journal, 18(19), 5370–5379.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Brent, R., & Finley Jr., R. L. (1997). Understanding gene and allele function with two-hybrid methods. Annual Review of Genetics, 31, 663–704.PubMedGoogle Scholar
  44. 44.
    Causier, B., & Davies, B. (2002). Analysing protein-protein interactions with the yeast two-hybrid system. Plant Molecular Biology, 50(6), 855–870.PubMedGoogle Scholar
  45. 45.
    Dube, D. H., Li, B., Greenblatt, E. J., Nimer, S., Raymond, A. K., & Kohler, J. J. (2010). A two-hybrid assay to study protein interactions within the secretory pathway. PLoS One, 5(12), e15648.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Petschnigg, J., Groisman, B., Kotlyar, M., Taipale, M., Zheng, Y., Kurat, C. F., et al. (2014). The mammalian-membrane two-hybrid assay (MaMTH) for probing membrane-protein interactions in human cells. Nature Methods, 11(5), 585–592.PubMedGoogle Scholar
  47. 47.
    Lievens, S., Gerlo, S., Lemmens, I., De Clercq, D. J., Risseeuw, M. D., Vanderroost, N., et al. (2014). Kinase Substrate Sensor (KISS), a mammalian in situ protein interaction sensor. Molecular & Cellular Proteomics, 13(12), 3332–3342.Google Scholar
  48. 48.
    Ulrichts, P., Lemmens, I., Lavens, D., Beyaert, R., & Tavernier, J. (2009). MAPPIT (mammalian protein-protein interaction trap) analysis of early steps in toll-like receptor signalling. Methods in Molecular Biology (Clifton, N.J.), 517, 133–144.Google Scholar
  49. 49.
    Phee, B.-K., Shin, D. H., Cho, J.-H., Kim, S.-H., Kim, J.-I., Lee, Y.-H., et al. (2006). Identification of phytochrome-interacting protein candidates in Arabidopsis thaliana by co-immunoprecipitation coupled with MALDI-TOF MS. Proteomics, 6(12), 3671–3680.PubMedGoogle Scholar
  50. 50.
    Monti, M., Orru, S., Pagnozzi, D., & Pucci, P. (2005). Interaction proteomics. Bioscience Reports, 25(1–2), 45–56.PubMedGoogle Scholar
  51. 51.
    Hayes, S., Malacrida, B., Kiely, M., & Kiely, P. A. (2016). Studying protein-protein interactions: Progress, pitfalls and solutions. Biochemical Society Transactions, 44(4), 994–1004.PubMedGoogle Scholar
  52. 52.
    Miernyk, J. A., & Thelen, J. J. (2008). Biochemical approaches for discovering protein-protein interactions. The Plant Journal, 53(4), 597–609.PubMedGoogle Scholar
  53. 53.
    Forler, D., Kocher, T., Rode, M., Gentzel, M., Izaurralde, E., & Wilm, M. (2003). An efficient protein complex purification method for functional proteomics in higher eukaryotes. Nature Biotechnology, 21(1), 89–92.PubMedGoogle Scholar
  54. 54.
    Dunham, W. H., Mullin, M., & Gingras, A. C. (2012). Affinity-purification coupled to mass spectrometry: Basic principles and strategies. Proteomics, 12(10), 1576–1590.PubMedGoogle Scholar
  55. 55.
    Smirle, J., Au, C. E., Jain, M., Dejgaard, K., Nilsson, T., & Bergeron, J. (2013). Cell biology of the endoplasmic reticulum and the Golgi apparatus through proteomics. Cold Spring Harbor Perspectives in Biology, 5(1), a015073.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Gingras, A. C., Gstaiger, M., Raught, B., & Aebersold, R. (2007). Analysis of protein complexes using mass spectrometry. Nature Reviews. Molecular Cell Biology, 8(8), 645–654.PubMedGoogle Scholar
  57. 57.
    Back, J. W., de Jong, L., Muijsers, A. O., & de Koster, C. G. (2003). Chemical cross-linking and mass spectrometry for protein structural modeling. Journal of Molecular Biology, 331(2), 303–313.PubMedGoogle Scholar
  58. 58.
    Barrios-Rodiles, M., Brown, K. R., Ozdamar, B., Bose, R., Liu, Z., Donovan, R. S., et al. (2005). High-throughput mapping of a dynamic signaling network in mammalian cells. Science (New York, N.Y.), 307(5715), 1621–1625.Google Scholar
  59. 59.
    Blasche, S., & Koegl, M. (2013). Analysis of protein-protein interactions using LUMIER assays. Methods in Molecular Biology (Clifton, N.J.), 1064, 17–27.Google Scholar
  60. 60.
    Berkowitz, S. A. (2006). Role of analytical ultracentrifugation in assessing the aggregation of protein biopharmaceuticals. The AAPS Journal, 8(3), E590–E605.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Philo, J. S. (2006). Is any measurement method optimal for all aggregate sizes and types? The AAPS Journal, 8(3), E564–E571.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Liu, J., Andya, J. D., & Shire, S. J. (2006). A critical review of analytical ultracentrifugation and field flow fractionation methods for measuring protein aggregation. The AAPS Journal, 8(3), E580–E589.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Howlett, G. J., Minton, A. P., & Rivas, G. (2006). Analytical ultracentrifugation for the study of protein association and assembly. Current Opinion in Chemical Biology, 10(5), 430–436.PubMedGoogle Scholar
  64. 64.
    Minton, A. P. (2000). Quantitative characterization of reversible macromolecular associations via sedimentation equilibrium: An introduction. Experimental & Molecular Medicine, 32(1), 1–5.Google Scholar
  65. 65.
    Correia, J. J. (2000). Analysis of weight average sedimentation velocity data. Methods in Enzymology, 321, 81–100.PubMedGoogle Scholar
  66. 66.
    Dam, J., & Schuck, P. (2004). Calculating sedimentation coefficient distributions by direct modeling of sedimentation velocity concentration profiles. Methods in Enzymology, 384, 185–212.PubMedGoogle Scholar
  67. 67.
    Cole, J. L. (2010). Analysis of PKR activation using analytical ultracentrifugation. Macromolecular Bioscience, 10(7), 703–713.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Vistica, J., Dam, J., Balbo, A., Yikilmaz, E., Mariuzza, R. A., Rouault, T. A., et al. (2004). Sedimentation equilibrium analysis of protein interactions with global implicit mass conservation constraints and systematic noise decomposition. Analytical Biochemistry, 326(2), 234–256.PubMedGoogle Scholar
  69. 69.
    Ghirlando, R. (2011). The analysis of macromolecular interactions by sedimentation equilibrium. Methods, 54(1), 145–156.PubMedGoogle Scholar
  70. 70.
    Brautigam, C. A. (2011). Using Lamm-Equation modeling of sedimentation velocity data to determine the kinetic and thermodynamic properties of macromolecular interactions. Methods, 54(1), 4–15.PubMedGoogle Scholar
  71. 71.
    Miyashita, T. (2015). Confocal microscopy for intracellular co-localization of proteins. Methods in Molecular Biology (Clifton, N.J.), 1278, 515–526.Google Scholar
  72. 72.
    Ma, L., Yang, F., & Zheng, J. (2014). Application of fluorescence resonance energy transfer in protein studies. Journal of Molecular Structure, 1077, 87–100.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Boute, N., Jockers, R., & Issad, T. (2002). The use of resonance energy transfer in high-throughput screening: BRET versus FRET. Trends in Pharmacological Sciences, 23(8), 351–354.PubMedGoogle Scholar
  74. 74.
    Sun, Y., Day, R. N., & Periasamy, A. (2011). Investigating protein-protein interactions in living cells using fluorescence lifetime imaging microscopy. Nature Protocols, 6(9), 1324–1340.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Hamdan, F. F., Percherancier, Y., Breton, B., Bouvier, M. (2006). Monitoring protein-protein interactions in living cells by bioluminescence resonance energy transfer (BRET). Current Protocols in Neuroscience, Chapter 5, Unit 5.23.Google Scholar
  76. 76.
    Kerppola, T. K. (2008). Bimolecular fluorescence complementation (BiFC) analysis as a probe of protein interactions in living cells. Annual Review of Biophysics, 37, 465–487.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Zhang, X. E., Cui, Z., & Wang, D. (2016). Sensing of biomolecular interactions using fluorescence complementing systems in living cells. Biosensors & Bioelectronics, 76, 243–250.Google Scholar
  78. 78.
    Hu, C. D., Chinenov, Y., & Kerppola, T. K. (2002). Visualization of interactions among bZIP and Rel family proteins in living cells using bimolecular fluorescence complementation. Molecular Cell, 9(4), 789–798.PubMedGoogle Scholar
  79. 79.
    Miller, K. E., Kim, Y., Huh, W. K., & Park, H. O. (2015). Bimolecular fluorescence complementation (BiFC) analysis: Advances and recent applications for genome-wide interaction studies. Journal of Molecular Biology, 427(11), 2039–2055.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Axelrod, D., Koppel, D. E., Schlessinger, J., Elson, E., & Webb, W. W. (1976). Mobility measurement by analysis of fluorescence photobleaching recovery kinetics. Biophysical Journal, 16(9), 1055–1069.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Koppel, D. E., Axelrod, D., Schlessinger, J., Elson, E. L., & Webb, W. W. (1976). Dynamics of fluorescence marker concentration as a probe of mobility. Biophysical Journal, 16(11), 1315–1329.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Ishikawa-Ankerhold, H. C., Ankerhold, R., & Drummen, G. P. (2012). Advanced fluorescence microscopy techniques—FRAP, FLIP, FLAP, FRET and FLIM. Molecules (Basel, Switzerland), 17(4), 4047–4132.Google Scholar
  83. 83.
    Roux, K. J., Kim, D. I., Raida, M., & Burke, B. (2012). A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. The Journal of Cell Biology, 196(6), 801–810.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Lambert, J. P., Tucholska, M., Go, C., Knight, J. D., & Gingras, A. C. (2015). Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of Proteomics, 118, 81–94.PubMedGoogle Scholar
  85. 85.
    Koos, B., Andersson, L., Clausson, C. M., Grannas, K., Klaesson, A., Cane, G., et al. (2014). Analysis of protein interactions in situ by proximity ligation assays. Current Topics in Microbiology and Immunology, 377, 111–126.PubMedGoogle Scholar
  86. 86.
    Chen, T. C., Lin, K. T., Chen, C. H., Lee, S. A., Lee, P. Y., Liu, Y. W., et al. (2014). Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network. Journal of Proteome Research, 13(12), 5339–5346.PubMedGoogle Scholar
  87. 87.
    Frei, A. P., Moest, H., Novy, K., & Wollscheid, B. (2013). Ligand-based receptor identification on living cells and tissues using TRICEPS. Nature Protocols, 8(7), 1321–1336.PubMedGoogle Scholar
  88. 88.
    Kerr, J. S., & Wright, G. J. (2012). Avidity-based extracellular interaction screening (AVEXIS) for the scalable detection of low-affinity extracellular receptor-ligand interactions. Journal of Visualized Experiments, (61), e3881.Google Scholar
  89. 89.
    Stephen, A. G., Esposito, D., Bagni, R. K., & McCormick, F. (2014). Dragging ras back in the ring. Cancer Cell, 25(3), 272–281.PubMedGoogle Scholar
  90. 90.
    McCormick, F. (2015). KRAS as a therapeutic target. Clinical Cancer Research, 21(8), 1797–1801.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Vandamme, D., Fitzmaurice, W., Kholodenko, B., & Kolch, W. (2013). Systems medicine: Helping us understand the complexity of disease. QJM, 106(10), 891–895.PubMedGoogle Scholar
  92. 92.
    Orchard, S., & Kerrien, S. (2010). Molecular interactions and data standardisation. Methods in Molecular Biology (Clifton, N.J.), 604, 309–318.Google Scholar
  93. 93.
    Kerrien, S., Orchard, S., Montecchi-Palazzi, L., Aranda, B., Quinn, A. F., Vinod, N., et al. (2007). Broadening the horizon—Level 2.5 of the HUPO-PSI format for molecular interactions. BMC Biology, 5, 44.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Salwinski, L., Miller, C. S., Smith, A. J., Pettit, F. K., Bowie, J. U., & Eisenberg, D. (2004). The Database of Interacting Proteins: 2004 update. Nucleic Acids Research, 32(Database issue), D449–D451.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Bader, G. D., Cary, M. P., & Sander, C. (2006). Pathguide: A pathway resource list. Nucleic Acids Research, 34(Database issue), D504–D506.PubMedGoogle Scholar
  96. 96.
    Orchard, S., Kerrien, S., Abbani, S., Aranda, B., Bhate, J., Bidwell, S., et al. (2012). Protein interaction data curation: The International Molecular Exchange (IMEx) consortium. Nature Methods, 9(4), 345–350.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Aranda, B., Blankenburg, H., Kerrien, S., Brinkman, F. S., Ceol, A., Chautard, E., et al. (2011). PSICQUIC and PSISCORE: Accessing and scoring molecular interactions. Nature Methods, 8(7), 528–529.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Szklarczyk, D., Franceschini, A., Wyder, S., Forslund, K., Heller, D., Huerta-Cepas, J., et al. (2015). STRING v10: Protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Research, 43(Database issue), D447–D452.PubMedGoogle Scholar
  99. 99.
    Zahiri, J., Bozorgmehr, J. H., & Masoudi-Nejad, A. (2013). Computational prediction of protein-protein interaction networks: Algorithms and resources. Current Genomics, 14(6), 397–414.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Zanzoni, A., Montecchi-Palazzi, L., Quondam, M., Ausiello, G., Helmer-Citterich, M., & Cesareni, G. (2002). MINT: A Molecular INTeraction database. FEBS Letters, 513(1), 135–140.PubMedGoogle Scholar
  101. 101.
    Hermjakob, H., Montecchi-Palazzi, L., Lewington, C., Mudali, S., Kerrien, S., Orchard, S., et al. (2004). IntAct: An open source molecular interaction database. Nucleic Acids Research, 32(Suppl_1), D452–D455.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Mewes, H. W., Frishman, D., Guldener, U., Mannhaupt, G., Mayer, K., Mokrejs, M., et al. (2002). MIPS: A database for genomes and protein sequences. Nucleic Acids Research, 30(1), 31–34.PubMedCentralGoogle Scholar
  103. 103.
    Xenarios, I., Salwínski, L., Duan, X. J., Higney, P., Kim, S.-M., & Eisenberg, D. (2002). DIP, the Database of Interacting Proteins: A research tool for studying cellular networks of protein interactions. Nucleic Acids Research, 30(1), 303–305.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Salwinski, L., & Eisenberg, D. (2003). Computational methods of analysis of protein-protein interactions. Current Opinion in Structural Biology, 13(3), 377–382.PubMedGoogle Scholar
  105. 105.
    Chatr-Aryamontri, A., Breitkreutz, B. J., Oughtred, R., Boucher, L., Heinicke, S., Chen, D., et al. (2015). The BioGRID interaction database: 2015 update. Nucleic Acids Research, 43(Database issue), D470–D478.PubMedGoogle Scholar
  106. 106.
    Zhang, Q. C., Petrey, D., Deng, L., Qiang, L., Shi, Y., Thu, C. A., et al. (2012). Structure-based prediction of protein-protein interactions on a genome-wide scale. Nature, 490(7421), 556–560.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Ohtsubo, K., & Marth, J. D. (2006). Glycosylation in cellular mechanisms of health and disease. Cell, 126(5), 855–867.PubMedGoogle Scholar
  108. 108.
    Walsh, C. T., Garneau-Tsodikova, S., & Gatto Jr., G. J. (2005). Protein posttranslational modifications: The chemistry of proteome diversifications. Angewandte Chemie (International ed. in English), 44(45), 7342–7372.Google Scholar
  109. 109.
    Witze, E. S., Old, W. M., Resing, K. A., & Ahn, N. G. (2007). Mapping protein post-translational modifications with mass spectrometry. Nature Methods, 4(10), 798–806.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Doll, S., & Burlingame, A. L. (2015). Mass spectrometry-based detection and assignment of protein posttranslational modifications. ACS Chemical Biology, 10(1), 63–71.PubMedGoogle Scholar
  111. 111.
    Mertins, P., Qiao, J. W., Patel, J., Udeshi, N. D., Clauser, K. R., Mani, D. R., et al. (2013). Integrated proteomic analysis of post-translational modifications by serial enrichment. Nature Methods, 10(7), 634–637.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Swaney, D. L., & Villen, J. (2016). Proteomic analysis of protein posttranslational modifications by mass spectrometry. Cold Spring Harbor Protocols, 2016(3), pdb.top077743.PubMedGoogle Scholar
  113. 113.
    Mann, M., & Jensen, O. N. (2003). Proteomic analysis of post-translational modifications. Nature Biotechnology, 21(3), 255–261.PubMedGoogle Scholar
  114. 114.
    Seo, J., & Lee, K. J. (2004). Post-translational modifications and their biological functions: Proteomic analysis and systematic approaches. Journal of Biochemistry and Molecular Biology, 37(1), 35–44.PubMedGoogle Scholar
  115. 115.
    Ngounou Wetie, A. G., Woods, A. G., & Darie, C. C. (2014). Mass spectrometric analysis of post-translational modifications (PTMs) and protein-protein interactions (PPIs). Advances in Experimental Medicine and Biology, 806, 205–235.PubMedGoogle Scholar
  116. 116.
    Malik, R., Dulla, K., Nigg, E. A., & Korner, R. (2010). From proteome lists to biological impact—Tools and strategies for the analysis of large MS data sets. Proteomics, 10(6), 1270–1283.PubMedGoogle Scholar
  117. 117.
    Cobbold, S. A., Santos, J. M., Ochoa, A., Perlman, D. H., & Llinas, M. (2016). Proteome-wide analysis reveals widespread lysine acetylation of major protein complexes in the malaria parasite. Scientific Reports, 6, 19722.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Jeffers, V., & Sullivan, W. J. (2012). Lysine acetylation is widespread on proteins of diverse function and localization in the protozoan parasite Toxoplasma gondii. Eukaryotic Cell, 11(6), 735–742.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Xue, B., Jeffers, V., Sullivan, W. J., & Uversky, V. N. (2013). Protein intrinsic disorder in the acetylome of intracellular and extracellular Toxoplasma gondii. Molecular BioSystems, 9(4), 645–657.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Miao, J., Lawrence, M., Jeffers, V., Zhao, F., Parker, D., Ge, Y., et al. (2013). Extensive lysine acetylation occurs in evolutionarily conserved metabolic pathways and parasite-specific functions during Plasmodium falciparum intraerythrocytic development. Molecular Microbiology, 89(4), 660–675.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Yakubu, R. R., Silmon de Monerri, N. C., Nieves, E., Kim, K., & Weiss, L. M. (2017). Comparative monomethylarginine proteomics suggests that PRMT1 is a significant contributor to arginine monomethylation in Toxoplasma gondii. Molecular & Cellular Proteomics, 16(4), 567–580.Google Scholar
  122. 122.
    Zeeshan, M., Kaur, I., Joy, J., Saini, E., Paul, G., Kaushik, A., et al. (2017). Proteomic identification and analysis of arginine-methylated proteins of Plasmodium falciparum at asexual blood stages. Journal of Proteome Research, 16(2), 368–383.PubMedGoogle Scholar
  123. 123.
    Kaur, I., Zeeshan, M., Saini, E., Kaushik, A., Mohmmed, A., Gupta, D., et al. (2016). Widespread occurrence of lysine methylation in Plasmodium falciparum proteins at asexual blood stages. Scientific Reports, 6, 35432.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Caballero, M. C., Alonso, A. M., Deng, B., Attias, M., de Souza, W., & Corvi, M. M. (2016). Identification of new palmitoylated proteins in Toxoplasma gondii. Biochimica et Biophysica Acta, 1864(4), 400–408.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Foe, I. T., Child, M. A., Majmudar, J. D., Krishnamurthy, S., van der Linden, W. A., Ward, G. E., et al. (2015). Global analysis of palmitoylated proteins in Toxoplasma gondii. Cell Host & Microbe, 18(4), 501–511.Google Scholar
  126. 126.
    Jones, M. L., Collins, M. O., Goulding, D., Choudhary, J. S., & Rayner, J. C. (2012). Analysis of protein palmitoylation reveals a pervasive role in Plasmodium development and pathogenesis. Cell Host & Microbe, 12(2), 246–258.Google Scholar
  127. 127.
    Treeck, M., Sanders, J. L., Elias, J. E., & Boothroyd, J. C. (2011). The phosphoproteomes of Plasmodium falciparum and Toxoplasma gondii reveal unusual adaptations within and beyond the parasites’ boundaries. Cell Host & Microbe, 10(4), 410–419.Google Scholar
  128. 128.
    Alam, M. M., Solyakov, L., Bottrill, A. R., Flueck, C., Siddiqui, F. A., Singh, S., et al. (2015). Phosphoproteomics reveals malaria parasite Protein Kinase G as a signalling hub regulating egress and invasion. Nature Communications, 6, 7285.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Lasonder, E., Green, J. L., Grainger, M., Langsley, G., & Holder, A. A. (2015). Extensive differential protein phosphorylation as intraerythrocytic Plasmodium falciparum schizonts develop into extracellular invasive merozoites. Proteomics, 15(15), 2716–2729.  https://doi.org/10.1002/pmic.201400508. PMID: 25886026.CrossRefPubMedGoogle Scholar
  130. 130.
    Lasonder, E., Green, J. L., Camarda, G., Talabani, H., Holder, A. A., Langsley, G., et al. (2012). The Plasmodium falciparum schizont phosphoproteome reveals extensive phosphatidylinositol and cAMP-protein kinase A signaling. Journal of Proteome Research, 11(11), 5323–5337.  https://doi.org/10.1021/pr300557m. PMID: 23025827.CrossRefPubMedGoogle Scholar
  131. 131.
    Solyakov, L., Halbert, J., Alam, M. M., Semblat, J. P., Dorin-Semblat, D., Reininger, L., et al. (2011). Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum. Nature Communications, 2, 565.  https://doi.org/10.1038/ncomms1558.CrossRefPubMedGoogle Scholar
  132. 132.
    Pease, B. N., Huttlin, E. L., Jedrychowski, M. P., Talevich, E., Harmon, J., Dillman, T., et al. (2013). Global analysis of protein expression and phosphorylation of three stages of Plasmodium falciparum intraerythrocytic development. Journal of Proteome Research, 12(9), 4028–4045.PubMedPubMedCentralGoogle Scholar
  133. 133.
    de Monerri, S., Natalie, C., Yakubu, R. R., Chen, A. L., Bradley, P. J., Nieves, E., et al. (2015). The ubiquitin proteome of Toxoplasma gondii reveals roles for protein ubiquitination in cell-cycle transitions. Cell Host & Microbe, 18(5), 621–633.Google Scholar
  134. 134.
    Ponts, N., Saraf, A., Chung, D. W., Harris, A., Prudhomme, J., Washburn, M. P., et al. (2011). Unraveling the ubiquitome of the human malaria parasite. The Journal of Biological Chemistry, 286(46), 40320–40330.PubMedPubMedCentralGoogle Scholar
  135. 135.
    Issar, N., Roux, E., Mattei, D., & Scherf, A. (2008). Identification of a novel post-translational modification in Plasmodium falciparum: Protein sumoylation in different cellular compartments. Cellular Microbiology, 10(10), 1999–2011.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Braun, L., Cannella, D., Pinheiro, A. M., Kieffer, S., Belrhali, H., Garin, J., et al. (2009). The small ubiquitin-like modifier (SUMO)-conjugating system of Toxoplasma gondii. International Journal for Parasitology, 39(1), 81–90.PubMedGoogle Scholar
  137. 137.
    Li, X., Hu, X., Wan, Y., Xie, G., Li, X., Chen, D., et al. (2014). Systematic identification of the lysine succinylation in the protozoan parasite Toxoplasma gondii. Journal of Proteome Research, 13(12), 6087–6095.  https://doi.org/10.1021/pr500992r.CrossRefPubMedGoogle Scholar
  138. 138.
    Olsen, J. V., Blagoev, B., Gnad, F., Macek, B., Kumar, C., Mortensen, P., et al. (2006). Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell, 127(3), 635–648.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Elsholz, A. K., Turgay, K., Michalik, S., Hessling, B., Gronau, K., Oertel, D., et al. (2012). Global impact of protein arginine phosphorylation on the physiology of Bacillus subtilis. Proceedings of the National Academy of Sciences of the United States of America, 109(19), 7451–7456.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Laub, M. T., & Goulian, M. (2007). Specificity in two-component signal transduction pathways. Annual Review of Genetics, 41, 121–145.PubMedGoogle Scholar
  141. 141.
    Thingholm, T. E., Jorgensen, T. J., Jensen, O. N., & Larsen, M. R. (2006). Highly selective enrichment of phosphorylated peptides using titanium dioxide. Nature Protocols, 1(4), 1929–1935.PubMedGoogle Scholar
  142. 142.
    Manning, G., Whyte, D. B., Martinez, R., Hunter, T., & Sudarsanam, S. (2002). The protein kinase complement of the human genome. Science (New York, N.Y.), 298(5600), 1912–1934.Google Scholar
  143. 143.
    Braconi Quintaje, S., & Orchard, S. (2008). The annotation of both human and mouse kinomes in UniProtKB/Swiss-Prot: One small step in manual annotation, one giant leap for full comprehension of genomes. Molecular & Cellular Proteomics, 7(8), 1409–1419.Google Scholar
  144. 144.
    Jackson, M. D., & Denu, J. M. (2001). Molecular reactions of protein phosphatases—Insights from structure and chemistry. Chemical Reviews, 101(8), 2313–2340.PubMedGoogle Scholar
  145. 145.
    Guan, K. L., & Dixon, J. E. (1991). Evidence for protein-tyrosine-phosphatase catalysis proceeding via a cysteine-phosphate intermediate. The Journal of Biological Chemistry, 266(26), 17026–17030.PubMedGoogle Scholar
  146. 146.
    Doerig, C., Rayner, J. C., Scherf, A., & Tobin, A. B. (2015). Post-translational protein modifications in malaria parasites. Nature Reviews Microbiology, 13(3), 160–172.PubMedGoogle Scholar
  147. 147.
    Jacot, D., & Soldati-Favre, D. (2012). Does protein phosphorylation govern host cell entry and egress by the Apicomplexa? International Journal of Medical Microbiology, 302(4–5), 195–202.PubMedGoogle Scholar
  148. 148.
    Barford, D. (1996). Molecular mechanisms of the protein serine/threonine phosphatases. Trends in Biochemical Sciences, 21(11), 407–412.PubMedGoogle Scholar
  149. 149.
    Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., et al. (2001). The sequence of the human genome. Science (New York, N.Y.), 291(5507), 1304–1351.Google Scholar
  150. 150.
    Johnson, L. N., & Barford, D. (1993). The effects of phosphorylation on the structure and function of proteins. Annual Review of Biophysics and Biomolecular Structure, 22, 199–232.PubMedGoogle Scholar
  151. 151.
    Hunter, T. (2007). The age of crosstalk: Phosphorylation, ubiquitination, and beyond. Molecular Cell, 28(5), 730–738.PubMedGoogle Scholar
  152. 152.
    Hubbard, M. J., & Cohen, P. (1993). On target with a new mechanism for the regulation of protein phosphorylation. Trends in Biochemical Sciences, 18(5), 172–177.PubMedGoogle Scholar
  153. 153.
    Bodenmiller, B., Mueller, L. N., Mueller, M., Domon, B., & Aebersold, R. (2007). Reproducible isolation of distinct, overlapping segments of the phosphoproteome. Nature Methods, 4(3), 231–237.PubMedPubMedCentralGoogle Scholar
  154. 154.
    Goshe, M. B., Conrads, T. P., Panisko, E. A., Angell, N. H., Veenstra, T. D., & Smith, R. D. (2001). Phosphoprotein isotope-coded affinity tag approach for isolating and quantitating phosphopeptides in proteome-wide analyses. Analytical Chemistry, 73(11), 2578–2586.PubMedGoogle Scholar
  155. 155.
    Knight, Z. A., Schilling, B., Row, R. H., Kenski, D. M., Gibson, B. W., & Shokat, K. M. (2003). Phosphospecific proteolysis for mapping sites of protein phosphorylation. Nature Biotechnology, 21(9), 1047–1054.PubMedGoogle Scholar
  156. 156.
    Oda, Y., Nagasu, T., & Chait, B. T. (2001). Enrichment analysis of phosphorylated proteins as a tool for probing the phosphoproteome. Nature Biotechnology, 19(4), 379–382.PubMedGoogle Scholar
  157. 157.
    Zhou, H., Watts, J. D., & Aebersold, R. (2001). A systematic approach to the analysis of protein phosphorylation. Nature Biotechnology, 19(4), 375–378.PubMedGoogle Scholar
  158. 158.
    Bodenmiller, B., Mueller, L. N., Pedrioli, P. G., Pflieger, D., Junger, M. A., Eng, J. K., et al. (2007). An integrated chemical, mass spectrometric and computational strategy for (quantitative) phosphoproteomics: Application to Drosophila melanogaster Kc167 cells. Molecular BioSystems, 3(4), 275–286.PubMedGoogle Scholar
  159. 159.
    Grønborg, M., Kristiansen, T. Z., Stensballe, A., Andersen, J. S., Ohara, O., Mann, M., et al. (2002). A mass spectrometry-based proteomic approach for identification of serine/threonine-phosphorylated proteins by enrichment with phospho-specific antibodies. Molecular & Cellular Proteomics, 1(7), 517–527.Google Scholar
  160. 160.
    Pandey, A., Fernandez, M. M., Steen, H., Blagoev, B., Nielsen, M. M., Roche, S., et al. (2000). Identification of a novel immunoreceptor tyrosine-based activation motif-containing molecule, STAM2, by mass spectrometry and its involvement in growth factor and cytokine receptor signaling pathways. The Journal of Biological Chemistry, 275(49), 38633–38639.PubMedGoogle Scholar
  161. 161.
    Guy, G. R., Philip, R., & Tan, Y. H. (1994). Analysis of cellular phosphoproteins by two-dimensional gel electrophoresis: Applications for cell signaling in normal and cancer cells. Electrophoresis, 15(3–4), 417–440.PubMedGoogle Scholar
  162. 162.
    McLachlin, D. T., & Chait, B. T. (2001). Analysis of phosphorylated proteins and peptides by mass spectrometry. Current Opinion in Chemical Biology, 5(5), 591–602.PubMedGoogle Scholar
  163. 163.
    Gruhler, A., Olsen, J. V., Mohammed, S., Mortensen, P., Faergeman, N. J., Mann, M., et al. (2005). Quantitative phosphoproteomics applied to the yeast pheromone signaling pathway. Molecular & Cellular Proteomics, 4(3), 310–327.Google Scholar
  164. 164.
    Carr, S. A., Huddleston, M. J., & Annan, R. S. (1996). Selective detection and sequencing of phosphopeptides at the femtomole level by mass spectrometry. Analytical Biochemistry, 239(2), 180–192.PubMedGoogle Scholar
  165. 165.
    Bateman, R. H., Carruthers, R., Hoyes, J. B., Jones, C., Langridge, J. I., Millar, A., et al. (2002). A novel precursor ion discovery method on a hybrid quadrupole orthogonal acceleration time-of-flight (Q-TOF) mass spectrometer for studying protein phosphorylation. Journal of the American Society for Mass Spectrometry, 13(7), 792–803.PubMedGoogle Scholar
  166. 166.
    Beausoleil, S. A., Jedrychowski, M., Schwartz, D., Elias, J. E., Villen, J., Li, J., et al. (2004). Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America, 101(33), 12130–12135.PubMedPubMedCentralGoogle Scholar
  167. 167.
    Nuhse, T. S., Stensballe, A., Jensen, O. N., & Peck, S. C. (2003). Large-scale analysis of in vivo phosphorylated membrane proteins by immobilized metal ion affinity chromatography and mass spectrometry. Molecular & Cellular Proteomics, 2(11), 1234–1243.Google Scholar
  168. 168.
    Ficarro, S. B., McCleland, M. L., Stukenberg, P. T., Burke, D. J., Ross, M. M., Shabanowitz, J., et al. (2002). Phosphoproteome analysis by mass spectrometry and its application to Saccharomyces cerevisiae. Nature Biotechnology, 20(3), 301–305.PubMedGoogle Scholar
  169. 169.
    Smith, J. C., & Figeys, D. (2006). Proteomics technology in systems biology. Molecular BioSystems, 2(8), 364–370.PubMedGoogle Scholar
  170. 170.
    Pinkse, M. W., Uitto, P. M., Hilhorst, M. J., Ooms, B., & Heck, A. J. (2004). Selective isolation at the femtomole level of phosphopeptides from proteolytic digests using 2D-NanoLC-ESI-MS/MS and titanium oxide precolumns. Analytical Chemistry, 76(14), 3935–3943.PubMedGoogle Scholar
  171. 171.
    Larsen, M. R., Thingholm, T. E., Jensen, O. N., Roepstorff, P., & Jorgensen, T. J. (2005). Highly selective enrichment of phosphorylated peptides from peptide mixtures using titanium dioxide microcolumns. Molecular & Cellular Proteomics, 4(7), 873–886.Google Scholar
  172. 172.
    Riley, N. M., & Coon, J. J. (2016). Phosphoproteomics in the age of rapid and deep proteome profiling. Analytical Chemistry, 88(1), 74–94.PubMedGoogle Scholar
  173. 173.
    Wu, J., Shakey, Q., Liu, W., Schuller, A., & Follettie, M. T. (2007). Global profiling of phosphopeptides by titania affinity enrichment. Journal of Proteome Research, 6(12), 4684–4689.PubMedGoogle Scholar
  174. 174.
    Li, X., Gerber, S. A., Rudner, A. D., Beausoleil, S. A., Haas, W., Villen, J., et al. (2007). Large-scale phosphorylation analysis of alpha-factor-arrested Saccharomyces cerevisiae. Journal of Proteome Research, 6(3), 1190–1197.PubMedGoogle Scholar
  175. 175.
    Wilson-Grady, J. T., Villen, J., & Gygi, S. P. (2008). Phosphoproteome analysis of fission yeast. Journal of Proteome Research, 7(3), 1088–1097.PubMedGoogle Scholar
  176. 176.
    Villen, J., Beausoleil, S. A., Gerber, S. A., & Gygi, S. P. (2007). Large-scale phosphorylation analysis of mouse liver. Proceedings of the National Academy of Sciences of the United States of America, 104(5), 1488–1493.PubMedPubMedCentralGoogle Scholar
  177. 177.
    Zhai, B., Villén, J., Beausoleil, S. A., Mintseris, J., & Gygi, S. P. (2008). Phosphoproteome analysis of Drosophila melanogaster embryos. Journal of Proteome Research, 7(4), 1675–1682.PubMedPubMedCentralGoogle Scholar
  178. 178.
    Elias, J. E., Haas, W., Faherty, B. K., & Gygi, S. P. (2005). Comparative evaluation of mass spectrometry platforms used in large-scale proteomics investigations. Nature Methods, 2(9), 667–675.PubMedGoogle Scholar
  179. 179.
    Haglund, K., & Dikic, I. (2005). Ubiquitylation and cell signaling. The EMBO Journal, 24(19), 3353–3359.PubMedPubMedCentralGoogle Scholar
  180. 180.
    Pickart, C. M., & Eddins, M. J. (2004). Ubiquitin: Structures, functions, mechanisms. Biochimica et Biophysica Acta, 1695(1–3), 55–72.PubMedGoogle Scholar
  181. 181.
    Nijman, S. M., Luna-Vargas, M. P., Velds, A., Brummelkamp, T. R., Dirac, A. M., Sixma, T. K., et al. (2005). A genomic and functional inventory of deubiquitinating enzymes. Cell, 123(5), 773–786.PubMedGoogle Scholar
  182. 182.
    Bhoj, V. G., & Chen, Z. J. (2009). Ubiquitylation in innate and adaptive immunity. Nature, 458(7237), 430–437.PubMedGoogle Scholar
  183. 183.
    Qian, S. B., Princiotta, M. F., Bennink, J. R., & Yewdell, J. W. (2006). Characterization of rapidly degraded polypeptides in mammalian cells reveals a novel layer of nascent protein quality control. The Journal of Biological Chemistry, 281(1), 392–400.PubMedGoogle Scholar
  184. 184.
    Anania, V. G., Pham, V. C., Huang, X., Masselot, A., Lill, J. R., & Kirkpatrick, D. S. (2014). Peptide level immunoaffinity enrichment enhances ubiquitination site identification on individual proteins. Molecular & Cellular Proteomics, 13(1), 145–156.Google Scholar
  185. 185.
    Corvi, M. M., Alonso, A. M., & Caballero, M. C. (2012). Protein palmitoylation and pathogenesis in apicomplexan parasites. Journal of Biomedicine & Biotechnology, 2012, 483969.Google Scholar
  186. 186.
    Martin, B. R., & Cravatt, B. F. (2009). Large-scale profiling of protein palmitoylation in mammalian cells. Nature Methods, 6(2), 135–138.PubMedPubMedCentralGoogle Scholar
  187. 187.
    Wan, J., Roth, A. F., Bailey, A. O., & Davis, N. G. (2007). Palmitoylated proteins: Purification and identification. Nature Protocols, 2(7), 1573–1584.PubMedGoogle Scholar
  188. 188.
    Fung, C., Beck, J. R., Robertson, S. D., Gubbels, M. J., & Bradley, P. J. (2012). Toxoplasma ISP4 is a central IMC sub-compartment protein whose localization depends on palmitoylation but not myristoylation. Molecular and Biochemical Parasitology, 184(2), 99–108.PubMedPubMedCentralGoogle Scholar
  189. 189.
    De Napoli, M. G., de Miguel, N., Lebrun, M., Moreno, S. N., Angel, S. O., & Corvi, M. M. (2013). N-terminal palmitoylation is required for Toxoplasma gondii HSP20 inner membrane complex localization. Biochimica et Biophysica Acta, 1833(6), 1329–1337.PubMedPubMedCentralGoogle Scholar
  190. 190.
    Drisdel, R. C., & Green, W. N. (2004). Labeling and quantifying sites of protein palmitoylation. BioTechniques, 36(2), 276–285.PubMedGoogle Scholar
  191. 191.
    Yang, W., Di Vizio, D., Kirchner, M., Steen, H., & Freeman, M. R. (2010). Proteome scale characterization of human S-acylated proteins in lipid raft-enriched and non-raft membranes. Molecular & Cellular Proteomics, 9(1), 54–70.Google Scholar
  192. 192.
    Naik, R. S., Branch, O. H., Woods, A. S., Vijaykumar, M., Perkins, D. J., Nahlen, B. L., et al. (2000). Glycosylphosphatidylinositol anchors of Plasmodium falciparum: Molecular characterization and naturally elicited antibody response that may provide immunity to malaria pathogenesis. The Journal of Experimental Medicine, 192(11), 1563–1576.PubMedPubMedCentralGoogle Scholar
  193. 193.
    Old, W. M., Meyer-Arendt, K., Aveline-Wolf, L., Pierce, K. G., Mendoza, A., Sevinsky, J. R., et al. (2005). Comparison of label-free methods for quantifying human proteins by shotgun proteomics. Molecular & Cellular Proteomics, 4(10), 1487–1502.Google Scholar
  194. 194.
    Apweiler, R., Hermjakob, H., & Sharon, N. (1999). On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochimica et Biophysica Acta, 1473(1), 4–8.PubMedGoogle Scholar
  195. 195.
    Spiro, R. G. (2002). Protein glycosylation: nature, distribution, enzymatic formation, and disease implications of glycopeptide bonds. Glycobiology, 12(4), 43R–56R.PubMedGoogle Scholar
  196. 196.
    Reis, C. A., Osorio, H., Silva, L., Gomes, C., & David, L. (2010). Alterations in glycosylation as biomarkers for cancer detection. Journal of Clinical Pathology, 63(4), 322–329.PubMedGoogle Scholar
  197. 197.
    Aggarwal, S. (2010). What’s fueling the biotech engine-2009–2010. Nature Biotechnology, 28(11), 1165–1171.PubMedGoogle Scholar
  198. 198.
    Kornfeld, R., & Kornfeld, S. (1985). Assembly of asparagine-linked oligosaccharides. Annual Review of Biochemistry, 54, 631–664.PubMedGoogle Scholar
  199. 199.
    Stanley, P. (2011). Golgi glycosylation. Cold Spring Harbor Perspectives in Biology, 3(4), a00519.Google Scholar
  200. 200.
    Halim, A., Brinkmalm, G., Ruetschi, U., Westman-Brinkmalm, A., Portelius, E., Zetterberg, H., et al. (2011). Site-specific characterization of threonine, serine, and tyrosine glycosylations of amyloid precursor protein/amyloid beta-peptides in human cerebrospinal fluid. Proceedings of the National Academy of Sciences of the United States of America, 108(29), 11848–11853.PubMedPubMedCentralGoogle Scholar
  201. 201.
    Steentoft, C., Vakhrushev, S. Y., Vester-Christensen, M. B., Schjoldager, K. T., Kong, Y., Bennett, E. P., et al. (2011). Mining the O-glycoproteome using zinc-finger nuclease-glycoengineered SimpleCell lines. Nature Methods, 8(11), 977–982.PubMedGoogle Scholar
  202. 202.
    Spiro, R. G. (1969). Characterization and quantitative determination of the hydroxylysine-linked carbohydrate units of several collagens. The Journal of Biological Chemistry, 244(4), 602–612.PubMedGoogle Scholar
  203. 203.
    Butkinaree, C., Park, K., & Hart, G. W. (2010). O-linked beta-N-acetylglucosamine (O-GlcNAc): Extensive crosstalk with phosphorylation to regulate signaling and transcription in response to nutrients and stress. Biochimica et Biophysica Acta, 1800(2), 96–106.PubMedGoogle Scholar
  204. 204.
    Banerjee, S., Robbins, P. W., & Samuelson, J. (2009). Molecular characterization of nucleocytosolic O-GlcNAc transferases of Giardia lamblia and Cryptosporidium parvum. Glycobiology, 19(4), 331–336.PubMedGoogle Scholar
  205. 205.
    Perez-Cervera, Y., Harichaux, G., Schmidt, J., Debierre-Grockiego, F., Dehennaut, V., Bieker, U., et al. (2011). Direct evidence of O-GlcNAcylation in the apicomplexan Toxoplasma gondii: A biochemical and bioinformatic study. Amino Acids, 40, 847–856.PubMedGoogle Scholar
  206. 206.
    Luo, Q., Upadhya, R., Zhang, H., Madrid-Aliste, C., Nieves, E., Kim, K., et al. (2011). Analysis of the glycoproteome of Toxoplasma gondii using lectin affinity chromatography and tandem mass spectrometry. Microbes and Infection, 13(14–15), 1199–1210.PubMedPubMedCentralGoogle Scholar
  207. 207.
    Luk, F. C., Johnson, T. M., & Beckers, C. J. (2008). N-linked glycosylation of proteins in the protozoan parasite Toxoplasma gondii. Molecular and Biochemical Parasitology, 157(2), 169–178.PubMedGoogle Scholar
  208. 208.
    Fauquenoy, S., Morelle, W., Hovasse, A., Bednarczyk, A., Slomianny, C., Schaeffer, C., et al. (2008). Proteomics and glycomics analyses of N-glycosylated structures involved in Toxoplasma gondii—Host cell interactions. Molecular & Cellular Proteomics, 7(5), 891–910.Google Scholar
  209. 209.
    Wang, K., Peng, E. D., Huang, A. S., Xia, D., Vermont, S. J., Lentini, G., et al. (2016). Identification of novel O-linked glycosylated Toxoplasma proteins by Vicia villosa lectin chromatography. PLoS One, 11(3), e0150561.PubMedPubMedCentralGoogle Scholar
  210. 210.
    Hunt, J. V., Dean, R. T., & Wolff, S. P. (1988). Hydroxyl radical production and autoxidative glycosylation. Glucose autoxidation as the cause of protein damage in the experimental glycation model of diabetes mellitus and ageing. The Biochemical Journal, 256(1), 205–212.PubMedPubMedCentralGoogle Scholar
  211. 211.
    Smith, M. A., Richey, P. L., Taneda, S., Kutty, R. K., Sayre, L. M., Monnier, V. M., et al. (1994). Advanced Maillard reaction end products, free radicals, and protein oxidation in Alzheimer’s disease. Annals of the New York Academy of Sciences, 738, 447–454.PubMedGoogle Scholar
  212. 212.
    Paik, W. K., & Kim, S. (1980). Natural occurrence of various methylated amino acid derivatives. In A. Meister (Ed.), Protein methylation. New York: John Wiley & sons.Google Scholar
  213. 213.
    Ishikawa, Y., & Melville, D. B. (1970). The enzymatic alpha-N-methylation of histidine. The Journal of Biological Chemistry, 245(22), 5967–5973.PubMedGoogle Scholar
  214. 214.
    Paik, W. K., Paik, D. C., & Kim, S. (2007). Historical review: The field of protein methylation. Trends in Biochemical Sciences, 32(3), 146–152.PubMedPubMedCentralGoogle Scholar
  215. 215.
    Bedford, M. T., & Clarke, S. G. (2009). Protein arginine methylation in mammals: Who, what, and why. Molecular Cell, 33(1), 1–13.PubMedPubMedCentralGoogle Scholar
  216. 216.
    Wang, C., Leffler, S., Thompson, D. H., & Hrycyna, C. A. (2005). A general fluorescence-based coupled assay for S-adenosylmethionine-dependent methyltransferases. Biochemical and Biophysical Research Communications, 331(1), 351–356.PubMedGoogle Scholar
  217. 217.
    Herrmann, F., Pably, P., Eckerich, C., Bedford, M. T., & Fackelmayer, F. O. (2009). Human protein arginine methyltransferases in vivo—Distinct properties of eight canonical members of the PRMT family. Journal of Cell Science, 122(Pt 5), 667–677.PubMedGoogle Scholar
  218. 218.
    Molina-Serrano, D., Schiza, V., & Kirmizis, A. (2013). Cross-talk among epigenetic modifications: Lessons from histone arginine methylation. Biochemical Society Transactions, 41(3), 751–759.PubMedGoogle Scholar
  219. 219.
    Yamagata, K., Daitoku, H., Takahashi, Y., Namiki, K., Hisatake, K., Kako, K., et al. (2008). Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Molecular Cell, 32(2), 221–231.PubMedGoogle Scholar
  220. 220.
    Sato, N., Maitra, A., Fukushima, N., van Heek, N. T., Matsubayashi, H., Iacobuzio-Donahue, C. A., et al. (2003). Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Research, 63(14), 4158–4166.PubMedGoogle Scholar
  221. 221.
    Balasubramanyam, K., Varier, R. A., Altaf, M., Swaminathan, V., Siddappa, N. B., Ranga, U., et al. (2004). Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. The Journal of Biological Chemistry, 279(49), 51163–51171.PubMedGoogle Scholar
  222. 222.
    Choudhary, C., Kumar, C., Gnad, F., Nielsen, M. L., Rehman, M., Walther, T. C., et al. (2009). Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science (New York, N.Y.), 325(5942), 834–840.Google Scholar
  223. 223.
    Wang, J., Dixon, S. E., Ting, L. M., Liu, T. K., Jeffers, V., Croken, M. M., et al. (2014). Lysine acetyltransferase GCN5b interacts with AP2 factors and is required for Toxoplasma gondii proliferation. PLoS Pathogens, 10(1), e1003830.PubMedPubMedCentralGoogle Scholar
  224. 224.
    Geiss-Friedlander, R., & Melchior, F. (2007). Concepts in sumoylation: A decade on. Nature Reviews. Molecular Cell Biology, 8(12), 947–956.PubMedGoogle Scholar
  225. 225.
    Park, J., Chen, Y., Tishkoff, D. X., Peng, C., Tan, M., Dai, L., et al. (2013). SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Molecular Cell, 50(6), 919–930.PubMedPubMedCentralGoogle Scholar
  226. 226.
    Rardin, M. J., He, W., Nishida, Y., Newman, J. C., Carrico, C., Danielson, S. R., et al. (2013). SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metabolism, 18(6), 920–933.PubMedPubMedCentralGoogle Scholar
  227. 227.
    Weinert, B. T., Scholz, C., Wagner, S. A., Iesmantavicius, V., Su, D., Daniel, J. A., et al. (2013). Lysine succinylation is a frequently occurring modification in prokaryotes and eukaryotes and extensively overlaps with acetylation. Cell Reports, 4(4), 842–851.PubMedGoogle Scholar
  228. 228.
    Hirschey, M. D., & Zhao, Y. (2015). Metabolic regulation by lysine malonylation, succinylation, and glutarylation. Molecular & Cellular Proteomics, 14(9), 2308–2315.Google Scholar
  229. 229.
    Radke, J. R., Striepen, B., Guerini, M. N., Jerome, M. E., Roos, D. S., & White, M. W. (2001). Defining the cell cycle for the tachyzoite stage of Toxoplasma gondii. Molecular and Biochemical Parasitology, 115, 165–175.PubMedGoogle Scholar
  230. 230.
    Behnke, M. S., Wootton, J. C., Lehmann, M. M., Radke, J. B., Lucas, O., Nawas, J., et al. (2010). Coordinated progression through two subtranscriptomes underlies the tachyzoite cycle of Toxoplasma gondii. PLoS One, 5(8), e12354.PubMedPubMedCentralGoogle Scholar
  231. 231.
    Conde de Felipe, M. M., Lehmann, M. M., Jerome, M. E., & White, M. W. (2008). Inhibition of Toxoplasma gondii growth by pyrrolidine dithiocarbamate is cell cycle specific and leads to population synchronization. Molecular and Biochemical Parasitology, 157(1), 22–31.PubMedGoogle Scholar
  232. 232.
    Bassermann, F., Eichner, R., & Pagano, M. (2014). The ubiquitin proteasome system—Implications for cell cycle control and the targeted treatment of cancer. Biochimica et Biophysica Acta, 1843(1), 150–162.PubMedGoogle Scholar
  233. 233.
    White, M. W., & Suvorova, E. S. (2018). Apicomplexa cell cycles: something old, borrowed, lost, and new. Trends in Parasitology, 34(9), 759–771.  https://doi.org/10.1016/j.pt.2018.07.006CrossRefPubMedPubMedCentralGoogle Scholar
  234. 234.
    Hartmann, J., Hu, K., He, C. Y., Pelletier, L., Roos, D. S., & Warren, G. (2006). Golgi and centrosome cycles in Toxoplasma gondii. Molecular and Biochemical Parasitology, 145(1), 125–127.PubMedGoogle Scholar
  235. 235.
    Nishi, M., Hu, K., Murray, J. M., & Roos, D. S. (2008). Organellar dynamics during the cell cycle of Toxoplasma gondii. Journal of Cell Science, 121(Pt 9), 1559–1568.PubMedPubMedCentralGoogle Scholar
  236. 236.
    Pelletier, L., Stern, C. A., Pypaert, M., Sheff, D., Ngo, H. M., Roper, N., et al. (2002). Golgi biogenesis in Toxoplasma gondii. Nature, 418(6897), 548–552.PubMedGoogle Scholar
  237. 237.
    Teixeira, L. K., & Reed, S. I. (2013). Ubiquitin ligases and cell cycle control. Annual Review of Biochemistry, 82, 387–414.PubMedGoogle Scholar
  238. 238.
    Baker, D. J., Dawlaty, M. M., Galardy, P., & van Deursen, J. M. (2007). Mitotic regulation of the anaphase-promoting complex. Cellular and Molecular Life Sciences, 64(5), 589–600.PubMedGoogle Scholar
  239. 239.
    Ponts, N., Yang, J., Chung, D. W., Prudhomme, J., Girke, T., Horrocks, P., et al. (2008). Deciphering the ubiquitin-mediated pathway in apicomplexan parasites: A potential strategy to interfere with parasite virulence. PLoS One, 3(6), e2386.PubMedPubMedCentralGoogle Scholar
  240. 240.
    Chick, J. M., Kolippakkam, D., Nusinow, D. P., Zhai, B., Rad, R., Huttlin, E. L., et al. (2015). A mass-tolerant database search identifies a large proportion of unassigned spectra in shotgun proteomics as modified peptides. Nature Biotechnology, 33(7), 743–749.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Rama R. Yakubu
    • 1
  • Edward Nieves
    • 2
    • 3
  • Louis M. Weiss
    • 1
    • 4
    Email author
  1. 1.Department of PathologyAlbert Einstein College of MedicineBronxUSA
  2. 2.Department of BiochemistryAlbert Einstein College of MedicineBronxUSA
  3. 3.Department of Developmental and Molecular BiologyAlbert Einstein College of MedicineBronxUSA
  4. 4.Department of MedicineAlbert Einstein College of MedicineBronxUSA

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