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Serine/Threonine Protein Kinases

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  • Authors: Sladjana Prisic1, Robert N. Husson2
  • Editors: Graham F. Hatfull3, William R. Jacobs Jr.4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Division of Infectious Diseases, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115; 2: Division of Infectious Diseases, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115; 3: University of Pittsburgh, Pittsburgh, PA; 4: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY
    • Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0006-2013
  • Received 13 April 2013 Accepted 22 October 2013 Published 12 September 2014
  • R. N. Husson, [email protected]
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  • Abstract:

    The genome encodes 11 serine/threonine protein kinases (STPKs). A similar number of two-component systems are also present, indicating that these two signal transduction mechanisms are both important in the adaptation of this bacterial pathogen to its environment. The phosphoproteome includes hundreds of Ser- and Thr-phosphorylated proteins that participate in all aspects of biology, supporting a critical role for the STPKs in regulating physiology. Nine of the STPKs are receptor type kinases, with an extracytoplasmic sensor domain and an intracellular kinase domain, indicating that these kinases transduce external signals. Two other STPKs are cytoplasmic and have regulatory domains that sense changes within the cell. Structural analysis of some of the STPKs has led to advances in our understanding of the mechanisms by which these STPKs are activated and regulated. Functional analysis has provided insights into the effects of phosphorylation on the activity of several proteins, but for most phosphoproteins the role of phosphorylation in regulating function is unknown. Major future challenges include characterizing the functional effects of phosphorylation for this large number of phosphoproteins, identifying the cognate STPKs for these phosphoproteins, and determining the signals that the STPKs sense. Ultimately, combining these STPK-regulated processes into larger, integrated regulatory networks will provide deeper insight into adaptive mechanisms that contribute to tuberculosis pathogenesis. Finally, the STPKs offer attractive targets for inhibitor development that may lead to new therapies for drug-susceptible and drug-resistant tuberculosis.

  • Citation: Prisic S, Husson R. 2014. Serine/Threonine Protein Kinases. Microbiol Spectrum 2(5):MGM2-0006-2013. doi:10.1128/microbiolspec.MGM2-0006-2013.

References

1. West AH, Stock AM. 2001. Histidine kinases and response regulator proteins in two-component signaling systems. Trends Biochem Sci 26:369–376. [PubMed][CrossRef]
2. Ulrich LE, Koonin EV, Zhulin IB. 2005. One-component systems dominate signal transduction in prokaryotes. Trends Microbiol 13:52–56. [PubMed][CrossRef]
3. Staroń A, Sofia H, Dietrich S, Ulrich L, Liesegang H, Mascher T. 2009. The third pillar of bacterial signal transduction: classification of the extracytoplasmic function (ECF) sigma factor protein family. Mol Microbiol 74:557–581. [PubMed][CrossRef]
4. Lonetto M, Brown K, Rudd K, Buttner M. 1994. Analysis of the Streptomyces coelicolor sigE gene reveals the existence of a subfamily of eubacterial RNA polymerase σ factors involved in the regulation of extracytoplasmic functions. Proc Natl Acad Sci USA 91:7573–7577. [PubMed][CrossRef]
5. Song T, Dove SL, Lee KH, Husson RN. 2003. RshA, an anti-sigma factor that regulates the activity of the mycobacterial stress response sigma factor SigH. Mol Microbiol 50:949–959. [PubMed][CrossRef]
6. Hahn MY, Raman S, Anaya M, Husson RN. 2005. The Mycobacterium tuberculosis ECF sigma factor SigL regulates polyketide synthases and membrane/secreted proteins, and is required for virulence. J Bacteriol 187:7062–7071. [PubMed][CrossRef]
7. Perez J, Castaneda-Garcia A, Jenke-Kodama H, Muller R, Munoz-Dorado J. 2008. Eukaryotic-like protein kinases in the prokaryotes and the myxobacterial kinome. Proc Natl Acad Sci USA 105:15950–15955. [PubMed][CrossRef]
8. Munoz-Dorado J, Inouye S, Inouye M. 1991. A gene encoding a protein serine/threonine kinase is required for normal development of M. xanthus, a gram-negative bacterium. Cell 67:995–1006. [PubMed][CrossRef]
9. Av-Gay Y, Everett M. 2000. The eukaryotic-like Ser/Thr protein kinases of Mycobacterium tuberculosis. Trends Microbiol 8:238–244. [PubMed][CrossRef]
10. Hanks S, Hunter T. 1995. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J 9:576–596. [PubMed]
11. Sassetti CM, Boyd DH, Rubin EJ. 2003. Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol 48:77–84. [PubMed][CrossRef]
12. Ortiz-Lombardia M, Pompeo F, Boitel B, Alzari PM. 2003. Crystal structure of the catalytic domain of the PknB serine/threonine kinase from Mycobacterium tuberculosis. J Biol Chem 278:13094–13100. [PubMed][CrossRef]
13. Young TA, Delagoutte B, Endrizzi JA, Falick AM, Alber T. 2003. Structure of Mycobacterium tuberculosis PknB supports a universal activation mechanism for Ser/Thr protein kinases. Nat Struct Biol 10:168–174. [PubMed][CrossRef]
14. Gay LM, Ng HL, Alber T. 2006. A conserved dimer and global conformational changes in the structure of apo-PknE Ser/Thr protein kinase from Mycobacterium tuberculosis. J Mol Biol 360:409–420. [PubMed][CrossRef]
15. Prisic S, Dankwa S, Schwartz D, Chou MF, Locasale JW, Kang CM, Bemis G, Church GM, Steen H, Husson RN. 2010. Extensive phosphorylation with overlapping specificity by Mycobacterium tuberculosis serine/threonine protein kinases. Proc Natl Acad Sci USA 107:7521–7526. [PubMed][CrossRef]
16. Boitel B, Ortiz-Lombardia M, Duran R, Pompeo F, Cole ST, Cervenansky C, Alzari PM. 2003. PknB kinase activity is regulated by phosphorylation in two Thr residues and dephosphorylation by PstP, the cognate phospho-Ser/Thr phosphatase, in Mycobacterium tuberculosis. Mol Microbiol 49:1493–1508. [PubMed][CrossRef]
17. Kang CM, Abbott DW, Park ST, Dascher CC, Cantley LC, Husson RN. 2005. The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape. Genes Dev 19:1692–1704. [PubMed][CrossRef]
18. Molle V, Zanella-Cleon I, Robin JP, Mallejac S, Cozzone AJ, Becchi M. 2006. Characterization of the phosphorylation sites of Mycobacterium tuberculosis serine/threonine protein kinases, PknA, PknD, PknE, and PknH by mass spectrometry. Proteomics 6:3754–3766. [PubMed][CrossRef]
19. O’Hare HM, Duran R, Cervenansky C, Bellinzoni M, Wehenkel AM, Pritsch O, Obal G, Baumgartner J, Vialaret J, Johnsson K, Alzari PM. 2008. Regulation of glutamate metabolism by protein kinases in mycobacteria. Mol Microbiol 70:1408–1423. [PubMed][CrossRef]
20. Duran R, Villarino A, Bellinzoni M, Wehenkel A, Fernandez P, Boitel B, Cole ST, Alzari PM, Cervenansky C. 2005. Conserved autophosphorylation pattern in activation loops and juxtamembrane regions of Mycobacterium tuberculosis Ser/Thr protein kinases. Biochem Biophys Res Comm 333:858–867. [PubMed][CrossRef]
21. Mieczkowski C, Iavarone AT, Alber T. 2008. Auto-activation mechanism of the Mycobacterium tuberculosis PknB receptor Ser/Thr kinase. Embo J 27:3186–3197. [PubMed][CrossRef]
22. Lombana TN, Echols N, Good MC, Thomsen ND, Ng H-L, Greenstein AE, Falick AM, King DS, Alber T. 2010. Allosteric activation mechanism of the Mycobacterium tuberculosis receptor Ser/Thr protein kinase, PknB. Structure 18:1667–1677. [PubMed][CrossRef]
23. Greenstein AE, Echols N, Lombana TN, King DS, Alber T. 2007. Allosteric activation by dimerization of the PknD receptor Ser/Thr protein kinase from Mycobacterium tuberculosis. J Biol Chem 282:11427–11435. [PubMed][CrossRef]
24. Wehenkel A, Bellinzoni M, Graña M, Duran R. 2008. Mycobacterial Ser/Thr protein kinases and phosphatases: physiological roles and therapeutic potential. Biochim Biophys Acta 1784:193–202. [PubMed][CrossRef]
25. Wehenkel A, Fernandez P, Bellinzoni M, Catherinot V, Barilone N, Labesse G, Jackson M, Alzari PM. 2006. The structure of PknB in complex with mitoxantrone, an ATP-competitive inhibitor, suggests a mode of protein kinase regulation in mycobacteria. FEBS Lett 580:3018–3022. [PubMed][CrossRef]
26. Dey M, Cao C, Dar AC, Tamura T, Ozato K, Sicheri F, Dever TE. 2005. Mechanistic link between PKR dimerization, autophosphorylation, and eIF2alpha substrate recognition. Cell 122:901–913. [PubMed][CrossRef]
27. Mir M, Asong J, Li X, Cardot J, Boons GJ, Husson RN. 2011. The extracytoplasmic domain of the Mycobacterium tuberculosis Ser/Thr kinase PknB binds specific muropeptides and is required for PknB localization. PLoS Pathog 7:e1002182. [PubMed][CrossRef]
28. Barthe P, Mukamolova GV, Roumestand C, Cohen-Gonsaud M. 2010. The structure of PknB extracellular PASTA domain from Mycobacterium tuberculosis suggests a ligand-dependent kinase activation. Structure 18:606–615. [PubMed][CrossRef]
29. Scherr N, Honnappa S, Kunz G, Mueller P, Jayachandran R, Winkler F, Pieters J, Steinmetz MO. 2007. Structural basis for the specific inhibition of protein kinase G, a virulence factor of Mycobacterium tuberculosis. Proc Natl Acad Sci USA 104:12151–12156. [PubMed][CrossRef]
30. Tiwari D, Singh RK, Goswami K, Verma SK, Prakash B, Nandicoori VK. 2009. Key residues in Mycobacterium tuberculosis protein kinase G play a role in regulating kinase activity and survival in the host. Journal of Biological Chemistry 284:27467–27479. [PubMed][CrossRef]
31. Gil M, Graña M, Schopfer FJ, Wagner T, Denicola A, Freeman BA, Alzari PM, Batthyány C, Duran R. 2013. Inhibition of Mycobacterium tuberculosis PknG by non-catalytic rubredoxin domain specific modification: reaction of an electrophilic nitro-fatty acid with the Fe-S center. Free Radic. Biol. Med. 65:150–161. [PubMed][CrossRef]
32. 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. Mol Cell Proteomics 7:1409–1419. [PubMed][CrossRef]
33. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. 2002. The protein kinase complement of the human genome. Science 298:1912–1934. [PubMed][CrossRef]
34. Kinexus March 1, 2013 2013, posting date. Phosphonet: Human Phospho-Site KnowledgeBase. [Online.]
35. Bach H, Wong D, Av-Gay Y. 2009. Mycobacterium tuberculosis PtkA is a novel protein tyrosine kinase whose substrate is PtpA. Biochem J 420:155–160. [PubMed][CrossRef]
36. Dasgupta A, Datta P, Kundu M, Basu J. 2006. The serine/threonine kinase PknB of Mycobacterium tuberculosis phosphorylates PBPA, a penicillin-binding protein required for cell division. Microbiology 152:493–504. [PubMed][CrossRef]
37. Gee CL, Papavinasasundaram KG, Blair SR, Baer CE, Falick AM, King DS, Griffin JE, Venghatakrishnan H, Zukauskas A, Wei JR, Dhiman RK, Crick DC, Rubin EJ, Sassetti CM, Alber T. 2012. A phosphorylated pseudokinase complex controls cell wall synthesis in mycobacteria. Sci Signal 5:ra7. [PubMed][CrossRef]
38. Ortega C, Liao R, Anderson LN, Rustad T, Ollodart AR, Wright AT, Sherman DR, Grundner C. 2014. Mycobacterium tuberculosis Ser/Thr protein kinase B mediates an oxygen-dependent replication switch. PLoS Biol. 12:e1001746. [PubMed][CrossRef]
39. Yeats C, Finn RD, Bateman A. 2002. The PASTA domain: a beta-lactam-binding domain. Trends Biochem Sci 27:438–440. [PubMed][CrossRef]
40. Shah IM, Laaberki MH, Popham DL, Dworkin J. 2008. A eukaryotic-like Ser/Thr kinase signals bacteria to exit dormancy in response to peptidoglycan fragments. Cell 135:486–496. [PubMed][CrossRef]
41. Squeglia F, Marchetti R, Ruggiero A, Lanzetta R, Marasco D, Dworkin J, Petoukhov M, Molinaro A, Berisio R, Silipo A. 2011. Chemical basis of peptidoglycan discrimination by PrkC, a key kinase involved in bacterial resuscitation from dormancy. J Am Chem Soc 133:20676–20679. [PubMed][CrossRef]
42. Kang CM, Nyayapathy S, Lee JY, Suh JW, Husson RN. 2008. Wag31, a homologue of the cell division protein DivIVA, regulates growth, morphology and polar cell wall synthesis in mycobacteria. Microbiology 154:725–735. [PubMed][CrossRef]
43. Daniel RA, Errington J. 2003. Control of cell morphogenesis in bacteria: two distinct ways to make a rod-shaped cell. Cell 113:767–776. [PubMed][CrossRef]
44. Ruiz N. 2008. Bioinformatics identification of MurJ (MviN) as the peptidoglycan lipid II flippase in Escherichia coli. Proc Natl Acad Sci USA 105:15553–15557. [PubMed][CrossRef]
45. Larsen MH, Vilchèze C, Kremer L, Besra GS, Parsons L, Salfinger M, Heifets L, Hazbon MH, Alland D, Sacchettini JC, Jacobs WR. 2002. Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis. Mol Microbiol 46:453–466. [PubMed][CrossRef]
46. Vilchèze C, Wang F, Arai M, Hazbón MH, Colangeli R, Kremer L, Weisbrod TR, Alland D, Sacchettini JC, Jacobs WR. 2006. Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid. Nat Med 12:1027–1029. [PubMed][CrossRef]
47. Khan S, Nagarajan SN, Parikh A, Samantaray S, Singh A, Kumar D, Roy RP, Bhatt A, Nandicoori VK. 2010. Phosphorylation of enoyl-acyl carrier protein reductase InhA impacts mycobacterial growth and survival. J Biol Chem 285:37860–37871. [PubMed][CrossRef]
48. Molle V, Gulten G, Vilchèze C, Veyron-Churlet R, Zanella-Cleon I, Sacchettini JC, Jacobs WR, Kremer L. 2010. Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of Mycobacterium tuberculosis. Mol Microbiol 78:1591–1605. [PubMed][CrossRef]
49. Molle V, Brown AK, Besra GS, Cozzone AJ, Kremer L. 2006. The condensing activities of the Mycobacterium tuberculosis type II fatty acid synthase are differentially regulated by phosphorylation. J Biol Chem 281:30094–30103. [PubMed][CrossRef]
50. Veyron-Churlet R, Zanella-Cleon I, Cohen-Gonsaud M, Molle V, Kremer L. 2010. Phosphorylation of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein reductase MabA regulates mycolic acid biosynthesis. J Biol Chem 285:12714–12725. [PubMed][CrossRef]
51. Veyron-Churlet R, Molle V, Taylor RC, Brown AK, Besra GS, Zanella-Cleon I, Fütterer K, Kremer L. 2009. The Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III activity is inhibited by phosphorylation on a single threonine residue. J Biol Chem 284:6414–6424. [PubMed][CrossRef]
52. Camus JC, Pryor MJ, Medigue C, Cole ST. 2002. Re-annotation of the genome sequence of Mycobacterium tuberculosis H37Rv. Microbiology 148:2967–2973. [PubMed]
53. Good MC, Greenstein AE, Young TA, Ng HL, Alber T. 2004. Sensor domain of the Mycobacterium tuberculosis receptor Ser/Thr protein kinase, PknD, forms a highly symmetric beta propeller. J Mol Biol 339:459–469. [PubMed][CrossRef]
54. Vanzembergh F, Peirs P, Lefèvre P, Celio N, Mathys V, Content J, Kalai M. 2010. Effect of PstS sub-units or PknD deficiency on the survival of Mycobacterium tuberculosis. Tuberculosis (Edinb) 90:338–345. [PubMed][CrossRef]
55. Greenstein AE, Macgurn JA, Baer CE, Falick AM, Cox JS, Alber T. 2007. M. tuberculosis Ser/Thr protein kinase D phosphorylates an anti-anti-sigma factor homolog. PLoS Pathog 3:e49. [PubMed][CrossRef]
56. Hatzios SK, Baer CE, Rustad TR, Siegrist MS, Pang JM, Ortega C, Alber T, Grundner C, Sherman DR, Bertozzi CR. 2013. Osmosensory signaling in Mycobacterium tuberculosis mediated by a eukaryotic-like Ser/Thr protein kinase. Proceedings of the National Academy of Sciences 110:E5069–5077. [PubMed][CrossRef]
57. Be NA, Bishai WR, Jain SK. 2012. Role of Mycobacterium tuberculosis pknD in the pathogenesis of central nervous system tuberculosis. BMC Microbiol 12:7. [PubMed][CrossRef]
58. Kumar D, Narayanan S. 2012. PknE, a serine/threonine kinase of Mycobacterium tuberculosis, modulates multiple apoptotic paradigms. Infect Genet Evol 12:737–747. [PubMed][CrossRef]
59. Hofmann K, Bucher P. 1995. The FHA domain: a putative nuclear signalling domain found in protein kinases and transcription factors. Trends Biochem Sci 20:347–349. [PubMed][CrossRef]
60. Molle V, Soulat D, Jault JM, Grangeasse C, Cozzone AJ, Prost JF. 2004. Two FHA domains on an ABC transporter, Rv1747, mediate its phosphorylation by PknF, a Ser/Thr protein kinase from Mycobacterium tuberculosis. FEMS Microbiol Lett 234:215–223. [PubMed][CrossRef]
61. Curry JM, Whalan R, Hunt DM, Gohil K, Strom M, Rickman L, Colston MJ, Smerdon SJ, Buxton RS. 2005. An ABC transporter containing a forkhead-associated domain interacts with a serine-threonine protein kinase and is required for growth of Mycobacterium tuberculosis in mice. Infect Immun 73:4471–4477. [PubMed][CrossRef]
62. Deol P, Vohra R, Saini AK, Singh A, Chandra H, Chopra P, Das TK, Tyagi AK, Singh Y. 2005. Role of Mycobacterium tuberculosis Ser/Thr kinase PknF: implications in glucose transport and cell division. J Bacteriol 187:3415–3420. [PubMed][CrossRef]
63. Spivey VL, Molle V, Whalan RH, Rodgers A, Leiba J, Stach L, Walker KB, Smerdon SJ, Buxton RS. 2011. Forkhead-associated (FHA) domain containing ABC transporter Rv1747 is positively regulated by Ser/Thr phosphorylation in Mycobacterium tuberculosis. J Biol Chem 286:26198–26209. [PubMed][CrossRef]
64. Marchler-Bauer A, Lu S, Anderson JB, Chitsaz F, Derbyshire MK, DeWeese-Scott C, Fong JH, Geer LY, Geer RC, Gonzales NR, Gwadz M, Hurwitz DI, Jackson JD, Ke Z, Lanczycki CJ, Lu F, Marchler GH, Mullokandov M, Omelchenko MV, Robertson CL, Song JS, Thanki N, Yamashita RA, Zhang D, Zhang N, Zheng C, Bryant SH. 2011. CDD: a Conserved Domain Database for the functional annotation of proteins. Nucleic Acids Res 39:D225–D229. [PubMed][CrossRef]
65. Walburger A, Koul A, Ferrari G, Nguyen L, Prescianotto-Baschong C, Huygen K, Klebl B, Thompson C, Bacher G, Pieters J. 2004. Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 304:1800–1804. [PubMed][CrossRef]
66. Cowley S, Ko M, Pick N, Chow R, Downing KJ, Gordhan BG, Betts JC, Mizrahi V, Smith DA, Stokes RW, Av-Gay Y. 2004. The Mycobacterium tuberculosis protein serine/threonine kinase PknG is linked to cellular glutamate/glutamine levels and is important for growth in vivo. Mol Microbiol 52:1691–1702. [PubMed][CrossRef]
67. Ventura M, Rieck B, Boldrin F, Degiacomi G, Bellinzoni M, Barilone N, Alzaidi F, Alzari PM, Manganelli R, O'Hare HM. 2013. GarA is an essential regulator of metabolism in Mycobacterium tuberculosis. Mol Microbiol 90:356-366. [PubMed]
68. Niebisch A, Kabus A, Schultz C, Weil B, Bott M. 2006. Corynebacterial protein kinase G controls 2-oxoglutarate dehydrogenase activity via the phosphorylation status of the OdhI protein. J Biol Chem 281:12300–12307. [PubMed][CrossRef]
69. Nott TJ, Kelly G, Stach L, Li J, Westcott S, Patel D, Hunt DM, Howell S, Buxton RS, O’Hare HM, Smerdon SJ. 2009. An intramolecular switch regulates phosphoindependent FHA domain interactions in Mycobacterium tuberculosis. Sci Signaling 2:1–9. [PubMed][CrossRef]
70. Cavazos A, Prigozhin DM, Alber T. 2012. Structure of the sensor domain of Mycobacterium tuberculosis PknH receptor kinase reveals a conserved binding cleft. J Mol Biol 422:488–494. [PubMed][CrossRef]
71. Molle V, Kremer L, Girard-Blanc C, Besra GS, Cozzone AJ, Prost JF. 2003. An FHA phosphoprotein recognition domain mediates protein EmbR phosphorylation by PknH, a Ser/Thr protein kinase from Mycobacterium tuberculosis. Biochemistry 42:15300–15309. [PubMed][CrossRef]
72. Zhang N, Torrelles JB, McNeil MR, Escuyer VE, Khoo K-H, Brennan PJ, Chatterjee D. 2003. The Emb proteins of mycobacteria direct arabinosylation of lipoarabinomannan and arabinogalactan via an N-terminal recognition region and a C-terminal synthetic region. Mol Microbiol 50:69–76. [PubMed][CrossRef]
73. Escuyer VE, Lety MA, Torrelles JB, Khoo KH, Tang JB, Rithner CD, Frehel C, Mcneil MR, Brennan PJ, Chatterjee D. 2001. The role of the embA and embB gene products in the biosynthesis of the terminal hexaarabinofuranosyl motif of Mycobacterium smegmatis arabinogalactan. J Biol Chem 276:48854–48862. [PubMed][CrossRef]
74. Sharma K, Gupta M, Pathak M, Gupta N, Koul A, Sarangi S, Baweja R, Singh Y. 2006. Transcriptional control of the mycobacterial embCAB operon by PknH through a regulatory protein, EmbR, in vivo. J Bacteriol 188:2936–2944. [PubMed][CrossRef]
75. Papavinasasundaram KG, Chan B, Chung JH, Colston MJ, Davis EO, Av-Gay Y. 2005. Deletion of the Mycobacterium tuberculosis pknH gene confers a higher bacillary load during the chronic phase of infection in BALB/c mice. J Bacteriol 187:5751–5760. [PubMed][CrossRef]
76. Gomez-Velasco A, Bach H, Rana AK, Cox LR, Bhatt A, Besra GS, Av-Gay Y. 2013. Disruption of the serine/threonine protein kinase H affects phthiocerol dimycocerosates synthesis in Mycobacterium tuberculosis. Microbiology 159:726–736. [PubMed][CrossRef]
77. Chao JD, Papavinasasundaram KG, Zheng X, Chávez-Steenbock A, Wang X, Lee GQ, Av-Gay Y. 2010. Convergence of Ser/Thr and two-component signaling to coordinate expression of the dormancy regulon in Mycobacterium tuberculosis. J Biol Chem 285:29239–29246. [PubMed][CrossRef]
78. Gopalaswamy R, Narayanan S, Chen B, Jacobs WR, Av-Gay Y. 2009. The serine/threonine protein kinase PknI controls the growth of Mycobacterium tuberculosis upon infection. FEMS Microbiol Lett 295:23–29. [PubMed][CrossRef]
79. Jang J, Stella A, Boudou F, Levillain F, Darthuy E, Vaubourgeix J, Wang C, Bardou F, Puzo G, Gilleron M, Burlet-Schiltz O, Monsarrat B, Brodin P, Gicquel B, Neyrolles O. 2010. Functional characterization of the Mycobacterium tuberculosis serine/threonine kinase PknJ. Microbiology 156:1619–1631. [PubMed][CrossRef]
80. Blatch GL, Lässle M. 1999. The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. Bioessays 21:932–939. [PubMed][CrossRef]
81. Kumar P, Kumar D, Parikh A, Rananaware D, Gupta M, Singh Y, Nandicoori VK. 2009. The Mycobacterium tuberculosis protein kinase K modulates activation of transcription from the promoter of mycobacterial monooxygenase operon through phosphorylation of the transcriptional regulator VirS. J Biol Chem 284:11090–11099. [PubMed][CrossRef]
82. Malhotra V, Arteaga-Cortés LT, Clay G, Clark-Curtiss JE. 2010. Mycobacterium tuberculosis protein kinase K confers survival advantage during early infection in mice and regulates growth in culture and during persistent infection: implications for immune modulation. Microbiology 156:2829–2841. [PubMed][CrossRef]
83. Malhotra V, Okon BP, Clark-Curtiss JE. 2012. Mycobacterium tuberculosis protein kinase K enables growth adaptation through translation control. J Bacteriol 194:4184–4196. [PubMed][CrossRef]
84. Narayan A, Sachdeva P, Sharma K, Saini AK, Tyagi AK, Singh Y. 2007. Serine threonine protein kinases of mycobacterial genus: phylogeny to function. Physiol Genomics 29:66–75. [PubMed][CrossRef]
85. Canova MJ, Veyron-Churlet R, Zanella-Cleon I, Cohen-Gonsaud M, Cozzone AJ, Becchi M, Kremer L, Molle V. 2008. The Mycobacterium tuberculosis serine/threonine kinase PknL phosphorylates Rv2175c: mass spectrometric profiling of the activation loop phosphorylation sites and their role in the recruitment of Rv2175c. Proteomics 8:521–533. [PubMed][CrossRef]
86. Barford D, Das AK, Egloff MP. 1998. The structure and mechanism of protein phosphatases: insights into catalysis and regulation. Annu Rev Biophys Biomol Struct 27:133–164. [PubMed][CrossRef]
87. Pullen KE, Ng H-L, Sung P-Y, Good MC, Smith SM, Alber T. 2004. An alternate conformation and a third metal in PstP/Ppp, the M. tuberculosis PP2C-family Ser/Thr protein phosphatase. Structure 12:1947–1954. [PubMed][CrossRef]
88. Koul A, Choidas A, Treder M, Tyagi AK, Drlica K, Singh Y, Ullrich A. 2000. Cloning and characterization of secretory tyrosine phosphatases of Mycobacterium tuberculosis. J Bacteriol 182:5425–5432. [PubMed][CrossRef]
89. Beresford N, Patel S, Armstrong J, Szöor B, Fordham-Skelton AP, Tabernero L. 2007. MptpB, a virulence factor from Mycobacterium tuberculosis, exhibits triple-specificity phosphatase activity. Biochem J 406:13–18. [PubMed][CrossRef]
90. Stehle T, Sreeramulu S, Löhr F, Richter C, Saxena K, Jonker HRA, Schwalbe H. 2012. The apo-structure of the low molecular weight protein-tyrosine phosphatase A (MptpA) from Mycobacterium tuberculosis allows for better target-specific drug development. J Biol Chem 287:34569–34582. [PubMed][CrossRef]
91. Madhurantakam C, Rajakumara E, Mazumdar PA, Saha B, Mitra D, Wiker HG, Sankaranarayanan R, Das AK. 2005. Crystal structure of low-molecular-weight protein tyrosine phosphatase from Mycobacterium tuberculosis at 1.9-A resolution. J Bacteriol 187:2175–2181. [PubMed][CrossRef]
92. Flynn EM, Hanson JA, Alber T, Yang H. 2010. Dynamic active-site protection by the M. tuberculosis protein tyrosine phosphatase PtpB lid domain. J Am Chem Soc 132:4772–4780. [PubMed][CrossRef]
93. Grundner C, Ng H-L, Alber T. 2005. Mycobacterium tuberculosis protein tyrosine phosphatase PtpB structure reveals a diverged fold and a buried active site. Structure 13:1625–1634. [PubMed][CrossRef]
94. Bach H, Papavinasasundaram KG, Wong D, Hmama Z, Av-Gay Y. 2008. Mycobacterium tuberculosis virulence is mediated by PtpA dephosphorylation of human vacuolar protein sorting 33B. Cell Host Microbe 3:316–322. [PubMed][CrossRef]
95. Wong D, Bach H, Sun J, Hmama Z, Av-Gay Y. 2011. Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes host vacuolar-H+-ATPase to inhibit phagosome acidification. Proc Natl Acad Sci USA 108:19371–19376. [PubMed][CrossRef]
96. Zhou B, He Y, Zhang X, Xu J, Luo Y, Wang Y, Franzblau SG, Yang Z, Chan RJ, Liu Y, Zheng J, Zhang Z-Y. 2010. Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents. Proc Natl Acad Sci USA 107:4573–4578. [PubMed][CrossRef]
97. Singh R, Rao V, Shakila H, Gupta R, Khera A, Dhar N, Singh A, Koul A, Singh Y, Naseema M, Narayanan PR, Paramasivan CN, Ramanathan VD, Tyagi AK. 2003. Disruption of mptpB impairs the ability of Mycobacterium tuberculosis to survive in guinea pigs. Mol Microbiol 50:751–762. [PubMed][CrossRef]
98. Saleh MT, Belisle JT. 2000. Secretion of an acid phosphatase (SapM) by Mycobacterium tuberculosis that is similar to eukaryotic acid phosphatases. J Bacteriol 182:6850–6853. [PubMed][CrossRef]
99. Vergne I, Chua J, Lee H-H, Lucas M, Belisle J, Deretic V. 2005. Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. Proc Natl Acad Sci USA 102:4033–4038. [PubMed][CrossRef]
100. Zhang J, Yang PL, Gray NS. 2009. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9:28–39. [PubMed][CrossRef]
101. Chapman TM, Bouloc N, Buxton RS, Chugh J, Lougheed KEA, Osborne SA, Saxty B, Smerdon SJ, Taylor DL, Whalley D. 2012. Substituted aminopyrimidine protein kinase B (PknB) inhibitors show activity against Mycobacterium tuberculosis. Bioorg Med Chem Lett 22:3349–3353. [PubMed][CrossRef]
102. Lougheed KEA, Osborne SA, Saxty B, Whalley D, Chapman T, Bouloc N, Chugh J, Nott TJ, Patel D, Spivey VL, Kettleborough CA, Bryans JS, Taylor DL, Smerdon SJ, Buxton RS. 2011. Effective inhibitors of the essential kinase PknB and their potential as anti-mycobacterial agents. Tuberculosis (Edinb) 91:277–286. [PubMed][CrossRef]
103. Hanzelka BL, Wang T, Bemis G, Zuccola H, Doyle T, Stuver-Moody C, Huang YN, Sears C, Fleming M, Erwin AL, Locher C, Muh U. 2009. Evidence that inhibition of the serine-threonine protein kinases of Mycobacterium tuberculosis holds promise for developing novel anti-tuberculosis drugs. Gordon Research Conference on Tuberculosis Drug Development, Oxford University, Oxford, U.K.
104. Székely R, Wáczek F, Szabadkai I, Németh G, Hegymegi-Barakonyi B, Eros D, Szokol B, Pató J, Hafenbradl D, Satchell J, Saint-Joanis B, Cole ST, Orfi L, Klebl BM, Kéri G. 2008. A novel drug discovery concept for tuberculosis: inhibition of bacterial and host cell signalling. Immunol Lett 116:225–231. [PubMed][CrossRef]
105. Wong D, Chao JD, Av-Gay Y. 2013. Mycobacterium tuberculosis-secreted phosphatases: from pathogenesis to targets for TB drug development. Trends Microbiol 21:100–109. [PubMed][CrossRef]
106. Vintonyak VV, Antonchick AP, Rauh D, Waldmann H. 2009. The therapeutic potential of phosphatase inhibitors. Curr Opin Chem Biol 13:272–283. [PubMed][CrossRef]
107. Manger M, Scheck M, Prinz H, von Kries JP, Langer T, Saxena K, Schwalbe H, Fürstner A, Rademann J, Waldmann H. 2005. Discovery of Mycobacterium tuberculosis protein tyrosine phosphatase A (MptpA) inhibitors based on natural products and a fragment-based approach. Chembiochem 6:1749–1753. [PubMed][CrossRef]
108. Chiaradia LD, Martins PGA, Cordeiro MNS, Guido RVC, Ecco G, Andricopulo AD, Yunes RA, Vernal J, Nunes RJ, Terenzi H. 2012. Synthesis, biological evaluation, and molecular modeling of chalcone derivatives as potent inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatases (PtpA and PtpB). J Med Chem 55:390–402. [PubMed][CrossRef]
109. Chiaradia LD, Mascarello A, Purificação M, Vernal J, Cordeiro MNS, Zenteno ME, Villarino A, Nunes RJ, Yunes RA, Terenzi H. 2008. Synthetic chalcones as efficient inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase PtpA. Bioorg Med Chem Lett 18:6227–6230. [PubMed][CrossRef]
110. Mascarello A, Chiaradia LD, Vernal J, Villarino A, Guido RVC, Perizzolo P, Poirier V, Wong D, Martins PGA, Nunes RJ, Yunes RA, Andricopulo AD, Av-Gay Y, Terenzi H. 2010. Inhibition of Mycobacterium tuberculosis tyrosine phosphatase PtpA by synthetic chalcones: kinetics, molecular modeling, toxicity and effect on growth. Bioorg Med Chem 18:3783–3789. [PubMed][CrossRef]
111. Rawls KA, Lang PT, Takeuchi J, Imamura S, Baguley TD, Grundner C, Alber T, Ellman JA. 2009. Fragment-based discovery of selective inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase PtpA. Bioorg Med Chem Lett 19:6851–6854. [PubMed][CrossRef]
112. Grundner C, Perrin D, Hooft van Huijsduijnen R, Swinnen D, Gonzalez J, Gee CL, Wells TN, Alber T. 2007. Structural basis for selective inhibition of Mycobacterium tuberculosis protein tyrosine phosphatase PtpB. Structure 15:499–509. [PubMed][CrossRef]
113. Soellner MB, Rawls KA, Grundner C, Alber T, Ellman JA. 2007. Fragment-based substrate activity screening method for the identification of potent inhibitors of the Mycobacterium tuberculosis phosphatase PtpB. J Am Chem Soc 129:9613–9615. [PubMed][CrossRef]
114. Beresford NJ, Mulhearn D, Szczepankiewicz B, Liu G, Johnson ME, Fordham-Skelton A, Abad-Zapatero C, Cavet JS, Tabernero L. 2009. Inhibition of MptpB phosphatase from Mycobacterium tuberculosis impairs mycobacterial survival in macrophages. J Antimicrob Chemother 63:928–936. [PubMed][CrossRef]
115. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE, 3rd, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Barrell BG. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544. [PubMed][CrossRef]
116. Zheng X, Papavinasasundaram KG, Av-Gay Y. 2007. Novel substrates of Mycobacterium tuberculosis PknH Ser/Thr kinase. Biochem Biophys Res Comm 355:162–168. [PubMed][CrossRef]
117. Sajid A, Arora G, Gupta M, Singhal A, Chakraborty K, Nandicoori VK, Singh Y. 2011. Interaction of Mycobacterium tuberculosis elongation factor Tu with GTP is regulated by phosphorylation. J Bacteriol 193:5347–5358. [PubMed][CrossRef]
118. Molle V, Reynolds RC, Alderwick LJ, Besra GS, Cozzone AJ, Fütterer K, Kremer L. 2008. EmbR2, a structural homologue of EmbR, inhibits the Mycobacterium tuberculosis kinase/substrate pair PknH/EmbR. Biochem J 410:309–317. [PubMed][CrossRef]
119. Sinha I, Boon C, Dick T. 2003. Apparent growth phase-dependent phosphorylation of malonyl coenzyme A:acyl carrier protein transacylase (MCAT), a major fatty acid synthase II component in Mycobacterium bovis BCG. FEMS Microbiol Lett 227:141–147. [PubMed][CrossRef]
120. Grundner C, Gay LM, Alber T. 2005. Mycobacterium tuberculosis serine/threonine kinases PknB, PknD, PknE, and PknF phosphorylate multiple FHA domains. Protein Sci 14:1918–1921. [PubMed][CrossRef]
121. Roumestand C, Leiba J, Galophe N, Margeat E, Padilla A, Bessin Y, Barthe P, Molle V, Cohen-Gonsaud M. 2011. Structural insight into the Mycobacterium tuberculosis Rv0020c protein and its interaction with the PknB kinase. Structure 19:1525–1534. [PubMed][CrossRef]
122. Sureka K, Hossain T, Mukherjee P, Chatterjee P, Datta P, Kundu M, Basu J. 2010. Novel role of phosphorylation-dependent interaction between FtsZ and FipA in mycobacterial cell division. PLoS One 5:e8590. [PubMed][CrossRef]
123. Thakur M, Chakraborti PK. 2006. GTPase activity of mycobacterial FtsZ is impaired due to its transphosphorylation by the eukaryotic-type Ser/Thr kinase, PknA. J Biol Chem 281:40107–40113. [PubMed][CrossRef]
124. Villarino A, Duran R, Wehenkel A, Fernandez P, England P, Brodin P, Cole ST, Zimny-Arndt U, Jungblut PR, Cervenansky C, Alzari PM. 2005. Proteomic identification of M. tuberculosis protein kinase substrates: PknB recruits GarA, a FHA domain-containing protein, through activation loop-mediated interactions. J Mol Biol 350:953–963. [PubMed][CrossRef]
125. Leiba J, Syson K, Baronian G, Zanella-Cleon I, Kalscheuer R, Kremer L, Bornemann S, Molle V. 2013. Mycobacterium tuberculosis maltosyltransferase GlgE, a genetically validated antituberculosis target, is negatively regulated by Ser/Thr phosphorylation. Journal of Biological Chemistry 288:16546–16556. [PubMed][CrossRef]
126. Parikh A, Verma SK, Khan S, Prakash B, Nandicoori VK. 2009. PknB-mediated phosphorylation of a novel substrate, N-acetylglucosamine-1-phosphate uridyltransferase, modulates its acetyltransferase activity. J Mol Biol 386:451–464. [PubMed][CrossRef]
127. Canova MJ, Kremer L, Molle V. 2009. The Mycobacterium tuberculosis GroEL1 chaperone is a substrate of Ser/Thr protein kinases. J Bacteriol 191:2876–2883. [PubMed][CrossRef]
128. Perez J, Garcia R, Bach H, de Waard JH, Jacobs WR Jr, Av-Gay Y, Bubis J, Takiff HE. 2006. Mycobacterium tuberculosis transporter MmpL7 is a potential substrate for kinase PknD. Biochem Biophys Res Commun 348:6–12. [PubMed][CrossRef]
129. Thakur M, Chakraborti PK. 2008. Ability of PknA, a mycobacterial eukaryotic-type serine/threonine kinase, to transphosphorylate MurD, a ligase involved in the process of peptidoglycan biosynthesis. Biochem J 415:27–33. [PubMed][CrossRef]
130. Gupta M, Sajid A, Arora G, Tandon V, Singh Y. 2009. Forkhead-associated domain-containing protein Rv0019c and polyketide-associated protein PapA5, from substrates of serine/threonine protein kinase PknB to interacting proteins of Mycobacterium tuberculosis. J Biol Chem 284:34723–34734. [PubMed][CrossRef]
131. Corrales RM, Molle V, Leiba J, Mourey L, de Chastellier C, Kremer L. 2012. Phosphorylation of mycobacterial PcaA inhibits mycolic acid cyclopropanation: consequences for intracellular survival and for phagosome maturation block. J Biol Chem 287:26187–26199. [PubMed][CrossRef]
132. Sajid A, Arora G, Gupta M, Upadhyay S, Nandicoori VK, Singh Y. 2011. Phosphorylation of Mycobacterium tuberculosis Ser/Thr phosphatase by PknA and PknB. PLoS One 6:e17871. [PubMed][CrossRef]
133. Arora G, Sajid A, Gupta M, Bhaduri A, Kumar P, Basu-Modak S, Singh Y. 2010. Understanding the role of PknJ in Mycobacterium tuberculosis: biochemical characterization and identification of novel substrate pyruvate kinase A. PLoS One 5:e10772. [PubMed][CrossRef]
134. Park ST, Kang CM, Husson RN. 2008. Regulation of the SigH stress response regulon by an essential protein kinase in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 105:13105–13110. [PubMed][CrossRef]
135. Cohen-Gonsaud M, Barthe P, Canova MJ, Stagier-Simon C, Kremer L, Roumestand C, Molle V. 2009. The Mycobacterium tuberculosis Ser/Thr kinase substrate Rv2175c is a DNA-binding protein regulated by phosphorylation. J Biol Chem 284:19290–19300. [PubMed][CrossRef]
136. Schultz J, Milpetz F, Bork P, Ponting CP. 1998. SMART, a simple modular architecture research tool: identification of signaling domains. Proc Natl Acad Sci USA 95:5857–5864. [PubMed][CrossRef]
137. Letunic I, Doerks T, Bork P. 2012. SMART 7: recent updates to the protein domain annotation resource. Nucleic Acids Res 40:D302–D305. [PubMed][CrossRef]
138. Parish T. 2014. Two-component regulatory systems of mycobacteria. Microbiol Spectrum 2(1) :MGM2-0010-2013. doi:10.1128/microbiolspec.MGM2-0010-2013. [CrossRef]
139. Manganelli R. 2014. Sigma factors: key molecules in Mycobacterium tuberculosis physiology and virulence. Microbiol Spectrum 2(1) :MGM2-0007-2013. doi:10.1128/microbiolspec.MGM2-0007-2013. [CrossRef]
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2014-09-12
2021-04-20

Abstract:

The genome encodes 11 serine/threonine protein kinases (STPKs). A similar number of two-component systems are also present, indicating that these two signal transduction mechanisms are both important in the adaptation of this bacterial pathogen to its environment. The phosphoproteome includes hundreds of Ser- and Thr-phosphorylated proteins that participate in all aspects of biology, supporting a critical role for the STPKs in regulating physiology. Nine of the STPKs are receptor type kinases, with an extracytoplasmic sensor domain and an intracellular kinase domain, indicating that these kinases transduce external signals. Two other STPKs are cytoplasmic and have regulatory domains that sense changes within the cell. Structural analysis of some of the STPKs has led to advances in our understanding of the mechanisms by which these STPKs are activated and regulated. Functional analysis has provided insights into the effects of phosphorylation on the activity of several proteins, but for most phosphoproteins the role of phosphorylation in regulating function is unknown. Major future challenges include characterizing the functional effects of phosphorylation for this large number of phosphoproteins, identifying the cognate STPKs for these phosphoproteins, and determining the signals that the STPKs sense. Ultimately, combining these STPK-regulated processes into larger, integrated regulatory networks will provide deeper insight into adaptive mechanisms that contribute to tuberculosis pathogenesis. Finally, the STPKs offer attractive targets for inhibitor development that may lead to new therapies for drug-susceptible and drug-resistant tuberculosis.

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Serine/Threonine Protein Kinases
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Citation: Prisic S, Husson R. 2014. serine/threonine protein kinases. microbiolspec 2(5): doi:10.1128/microbiolspec.MGM2-0006-2013
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FIGURE 1
Domain organization of STPKs from Domains were predicted using the SMART algorithm ( 136 , 137 ). Kinase domains are shown as green boxes, transmembrane portions are in blue, and some known extracellular domains are in light red.
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FIGURE 1

Domain organization of STPKs from Domains were predicted using the SMART algorithm ( 136 , 137 ). Kinase domains are shown as green boxes, transmembrane portions are in blue, and some known extracellular domains are in light red.

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FIGURE 2
Sequence alignment of STPKs from Kinase domains predicted by the SMART algorithm (see Fig. 1 ) were aligned and grouped using AlignX software (Life Technologies). Human Clk1 kinase is also included for comparison. Major features are noted. Selected conserved residues are labeled with the following symbols (residue numbers from PknB): *, Lys40; #, Glu59; &, Asp138; $, Asn143; %, Asp156; p, major phosphorylation sites in the activation loop.
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FIGURE 2

Sequence alignment of STPKs from Kinase domains predicted by the SMART algorithm (see Fig. 1 ) were aligned and grouped using AlignX software (Life Technologies). Human Clk1 kinase is also included for comparison. Major features are noted. Selected conserved residues are labeled with the following symbols (residue numbers from PknB): *, Lys40; #, Glu59; &, Asp138; $, Asn143; %, Asp156; p, major phosphorylation sites in the activation loop.

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FIGURE 3
Dendrogram of KDs of STPKs. KDs identified by the SMART algorithm were aligned and grouped using the AlignX software (Life Technologies). Human Clk1 kinase is also included for comparison. Distance scores as given by AlignX are shown in parentheses.
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FIGURE 3

Dendrogram of KDs of STPKs. KDs identified by the SMART algorithm were aligned and grouped using the AlignX software (Life Technologies). Human Clk1 kinase is also included for comparison. Distance scores as given by AlignX are shown in parentheses.

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FIGURE 4
Overview of the STPK’s KD. Major features of the PknB KD (1MRU_B): N-terminal (upper) and C-terminal (lower) lobes are labeled. The ATP analog is in blue, and two Mg ions are in green. Overlap of PknB (green) and Clk1 (magenta). Clk1 was a top hit when the PknB structure was used to search similar three-dimensional structures using the NCBI VAST program. For clarity, residues 298 to 319 and 395 to 443 in Clk1 that are absent in STPKs (see Fig. 2 ) are truncated in Clk1. PknB (1MRU_B), PknE (2H34_B), PknG (2PZI_A), and Clk1 (1Z57). α-Helix is in red, β-sheet is in yellow. Figures were made using PyMOL (Schrödinger) and POV-Ray (povray.org).
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FIGURE 4

Overview of the STPK’s KD. Major features of the PknB KD (1MRU_B): N-terminal (upper) and C-terminal (lower) lobes are labeled. The ATP analog is in blue, and two Mg ions are in green. Overlap of PknB (green) and Clk1 (magenta). Clk1 was a top hit when the PknB structure was used to search similar three-dimensional structures using the NCBI VAST program. For clarity, residues 298 to 319 and 395 to 443 in Clk1 that are absent in STPKs (see Fig. 2 ) are truncated in Clk1. PknB (1MRU_B), PknE (2H34_B), PknG (2PZI_A), and Clk1 (1Z57). α-Helix is in red, β-sheet is in yellow. Figures were made using PyMOL (Schrödinger) and POV-Ray (povray.org).

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FIGURE 5
Active site of PknB KD. Overlap of “closed” PknB KD (1MRU_B) in green and “open” apo-PknE-KD (2H34) in blue, with the PknE C helix labeled in red. PknB active site (1MRU_B) P loop (GFGGMS), magenta; Mg, red balls; ATPγS, yellow; C-helix, green (Glu59-green); Lys40, aqua; catalytic loop, red (Asp138-orange, Asn143-red); DFG motif, purple (Asp156-purple). Figures were made using PyMOL (Schrödinger) and POV-Ray (povray.org).
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FIGURE 5

Active site of PknB KD. Overlap of “closed” PknB KD (1MRU_B) in green and “open” apo-PknE-KD (2H34) in blue, with the PknE C helix labeled in red. PknB active site (1MRU_B) P loop (GFGGMS), magenta; Mg, red balls; ATPγS, yellow; C-helix, green (Glu59-green); Lys40, aqua; catalytic loop, red (Asp138-orange, Asn143-red); DFG motif, purple (Asp156-purple). Figures were made using PyMOL (Schrödinger) and POV-Ray (povray.org).

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FIGURE 6
Back-to-back dimerization of KDs. PknB-KD dimer showing “back-to-back” interaction. Overlap of PknB-KD in active form (1MRU_B-blue) and conformations of the PknB-KD L33D mutant that perturbs the dimer interface (3ORK, yellow; 3ORI_A, red; 3ORL, green). The C helix is shown in ribbon, while the rest of the structure is shown in wire. C helix from the PknB structures in panel B magnified to highlight differences in the position of Glu59. Figures were made using PyMOL (Schrödinger) and POV-Ray (povray.org).
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FIGURE 6

Back-to-back dimerization of KDs. PknB-KD dimer showing “back-to-back” interaction. Overlap of PknB-KD in active form (1MRU_B-blue) and conformations of the PknB-KD L33D mutant that perturbs the dimer interface (3ORK, yellow; 3ORI_A, red; 3ORL, green). The C helix is shown in ribbon, while the rest of the structure is shown in wire. C helix from the PknB structures in panel B magnified to highlight differences in the position of Glu59. Figures were made using PyMOL (Schrödinger) and POV-Ray (povray.org).

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FIGURE 7
Distinct modes of monomer interaction in dimers of PknB versus PknG “Front-to-front” dimer of mutant PknB KD (3F69) in complex with Kt5720 inhibitor (yellow). The “substrate” subunit (magenta) has most of its activation loop disordered (red), while the “enzyme” subunit (blue) has a well-defined activation loop (orange) with visible phosphorylated Thr171 (green). Structure of PknG (2PZI) in complex with inhibitor Ax20017 (magenta). Three domains: rubredoxin (yellow), KD (green), and TPR domain (red) are shown only in one subunit. The second subunit is depicted in gray. Figures were made in PyMOL (Schrödinger) and POV-Ray (povray.org).
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FIGURE 7

Distinct modes of monomer interaction in dimers of PknB versus PknG “Front-to-front” dimer of mutant PknB KD (3F69) in complex with Kt5720 inhibitor (yellow). The “substrate” subunit (magenta) has most of its activation loop disordered (red), while the “enzyme” subunit (blue) has a well-defined activation loop (orange) with visible phosphorylated Thr171 (green). Structure of PknG (2PZI) in complex with inhibitor Ax20017 (magenta). Three domains: rubredoxin (yellow), KD (green), and TPR domain (red) are shown only in one subunit. The second subunit is depicted in gray. Figures were made in PyMOL (Schrödinger) and POV-Ray (povray.org).

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FIGURE 8
phosphoproteome. Phosphoproteins were identified in all functional categories of proteins ( 15 ).
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FIGURE 8

phosphoproteome. Phosphoproteins were identified in all functional categories of proteins ( 15 ).

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Tables

Serine/Threonine Protein Kinases
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Citation: Prisic S, Husson R. 2014. serine/threonine protein kinases. microbiolspec 2(5): doi:10.1128/microbiolspec.MGM2-0006-2013
/content/microbiolspec/10.1128/microbiolspec.MGM2-0006-2013.T1
TABLE 1
Closest orthologs of STPKs
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TABLE 1

Closest orthologs of STPKs

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0006-2013
/content/microbiolspec/10.1128/microbiolspec.MGM2-0006-2013.T2
TABLE 2
Structures of STPKs available in the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Database (PDB)
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TABLE 2

Structures of STPKs available in the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Database (PDB)

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0006-2013
/content/microbiolspec/10.1128/microbiolspec.MGM2-0006-2013.T3
TABLE 3
Phosphorylated proteins in in addition to those identified in the phosphoproteomic study of Prisic et al. ( 15 )
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TABLE 3

Phosphorylated proteins in in addition to those identified in the phosphoproteomic study of Prisic et al. ( 15 )

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.MGM2-0006-2013

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