Journal of Molecular Evolution

, Volume 68, Issue 6, pp 587–602 | Cite as

The Evolution of Guanylyl Cyclases as Multidomain Proteins: Conserved Features of Kinase-Cyclase Domain Fusions

  • Kabir Hassan Biswas
  • Avinash R. Shenoy
  • Anindya Dutta
  • Sandhya S. Visweswariah


Guanylyl cyclases (GCs) are enzymes that generate cyclic GMP and regulate different physiologic and developmental processes in a number of organisms. GCs possess sequence similarity to class III adenylyl cyclases (ACs) and are present as either membrane-bound receptor GCs or cytosolic soluble GCs. We sought to determine the evolution of GCs using a large-scale bioinformatic analysis and found multiple lineage-specific expansions of GC genes in the genomes of many eukaryotes. Moreover, a few GC-like proteins were identified in prokaryotes, which come fused to a number of different domains, suggesting allosteric regulation of nucleotide cyclase activity. Eukaryotic receptor GCs are associated with a kinase homology domain (KHD), and phylogenetic analysis of these proteins suggest coevolution of the KHD and the associated cyclase domain as well as a conservation of the sequence and the size of the linker region between the KHD and the associated cyclase domain. Finally, we also report the existence of mimiviral proteins that contain putative active kinase domains associated with a cyclase domain, which could suggest early evolution of the fusion of these two important domains involved in signal transduction.


Guanylyl cyclase Kinase homology domain Mimivirus Phylogeny cGMP Coevolution 

Supplementary material

239_2009_9242_MOESM1_ESM.doc (294 kb)
Supplementary material 1 (DOC 294 kb)


  1. Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402PubMedCrossRefGoogle Scholar
  2. Anantharaman V, Balaji S, Aravind L (2006) The signaling helix: a common functional theme in diverse signaling proteins. Biol Direct 1:25PubMedCrossRefGoogle Scholar
  3. Aparicio JG, Applebury ML (1996) The photoreceptor guanylate cyclase is an autophosphorylating protein kinase. J Biol Chem 271:27083–27089PubMedCrossRefGoogle Scholar
  4. Baker DA, Kelly JM (2004) Structure, function and evolution of microbial adenylyl and guanylyl cyclases. Mol Microbiol 52:1229–1242PubMedCrossRefGoogle Scholar
  5. Bateman A, Coin L, Durbin R, Finn RD, Hollich V, Griffiths-Jones S, Khanna A, Marshall M, Moxon S, Sonnhammer EL et al (2004) The Pfam protein families database. Nucleic Acids Res 32:D138–D141PubMedCrossRefGoogle Scholar
  6. Beuve A, Boesten B, Crasnier M, Danchin A, O’Gara F (1990) Rhizobium meliloti adenylate cyclase is related to eucaryotic adenylate and guanylate cyclases. J Bacteriol 172:2614–2621PubMedGoogle Scholar
  7. Beuve A, Krin E, Danchin A (1993) Rhizobium meliloti adenylate cyclase: probing of a NTP-binding site common to cyclases and cation transporters. C R Acad Sci III 316:553–559PubMedGoogle Scholar
  8. Bhandari R, Srinivasan N, Mahaboobi M, Ghanekar Y, Suguna K, Visweswariah SS (2001) Functional inactivation of the human guanylyl cyclase C receptor: modeling and mutation of the protein kinase-like domain. Biochemistry 40:9196–9206PubMedCrossRefGoogle Scholar
  9. Bhaya D, Nakasugi K, Fazeli F, Burriesci MS (2006) Phototaxis and impaired motility in adenylyl cyclase and cyclase receptor protein mutants of Synechocystis sp. strain PCC 6803. J Bacteriol 188:7306–7310PubMedCrossRefGoogle Scholar
  10. Boudeau J, Miranda-Saavedra D, Barton GJ, Alessi DR (2006) Emerging roles of pseudokinases. Trends Cell Biol 16:443–452PubMedCrossRefGoogle Scholar
  11. Cadoret JC, Rousseau B, Perewoska I, Sicora C, Cheregi O, Vass I, Houmard J (2005) Cyclic nucleotides, the photosynthetic apparatus and response to a UV-B stress in the Cyanobacterium Synechocystis sp. PCC 6803. J Biol Chem 280:33935–33944PubMedCrossRefGoogle Scholar
  12. Caenepeel S, Charydczak G, Sudarsanam S, Hunter T, Manning G (2004) The mouse kinome: discovery and comparative genomics of all mouse protein kinases. Proc Natl Acad Sci USA 101:11707–11712PubMedCrossRefGoogle Scholar
  13. Crooks GE, Hon G, Chandonia JM, Brenner SE (2004) WebLogo: a sequence logo generator. Genome Res 14:1188–1190PubMedCrossRefGoogle Scholar
  14. Dizhoor AM (2000) Regulation of cGMP synthesis in photoreceptors: role in signal transduction and congenital diseases of the retina. Cell Signal 12:711–719PubMedCrossRefGoogle Scholar
  15. Filee J, Siguier P, Chandler M (2007) I am what I eat and I eat what I am: acquisition of bacterial genes by giant viruses. Trends Genet 23:10–15PubMedCrossRefGoogle Scholar
  16. Fitzpatrick DA, O’Halloran DM, Burnell AM (2006) Multiple lineage specific expansions within the guanylyl cyclase gene family. BMC Evol Biol 6:26PubMedCrossRefGoogle Scholar
  17. Forte LR Jr (2004) Uroguanylin and guanylin peptides: pharmacology and experimental therapeutics. Pharmacol Ther 104:137–162PubMedCrossRefGoogle Scholar
  18. Foster DC, Wedel BJ, Robinson SW, Garbers DL (1999) Mechanisms of regulation and functions of guanylyl cyclases. Rev Physiol Biochem Pharmacol 135:1–39PubMedCrossRefGoogle Scholar
  19. Goh CS, Bogan AA, Joachimiak M, Walther D, Cohen FE (2000) Co-evolution of proteins with their interaction partners. J Mol Biol 299:283–293PubMedCrossRefGoogle Scholar
  20. Goldberg JM, Manning G, Liu A, Fey P, Pilcher KE, Xu Y, Smith JL (2006) The dictyostelium kinome—analysis of the protein kinases from a simple model organism. PLoS Genet 2:291–303CrossRefGoogle Scholar
  21. Hon WC, McKay GA, Thompson PR, Sweet RM, Yang DS, Wright GD, Berghuis AM (1997) Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases. Cell 89:887–895PubMedCrossRefGoogle Scholar
  22. Hughes JM, Murad F, Chang B, Guerrant RL (1978) Role of cyclic GMP in the action of heat-stable enterotoxin of Escherichia coli. Nature 271:755–756PubMedCrossRefGoogle Scholar
  23. Hunter T, Plowman GD (1997) The protein kinases of budding yeast: six score and more. Trends Biochem Sci 22:18–22PubMedCrossRefGoogle Scholar
  24. Huse M, Kuriyan J (2002) The conformational plasticity of protein kinases. Cell 109:275–282PubMedCrossRefGoogle Scholar
  25. Imashimizu M, Yoshimura H, Katoh H, Ehira S, Ohmori M (2005) NaCl enhances cellular cAMP and upregulates genes related to heterocyst development in the cyanobacterium, Anabaena sp. strain PCC 7120. FEMS Microbiol Lett 252:97–103PubMedCrossRefGoogle Scholar
  26. Iyer LM, Anantharaman V, Aravind L (2003) Ancient conserved domains shared by animal soluble guanylyl cyclases and bacterial signaling proteins. BMC Genomics 4:5PubMedCrossRefGoogle Scholar
  27. Jaleel M, Saha S, Shenoy AR, Visweswariah SS (2006) The kinase homology domain of receptor guanylyl cyclase C: ATP binding and identification of an adenine nucleotide sensitive site. Biochemistry 45:1888–1898PubMedCrossRefGoogle Scholar
  28. Kanacher T, Schultz A, Linder JU, Schultz JE (2002) A GAF-domain-regulated adenylyl cyclase from Anabaena is a self-activating cAMP switch. EMBO J 21:3672–3680PubMedCrossRefGoogle Scholar
  29. Kannan N, Taylor SS (2008) Rethinking pseudokinases. Cell 133:204–205PubMedCrossRefGoogle Scholar
  30. Kasahara M, Unno T, Yashiro K, Ohmori M (2001) CyaG, a novel cyanobacterial adenylyl cyclase and a possible ancestor of mammalian guanylyl cyclases. J Biol Chem 276:10564–10569PubMedCrossRefGoogle Scholar
  31. Katayama M, Ohmori M (1997) Isolation and characterization of multiple adenylate cyclase genes from the cyanobacterium Anabaena sp. strain PCC 7120. J Bacteriol 179:3588–3593PubMedGoogle Scholar
  32. Kojima M, Hisaki K, Matsuo H, Kangawa K (1995) A new type soluble guanylyl cyclase, which contains a kinase-like domain: its structure and expression. Biochem Biophys Res Commun 217:993–1000PubMedCrossRefGoogle Scholar
  33. Koller KJ, de Sauvage FJ, Lowe DG, Goeddel DV (1992) Conservation of the kinaselike regulatory domain is essential for activation of the natriuretic peptide receptor guanylyl cyclases. Mol Cell Biol 12:2581–2590PubMedGoogle Scholar
  34. Koonin EV, Tatusov RL (1994) Computer analysis of bacterial haloacid dehalogenases defines a large superfamily of hydrolases with diverse specificity. Application of an iterative approach to database search. J Mol Biol 244:125–132PubMedCrossRefGoogle Scholar
  35. Kuhn M (2004) Molecular physiology of natriuretic peptide signalling. Basic Res Cardiol 99:76–82PubMedCrossRefGoogle Scholar
  36. La Scola B, Marrie TJ, Auffray JP, Raoult D (2005) Mimivirus in pneumonia patients. Emerg Infect Dis 11:449–452PubMedGoogle Scholar
  37. Laurent F, McCole D, Eckmann L, Kagnoff MF (1999) Pathogenesis of Cryptosporidium parvum infection. Microbes Infect 1:141–148PubMedCrossRefGoogle Scholar
  38. Letunic I, Copley RR, Pils B, Pinkert S, Schultz J, Bork P (2006) SMART 5: domains in the context of genomes and networks. Nucleic Acids Res 34:D257–D260PubMedCrossRefGoogle Scholar
  39. Lin Z, Johnson LC, Weissbach H, Brot N, Lively MO, Lowther WT (2007) Free methionine-(R)-sulfoxide reductase from Escherichia coli reveals a new GAF domain function. Proc Natl Acad Sci USA 104:9597–9602PubMedCrossRefGoogle Scholar
  40. Linder JU, Engel P, Reimer A, Kruger T, Plattner H, Schultz A, Schultz JE (1999) Guanylyl cyclases with the topology of mammalian adenylyl cyclases and an N-terminal P-type ATPase-like domain in Paramecium, Tetrahymena and Plasmodium. EMBO J 18:4222–4232PubMedCrossRefGoogle Scholar
  41. Linder JU, Hoffmann T, Kurz U, Schultz JE (2000) A guanylyl cyclase from Paramecium with 22 transmembrane spans. Expression of the catalytic domains and formation of chimeras with the catalytic domains of mammalian adenylyl cyclases. J Biol Chem 275:11235–11240PubMedCrossRefGoogle Scholar
  42. Linder JU, Schultz JE (2002) Guanylyl cyclases in unicellular organisms. Mol Cell Biochem 230:149–158PubMedCrossRefGoogle Scholar
  43. Linder JU, Schultz JE (2003) The class III adenylyl cyclases: multi-purpose signalling modules. Cell Signal 15:1081–1089PubMedCrossRefGoogle Scholar
  44. Lucas KA, Pitari GM, Kazerounian S, Ruiz-Stewart I, Park J, Schulz S, Chepenik KP, Waldman SA (2000) Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 52:375–414PubMedGoogle Scholar
  45. Ludidi N, Gehring C (2003) Identification of a novel protein with guanylyl cyclase activity in Arabidopsis thaliana. J Biol Chem 278:6490–6494PubMedCrossRefGoogle Scholar
  46. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912–1934PubMedCrossRefGoogle Scholar
  47. Martinez SE, Beavo JA, Hol WG (2002) GAF domains: two-billion-year-old molecular switches that bind cyclic nucleotides. Mol Interv 2:317–323PubMedCrossRefGoogle Scholar
  48. McDonald V (2000) Host cell-mediated responses to infection with Cryptosporidium. Parasite Immunol 22:597–604PubMedCrossRefGoogle Scholar
  49. McNeil L, Chinkers M, Forte M (1995) Identification, characterization, and developmental regulation of a receptor guanylyl cyclase expressed during early stages of Drosophila development. J Biol Chem 270:7189–7196PubMedCrossRefGoogle Scholar
  50. Monier A, Claverie JM, Ogata H (2007) Horizontal gene transfer and nucleotide compositional anomaly in large DNA viruses. BMC Genomics 8:456PubMedCrossRefGoogle Scholar
  51. Moreira D, Brochier-Armanet C (2008) Giant viruses, giant chimeras: the multiple evolutionary histories of Mimivirus genes. BMC Evol Biol 8:12PubMedCrossRefGoogle Scholar
  52. Morton DB, Langlais KK, Stewart JA, Vermehren A (2005) Comparison of the properties of the five soluble guanylyl cyclase subunits in Drosophila melanogaster. J Insect Sci 5:12PubMedGoogle Scholar
  53. Mougel C, Zhulin IB (2001) CHASE: an extracellular sensing domain common to transmembrane receptors from prokaryotes, lower eukaryotes and plants. Trends Biochem Sci 26:582–584PubMedCrossRefGoogle Scholar
  54. Mukherjee K, Sharma M, Urlaub H, Bourenkov GP, Jahn R, Sudhof TC, Wahl MC (2008) CASK Functions as a Mg2+-independent neurexin kinase. Cell 133:328–339PubMedCrossRefGoogle Scholar
  55. Nolen B, Taylor S, Ghosh G (2004) Regulation of protein kinases: controlling activity through activation segment conformation. Mol Cell 15:661–675PubMedCrossRefGoogle Scholar
  56. Ochoa De Alda JA, Ajlani G, Houmard J (2000) Synechocystis strain PCC 6803 cya2, a prokaryotic gene that encodes a guanylyl cyclase. J Bacteriol 182:3839–3842PubMedCrossRefGoogle Scholar
  57. Ortiz CO, Etchberger JF, Posy SL, Frokjaer-Jensen C, Lockery S, Honig B, Hobert O (2006) Searching for neuronal left/right asymmetry: genomewide analysis of nematode receptor-type guanylyl cyclases. Genetics 173:131–149PubMedCrossRefGoogle Scholar
  58. Park H, Inouye M (1997) Mutational analysis of the linker region of EnvZ, an osmosensor in Escherichia coli. J Bacteriol 179:4382–4390PubMedGoogle Scholar
  59. Perkins WJ (2006) Regulation of soluble guanylyl cyclase: looking beyond NO. Am J Physiol Lung Cell Mol Physiol 291:L334–L336PubMedCrossRefGoogle Scholar
  60. Plowman GD, Sudarsanam S, Bingham J, Whyte D, Hunter T (1999) The protein kinases of Caenorhabditis elegans: a model for signal transduction in multicellular organisms. Proc Natl Acad Sci USA 96:13603–13610PubMedCrossRefGoogle Scholar
  61. Ramamurthy V, Tucker C, Wilkie SE, Daggett V, Hunt DM, Hurley JB (2001) Interactions within the coiled-coil domain of RetGC-1 guanylyl cyclase are optimized for regulation rather than for high affinity. J Biol Chem 276:26218–26229PubMedCrossRefGoogle Scholar
  62. Raoult D, La Scola B, Birtles R (2007) The discovery and characterization of Mimivirus, the largest known virus and putative pneumonia agent. Clin Infect Dis 45:95–102PubMedCrossRefGoogle Scholar
  63. Roelofs J, Snippe H, Kleineidam RG, Van Haastert PJ (2001) Guanylate cyclase in Dictyostelium discoideum with the topology of mammalian adenylate cyclase. Biochem J 354:697–706PubMedCrossRefGoogle Scholar
  64. Roelofs J, Van Haastert PJ (2002) Characterization of two unusual guanylyl cyclases from dictyostelium. J Biol Chem 277:9167–9174PubMedCrossRefGoogle Scholar
  65. Romling U, Amikam D (2006) Cyclic di-GMP as a second messenger. Curr Opin Microbiol 9:218–228PubMedCrossRefGoogle Scholar
  66. Sabatini MJ, Ebert P, Lewis DA, Levitt P, Cameron JL, Mirnics K (2007) Amygdala gene expression correlates of social behavior in monkeys experiencing maternal separation. J Neurosci 27:3295–3304PubMedCrossRefGoogle Scholar
  67. Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4:406–425PubMedGoogle Scholar
  68. Schultz J, Copley RR, Doerks T, Ponting CP, Bork P (2000) SMART: a web-based tool for the study of genetically mobile domains. Nucleic Acids Res 28:231–234PubMedCrossRefGoogle Scholar
  69. Schulz S, Green CK, Yuen PS, Garbers DL (1990) Guanylyl cyclase is a heat-stable enterotoxin receptor. Cell 63:941–948PubMedCrossRefGoogle Scholar
  70. Seeliger MA, Nagar B, Frank F, Cao X, Henderson MN, Kuriyan J (2007) c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty. Structure 15:299–311PubMedCrossRefGoogle Scholar
  71. Shenoy AR, Srinivasan N, Subramaniam M, Visweswariah SS (2003) Mutational analysis of the Mycobacterium tuberculosis Rv1625c adenylyl cyclase: residues that confer nucleotide specificity contribute to dimerization. FEBS Lett 545:253–259PubMedCrossRefGoogle Scholar
  72. Shenoy AR, Visweswariah SS (2004) Class III nucleotide cyclases in bacteria and archaebacteria: lineage-specific expansion of adenylyl cyclases and a dearth of guanylyl cyclases. FEBS Lett 561:11–21CrossRefGoogle Scholar
  73. Suhre K (2005) Gene and genome duplication in Acanthamoeba polyphaga Mimivirus. J Virol 79:14095–14101PubMedCrossRefGoogle Scholar
  74. Sunahara RK, Beuve A, Tesmer JJ, Sprang SR, Garbers DL, Gilman AG (1998) Exchange of substrate and inhibitor specificities between adenylyl and guanylyl cyclases. J Biol Chem 273:16332–16338PubMedCrossRefGoogle Scholar
  75. Suzan-Monti M, La Scola B, Raoult D (2006) Genomic and evolutionary aspects of Mimivirus. Virus Res 117:145–155PubMedCrossRefGoogle Scholar
  76. Szmidt-Jaworska A, Jaworski K, Kopcewicz J (2007) Involvement of cyclic GMP in phytochrome-controlled flowering of Pharbitis nil. J Plant Physiol 165:858–867PubMedCrossRefGoogle Scholar
  77. Tamura K, Dudley J, Nei M, Kumar S (2007) MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 24:1596–1599PubMedCrossRefGoogle Scholar
  78. Tang WJ, Hurley JH (1998) Catalytic mechanism and regulation of mammalian adenylyl cyclases. Mol Pharmacol 54:231–240PubMedGoogle Scholar
  79. Taylor SS, Knighton DR, Zheng J, Sowadski JM, Gibbs CS, Zoller MJ (1993) A template for the protein kinase family. Trends Biochem Sci 18:84–89PubMedCrossRefGoogle Scholar
  80. Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR (1997) Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS. Science 278:1907–1916PubMedCrossRefGoogle Scholar
  81. Tesmer JJ, Sunahara RK, Johnson RA, Gosselin G, Gilman AG, Sprang SR (1999) Two-metal-ion catalysis in adenylyl cyclase. Science 285:756–760PubMedCrossRefGoogle Scholar
  82. Tucker CL, Hurley JH, Miller TR, Hurley JB (1998) Two amino acid substitutions convert a guanylyl cyclase, RetGC-1, into an adenylyl cyclase. Proc Natl Acad Sci USA 95:5993–5997PubMedCrossRefGoogle Scholar
  83. Vigil D, Blumenthal DK, Heller WT, Brown S, Canaves JM, Taylor SS, Trewhella J (2004) Conformational differences among solution structures of the type Ialpha, IIalpha and IIbeta protein kinase A regulatory subunit homodimers: role of the linker regions. J Mol Biol 337:1183–1194PubMedCrossRefGoogle Scholar
  84. Vijayachandra K, Guruprasad M, Bhandari R, Manjunath UH, Somesh BP, Srinivasan N, Suguna K, Visweswariah SS (2000) Biochemical characterization of the intracellular domain of the human guanylyl cyclase C receptor provides evidence for a catalytically active homotrimer. Biochemistry 39:16075–16083PubMedCrossRefGoogle Scholar
  85. Wedel B, Garbers D (2001) The guanylyl cyclase family at Y2 K. Annu Rev Physiol 63:215–233PubMedCrossRefGoogle Scholar
  86. Wu J, Bai J, Bao Q, Zhao F (2008) Lineage-specific domain fusion in the evolution of purine nucleotide cyclases in cyanobacteria. J Mol Evol 67:85–94PubMedCrossRefGoogle Scholar
  87. Yamada RX, Matsuki N, Ikegaya Y (2006) Soluble guanylyl cyclase inhibitor prevents Sema3F-induced collapse of axonal and dendritic growth cones of dentate granule cells. Biol Pharm Bull 29:796–798PubMedCrossRefGoogle Scholar
  88. Yamagami S, Suzuki N (2005) Diverse forms of guanylyl cyclases in medaka fish—their genomic structure and phylogenetic relationships to those in vertebrates and invertebrates. Zoolog Sci 22:819–835PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Kabir Hassan Biswas
    • 1
  • Avinash R. Shenoy
    • 1
  • Anindya Dutta
    • 1
  • Sandhya S. Visweswariah
    • 1
  1. 1.Department of Molecular Reproduction, Development and GeneticsIndian Institute of ScienceBangaloreIndia

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