Skip to main content

Advertisement

Log in

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

  • Published:
Journal of Molecular Evolution Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • 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 25:3389–3402

    Article  PubMed  CAS  Google Scholar 

  • Anantharaman V, Balaji S, Aravind L (2006) The signaling helix: a common functional theme in diverse signaling proteins. Biol Direct 1:25

    Article  PubMed  Google Scholar 

  • Aparicio JG, Applebury ML (1996) The photoreceptor guanylate cyclase is an autophosphorylating protein kinase. J Biol Chem 271:27083–27089

    Article  PubMed  CAS  Google Scholar 

  • Baker DA, Kelly JM (2004) Structure, function and evolution of microbial adenylyl and guanylyl cyclases. Mol Microbiol 52:1229–1242

    Article  PubMed  CAS  Google Scholar 

  • 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–D141

    Article  PubMed  CAS  Google Scholar 

  • 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 172:2614–2621

    PubMed  CAS  Google Scholar 

  • 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 316:553–559

    PubMed  CAS  Google Scholar 

  • 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 40:9196–9206

    Article  PubMed  CAS  Google Scholar 

  • 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 188:7306–7310

    Article  PubMed  CAS  Google Scholar 

  • Boudeau J, Miranda-Saavedra D, Barton GJ, Alessi DR (2006) Emerging roles of pseudokinases. Trends Cell Biol 16:443–452

    Article  PubMed  CAS  Google Scholar 

  • 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 280:33935–33944

    Article  PubMed  CAS  Google Scholar 

  • 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 101:11707–11712

    Article  PubMed  CAS  Google Scholar 

  • Crooks GE, Hon G, Chandonia JM, Brenner SE (2004) WebLogo: a sequence logo generator. Genome Res 14:1188–1190

    Article  PubMed  CAS  Google Scholar 

  • Dizhoor AM (2000) Regulation of cGMP synthesis in photoreceptors: role in signal transduction and congenital diseases of the retina. Cell Signal 12:711–719

    Article  PubMed  CAS  Google Scholar 

  • 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 23:10–15

    Article  PubMed  CAS  Google Scholar 

  • Fitzpatrick DA, O’Halloran DM, Burnell AM (2006) Multiple lineage specific expansions within the guanylyl cyclase gene family. BMC Evol Biol 6:26

    Article  PubMed  Google Scholar 

  • Forte LR Jr (2004) Uroguanylin and guanylin peptides: pharmacology and experimental therapeutics. Pharmacol Ther 104:137–162

    Article  PubMed  CAS  Google Scholar 

  • Foster DC, Wedel BJ, Robinson SW, Garbers DL (1999) Mechanisms of regulation and functions of guanylyl cyclases. Rev Physiol Biochem Pharmacol 135:1–39

    Article  PubMed  CAS  Google Scholar 

  • Goh CS, Bogan AA, Joachimiak M, Walther D, Cohen FE (2000) Co-evolution of proteins with their interaction partners. J Mol Biol 299:283–293

    Article  PubMed  CAS  Google Scholar 

  • 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 2:291–303

    Article  CAS  Google Scholar 

  • 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 89:887–895

    Article  PubMed  CAS  Google Scholar 

  • Hughes JM, Murad F, Chang B, Guerrant RL (1978) Role of cyclic GMP in the action of heat-stable enterotoxin of Escherichia coli. Nature 271:755–756

    Article  PubMed  CAS  Google Scholar 

  • Hunter T, Plowman GD (1997) The protein kinases of budding yeast: six score and more. Trends Biochem Sci 22:18–22

    Article  PubMed  CAS  Google Scholar 

  • Huse M, Kuriyan J (2002) The conformational plasticity of protein kinases. Cell 109:275–282

    Article  PubMed  CAS  Google Scholar 

  • 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 252:97–103

    Article  PubMed  CAS  Google Scholar 

  • Iyer LM, Anantharaman V, Aravind L (2003) Ancient conserved domains shared by animal soluble guanylyl cyclases and bacterial signaling proteins. BMC Genomics 4:5

    Article  PubMed  Google Scholar 

  • 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 45:1888–1898

    Article  PubMed  CAS  Google Scholar 

  • 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 21:3672–3680

    Article  PubMed  CAS  Google Scholar 

  • Kannan N, Taylor SS (2008) Rethinking pseudokinases. Cell 133:204–205

    Article  PubMed  CAS  Google Scholar 

  • 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 276:10564–10569

    Article  PubMed  CAS  Google Scholar 

  • Katayama M, Ohmori M (1997) Isolation and characterization of multiple adenylate cyclase genes from the cyanobacterium Anabaena sp. strain PCC 7120. J Bacteriol 179:3588–3593

    PubMed  CAS  Google Scholar 

  • 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 217:993–1000

    Article  PubMed  CAS  Google Scholar 

  • 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 12:2581–2590

    PubMed  CAS  Google Scholar 

  • 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 244:125–132

    Article  PubMed  CAS  Google Scholar 

  • Kuhn M (2004) Molecular physiology of natriuretic peptide signalling. Basic Res Cardiol 99:76–82

    Article  PubMed  CAS  Google Scholar 

  • La Scola B, Marrie TJ, Auffray JP, Raoult D (2005) Mimivirus in pneumonia patients. Emerg Infect Dis 11:449–452

    PubMed  Google Scholar 

  • Laurent F, McCole D, Eckmann L, Kagnoff MF (1999) Pathogenesis of Cryptosporidium parvum infection. Microbes Infect 1:141–148

    Article  PubMed  CAS  Google Scholar 

  • 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–D260

    Article  PubMed  CAS  Google Scholar 

  • 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 104:9597–9602

    Article  PubMed  CAS  Google Scholar 

  • 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 18:4222–4232

    Article  PubMed  CAS  Google Scholar 

  • 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 275:11235–11240

    Article  PubMed  CAS  Google Scholar 

  • Linder JU, Schultz JE (2002) Guanylyl cyclases in unicellular organisms. Mol Cell Biochem 230:149–158

    Article  PubMed  CAS  Google Scholar 

  • Linder JU, Schultz JE (2003) The class III adenylyl cyclases: multi-purpose signalling modules. Cell Signal 15:1081–1089

    Article  PubMed  CAS  Google Scholar 

  • 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 52:375–414

    PubMed  CAS  Google Scholar 

  • Ludidi N, Gehring C (2003) Identification of a novel protein with guanylyl cyclase activity in Arabidopsis thaliana. J Biol Chem 278:6490–6494

    Article  PubMed  CAS  Google Scholar 

  • Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912–1934

    Article  PubMed  CAS  Google Scholar 

  • Martinez SE, Beavo JA, Hol WG (2002) GAF domains: two-billion-year-old molecular switches that bind cyclic nucleotides. Mol Interv 2:317–323

    Article  PubMed  CAS  Google Scholar 

  • McDonald V (2000) Host cell-mediated responses to infection with Cryptosporidium. Parasite Immunol 22:597–604

    Article  PubMed  CAS  Google Scholar 

  • 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 270:7189–7196

    Article  PubMed  CAS  Google Scholar 

  • Monier A, Claverie JM, Ogata H (2007) Horizontal gene transfer and nucleotide compositional anomaly in large DNA viruses. BMC Genomics 8:456

    Article  PubMed  Google Scholar 

  • Moreira D, Brochier-Armanet C (2008) Giant viruses, giant chimeras: the multiple evolutionary histories of Mimivirus genes. BMC Evol Biol 8:12

    Article  PubMed  Google Scholar 

  • 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 5:12

    PubMed  Google Scholar 

  • Mougel C, Zhulin IB (2001) CHASE: an extracellular sensing domain common to transmembrane receptors from prokaryotes, lower eukaryotes and plants. Trends Biochem Sci 26:582–584

    Article  PubMed  CAS  Google Scholar 

  • Mukherjee K, Sharma M, Urlaub H, Bourenkov GP, Jahn R, Sudhof TC, Wahl MC (2008) CASK Functions as a Mg2+-independent neurexin kinase. Cell 133:328–339

    Article  PubMed  CAS  Google Scholar 

  • Nolen B, Taylor S, Ghosh G (2004) Regulation of protein kinases: controlling activity through activation segment conformation. Mol Cell 15:661–675

    Article  PubMed  CAS  Google Scholar 

  • Ochoa De Alda JA, Ajlani G, Houmard J (2000) Synechocystis strain PCC 6803 cya2, a prokaryotic gene that encodes a guanylyl cyclase. J Bacteriol 182:3839–3842

    Article  PubMed  CAS  Google Scholar 

  • 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 173:131–149

    Article  PubMed  CAS  Google Scholar 

  • Park H, Inouye M (1997) Mutational analysis of the linker region of EnvZ, an osmosensor in Escherichia coli. J Bacteriol 179:4382–4390

    PubMed  CAS  Google Scholar 

  • Perkins WJ (2006) Regulation of soluble guanylyl cyclase: looking beyond NO. Am J Physiol Lung Cell Mol Physiol 291:L334–L336

    Article  PubMed  CAS  Google Scholar 

  • 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 96:13603–13610

    Article  PubMed  CAS  Google Scholar 

  • 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 276:26218–26229

    Article  PubMed  CAS  Google Scholar 

  • 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 45:95–102

    Article  PubMed  CAS  Google Scholar 

  • Roelofs J, Snippe H, Kleineidam RG, Van Haastert PJ (2001) Guanylate cyclase in Dictyostelium discoideum with the topology of mammalian adenylate cyclase. Biochem J 354:697–706

    Article  PubMed  CAS  Google Scholar 

  • Roelofs J, Van Haastert PJ (2002) Characterization of two unusual guanylyl cyclases from dictyostelium. J Biol Chem 277:9167–9174

    Article  PubMed  CAS  Google Scholar 

  • Romling U, Amikam D (2006) Cyclic di-GMP as a second messenger. Curr Opin Microbiol 9:218–228

    Article  PubMed  Google Scholar 

  • 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 27:3295–3304

    Article  PubMed  CAS  Google Scholar 

  • Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4:406–425

    PubMed  CAS  Google Scholar 

  • 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 28:231–234

    Article  PubMed  CAS  Google Scholar 

  • Schulz S, Green CK, Yuen PS, Garbers DL (1990) Guanylyl cyclase is a heat-stable enterotoxin receptor. Cell 63:941–948

    Article  PubMed  CAS  Google Scholar 

  • 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 15:299–311

    Article  PubMed  CAS  Google Scholar 

  • 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 545:253–259

    Article  PubMed  CAS  Google Scholar 

  • 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 561:11–21

    Article  CAS  Google Scholar 

  • Suhre K (2005) Gene and genome duplication in Acanthamoeba polyphaga Mimivirus. J Virol 79:14095–14101

    Article  PubMed  CAS  Google Scholar 

  • 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 273:16332–16338

    Article  PubMed  CAS  Google Scholar 

  • Suzan-Monti M, La Scola B, Raoult D (2006) Genomic and evolutionary aspects of Mimivirus. Virus Res 117:145–155

    Article  PubMed  CAS  Google Scholar 

  • Szmidt-Jaworska A, Jaworski K, Kopcewicz J (2007) Involvement of cyclic GMP in phytochrome-controlled flowering of Pharbitis nil. J Plant Physiol 165:858–867

    Article  PubMed  Google Scholar 

  • Tamura K, Dudley J, Nei M, Kumar S (2007) MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol 24:1596–1599

    Article  PubMed  CAS  Google Scholar 

  • Tang WJ, Hurley JH (1998) Catalytic mechanism and regulation of mammalian adenylyl cyclases. Mol Pharmacol 54:231–240

    PubMed  CAS  Google Scholar 

  • Taylor SS, Knighton DR, Zheng J, Sowadski JM, Gibbs CS, Zoller MJ (1993) A template for the protein kinase family. Trends Biochem Sci 18:84–89

    Article  PubMed  CAS  Google Scholar 

  • 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 278:1907–1916

    Article  PubMed  CAS  Google Scholar 

  • Tesmer JJ, Sunahara RK, Johnson RA, Gosselin G, Gilman AG, Sprang SR (1999) Two-metal-ion catalysis in adenylyl cyclase. Science 285:756–760

    Article  PubMed  CAS  Google Scholar 

  • 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 95:5993–5997

    Article  PubMed  CAS  Google Scholar 

  • 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 337:1183–1194

    Article  PubMed  CAS  Google Scholar 

  • 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 39:16075–16083

    Article  PubMed  CAS  Google Scholar 

  • Wedel B, Garbers D (2001) The guanylyl cyclase family at Y2 K. Annu Rev Physiol 63:215–233

    Article  PubMed  CAS  Google Scholar 

  • 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 67:85–94

    Article  PubMed  CAS  Google Scholar 

  • 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 29:796–798

    Article  PubMed  CAS  Google Scholar 

  • 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 22:819–835

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Financial support from the Department of Biotechnology, Government of India, is acknowledged. K. H. B. is a recipient of a research fellowship from the Council of Scientific and Industrial Research, Government of India. Useful discussions with Ritwick Sawarkar are gratefully acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sandhya S. Visweswariah.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 294 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Biswas, K.H., Shenoy, A.R., Dutta, A. et al. The Evolution of Guanylyl Cyclases as Multidomain Proteins: Conserved Features of Kinase-Cyclase Domain Fusions. J Mol Evol 68, 587–602 (2009). https://doi.org/10.1007/s00239-009-9242-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00239-009-9242-5

Keywords

Navigation