Skip to main content
SpringerLink
Log in

Plant Cyclotides: An Unusual Protein Family with Multiple Functions

  • Chapter
  • First Online:
Plant Defence: Biological Control

Part of the book series: Progress in Biological Control ((PIBC,volume 12))

Abstract

Over the years, a number of peptides containing a cyclic structure have been discovered. Among these molecules, there is the family of cyclotides, which are small cyclic peptides, containing six conserved cysteine residues connected by disulfide bridges forming a cyclic cysteine knot, giving great stability in the structure against thermal, chemical and proteolytic degradation. The cyclotides are divided into two major subfamilies, Möbius and bracelet; the main difference between them is the presence in Möbius of a proline residue in cis position in loop 5, which is not seen in Bracelets. In this work, we have carried out a short review of the discovery, biosynthesis, structural characteristics and biological activity of cyclotides. Given the wide range of cyclotide activities, there is much interest in exploring the potential of these peptides, mainly thanks to the countless possibilities for their use by agribusiness and the pharmaceutical industry.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Saether O, Craik DJ, Campbell ID, Sletten K, Juul J, Norman DG (1995) Elucidation of the primary and three-dimensional structure of the uterotonic polypeptide kalata B1. Biochemistry 34:4147–4158

    Article  PubMed  CAS  Google Scholar 

  2. Rosengren KJ, Daly NL, Plan MR, Waine C, Craik DJ (2003) Twists, knots, and rings in proteins. Structural definition of the cyclotide framework. J Biol Chem 278:8606–8616

    Article  PubMed  CAS  Google Scholar 

  3. Craik DJ (2009) Circling the enemy: cyclic proteins in plant defence. Trends Plant Sci 14:328–335

    Article  PubMed  CAS  Google Scholar 

  4. Gran L, Sandberg F, Sletten K (2000) Oldenlandia affinis (R&S) DC. A plant containing uteroactive peptides used in African traditional medicine. J Ethnopharmacol 70:197–203

    Article  PubMed  CAS  Google Scholar 

  5. Felizmenio-Quimio ME, Daly NL, Craik DJ (2001) Circular proteins in plants: solution structure of a novel macrocyclic trypsin inhibitor from Momordica cochinchinensis. J Biol Chem 276:22875–22882

    Article  PubMed  CAS  Google Scholar 

  6. Jennings CV, Rosengren KJ, Daly NL, Plan M, Stevens J, Scanlon MJ, Waine C, Norman DG, Anderson MA, Craik DJ (2005) Isolation, solution structure, and insecticidal activity of kalata B2, a circular protein with a twist: do Mobius strips exist in nature? Biochemistry 44:851–860

    Article  PubMed  CAS  Google Scholar 

  7. Pelegrini PB, Quirino BF, Franco OL (2007) Plant cyclotides: an unusual class of defense compounds. Peptides 28:1475–1481

    Article  PubMed  CAS  Google Scholar 

  8. Craik DJ, Daly NL, Bond T, Waine C (1999) Plant cyclotides: a unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. J Mol Biol 294:1327–1336

    Article  PubMed  CAS  Google Scholar 

  9. Craik DJ, Daly NL, Waine C (2001) The cystine knot motif in toxins and implications for drug design. Toxicon 39:43–60

    Article  PubMed  CAS  Google Scholar 

  10. Trabi M, Craik DJ (2004) Tissue-specific expression of head-to-tail cyclized miniproteins in Violaceae and structure determination of the root cyclotide Viola hederacea root cyclotide 1. Plant Cell 16:2204–2216

    Article  PubMed  CAS  Google Scholar 

  11. Craik DJ (2010) The folding of disulfide-rich proteins. Antioxid Redox Signal 14:61–64

    Article  PubMed  Google Scholar 

  12. Craik DJ (2010) Discovery and applications of the plant cyclotides. Toxicon 56:1092–1102

    Article  PubMed  CAS  Google Scholar 

  13. Gruber CW, Cemazar M, Anderson MA, Craik DJ (2007) Insecticidal plant cyclotides and related cystine knot toxins. Toxicon 49:561–575

    Article  PubMed  CAS  Google Scholar 

  14. Camarero JA, Muir TW (2001) Native chemical ligation of polypeptides. Curr Protoc Protein Sci Chapter 18:Unit18 14

    Google Scholar 

  15. Mylne JS, Wang CK, van der Weerden NL, Craik DJ (2010) Cyclotides are a component of the innate defence of Oldenlandia affinis. Biopolymers 94:635–646

    Article  PubMed  CAS  Google Scholar 

  16. Jennings C, West J, Waine C, Craik D, Anderson M (2001) Biosynthesis and insecticidal properties of plant cyclotides: the cyclic knotted proteins from Oldenlandia affinis. Proc Natl Acad Sci USA 98:10614–10619

    Article  PubMed  CAS  Google Scholar 

  17. Saska I, Gillon AD, Hatsugai N, Dietzgen RG, Hara-Nishimura I, Anderson MA, Craik DJ (2007) An asparaginyl endopeptidase mediates in vivo protein backbone cyclization. J Biol Chem 282:29721–29728

    Article  PubMed  CAS  Google Scholar 

  18. Burman R, Gruber CW, Rizzardi K, Herrmann A, Craik DJ, Gupta MP, Goransson U (2009) Cyclotide proteins and precursors from the genus Gloeospermum: filling a blank spot in the cyclotide map of Violaceae. Phytochemistry 71:13–20

    Article  PubMed  Google Scholar 

  19. Picchi DG, Altei WF, MnS S, VdS B, Cilli EM (2009) Peptídeos cíclicos de biomassa vegetal: caracteristicas, diversidade, biossíntese e atividades biológicas. Química Nova 32:1262–1277

    Article  CAS  Google Scholar 

  20. Herrmann A, Burman R, Mylne JS, Karlsson G, Gullbo J, Craik DJ, Clark RJ, Goransson U (2008) The alpine violet, Viola biflora, is a rich source of cyclotides with potent cytotoxicity. Phytochemistry 69:939–952

    Article  PubMed  CAS  Google Scholar 

  21. Trabi M, Mylne JS, Sando L, Craik DJ (2009) Circular proteins from Melicytus (Violaceae) refine the conserved protein and gene architecture of cyclotides. Org Biomol Chem 7:2378–2388

    Article  PubMed  CAS  Google Scholar 

  22. Camarero C, Ramos N, Moreno A, Asensio A, Mateos ML, Roldan B (2008) Hepatitis C virus infection acquired in childhood. Eur J Pediatr 167:219–224

    Article  PubMed  Google Scholar 

  23. Conlan BF, Gillon AD, Craik DJ, Anderson MA (2010) Circular proteins and mechanisms of cyclization. Biopolymers 94:573–583

    Article  PubMed  CAS  Google Scholar 

  24. Camarero JA, Kimura RH, Woo YH, Shekhtman A, Cantor J (2007) Biosynthesis of a fully functional cyclotide inside living bacterial cells. Chembiochem 8:1363–1366

    Article  PubMed  CAS  Google Scholar 

  25. Trabi M, Schirra HJ, Craik DJ (2001) Three-dimensional structure of RTD-1, a cyclic antimicrobial defensin from Rhesus macaque leukocytes. Biochemistry 40:4211–4221

    Article  PubMed  CAS  Google Scholar 

  26. Gruber CW, Elliott AG, Ireland DC, Delprete PG, Dessein S, Goransson U, Trabi M, Wang CK, Kinghorn AB, Robbrecht E, Craik DJ (2008) Distribution and evolution of circular miniproteins in flowering plants. Plant Cell 20:2471–2483

    Article  PubMed  CAS  Google Scholar 

  27. Craik DJ, Daly NL (2007) NMR as a tool for elucidating the structures of circular and knotted proteins. Mol Biosyst 3:257–265

    Article  PubMed  CAS  Google Scholar 

  28. Simonsen SM, Sando L, Ireland DC, Colgrave ML, Bharathi R, Goransson U, Craik DJ (2005) A continent of plant defense peptide diversity: cyclotides in Australian Hybanthus (Violaceae). Plant Cell 17:3176–3189

    Article  PubMed  CAS  Google Scholar 

  29. Svangard E, Goransson U, Hocaoglu Z, Gullbo J, Larsson R, Claeson P, Bohlin L (2004) Cytotoxic cyclotides from Viola tricolor. J Nat Prod 67:144–147

    Article  PubMed  Google Scholar 

  30. Chen B, Colgrave ML, Daly NL, Rosengren KJ, Gustafson KR, Craik DJ (2005) Isolation and characterization of novel cyclotides from Viola hederaceae: solution structure and anti-HIV activity of vhl-1, a leaf-specific expressed cyclotide. J Biol Chem 280:22395–22405

    Article  PubMed  CAS  Google Scholar 

  31. Daly NL, Rosengren KJ, Craik DJ (2009) Discovery, structure and biological activities of cyclotides. Adv Drug Deliv Rev 61:918–930

    Article  PubMed  CAS  Google Scholar 

  32. Henriques ST, Craik DJ (2009) Cyclotides as templates in drug design. Drug Discov Today 15:57–64

    Article  PubMed  Google Scholar 

  33. Huang YH, Colgrave ML, Daly NL, Keleshian A, Martinac B, Craik DJ (2009) The biological activity of the prototypic cyclotide kalata b1 is modulated by the formation of multimeric pores. J Biol Chem 284:20699–20707

    Article  PubMed  CAS  Google Scholar 

  34. Shenkarev ZO, Nadezhdin KD, Sobol VA, Sobol AG, Skjeldal L, Arseniev AS (2006) Conformation and mode of membrane interaction in cyclotides. Spatial structure of kalata B1 bound to a dodecylphosphocholine micelle. FEBS J 273:2658–2672

    Article  PubMed  CAS  Google Scholar 

  35. Witherup KM, Bogusky MJ, Anderson PS, Ramjit H, Ransom RW, Wood T, Sardana M (1994) Cyclopsychotride A, a biologically active, 31-residue cyclic peptide isolated from Psychotria longipes. J Nat Prod 57:1619–1625

    Article  PubMed  CAS  Google Scholar 

  36. Tam JP, Lu YA, Yang JL, Chiu KW (1999) An unusual structural motif of antimicrobial peptides containing end-to-end macrocycle and cystine-knot disulfides. Proc Natl Acad Sci USA 96:8913–8918

    Article  PubMed  CAS  Google Scholar 

  37. Barbeta BL, Marshall AT, Gillon AD, Craik DJ, Anderson MA (2008) Plant cyclotides disrupt epithelial cells in the midgut of lepidopteran larvae. Proc Natl Acad Sci USA 105:1221–1225

    Article  PubMed  CAS  Google Scholar 

  38. Plan MR, Saska I, Cagauan AG, Craik DJ (2008) Backbone cyclised peptides from plants show molluscicidal activity against the rice pest Pomacea canaliculata (golden apple snail). J Agric Food Chem 56:5237–5241

    Article  PubMed  CAS  Google Scholar 

  39. Triebskorn R, Casper H, Scheil V, Schwaiger J (2007) Ultrastructural effects of pharmaceuticals (carbamazepine, clofibric acid, metoprolol, diclofenac) in rainbow trout (Oncorhynchus mykiss) and common carp (Cyprinus carpio). Anal Bioanal Chem 387:1405–1416

    Article  PubMed  CAS  Google Scholar 

  40. Lindholm P, Goransson U, Johansson S, Claeson P, Gullbo J, Larsson R, Bohlin L, Backlund A (2002) Cyclotides: a novel type of cytotoxic agents. Mol Cancer Ther 1:365–369

    Article  PubMed  CAS  Google Scholar 

  41. Colgrave ML, Huang YH, Craik DJ, Kotze AC (2010) Cyclotide interactions with the nematode external surface. Antimicrob Agents Chemother 54:2160–2166

    Article  PubMed  CAS  Google Scholar 

  42. Barry DG, Daly NL, Clark RJ, Sando L, Craik DJ (2003) Linearization of a naturally occurring circular protein maintains structure but eliminates hemolytic activity. Biochemistry 42:6688–6695

    Article  PubMed  CAS  Google Scholar 

  43. Bokesch HR, Pannell LK, Cochran PK, Sowder RC 2nd, McKee TC, Boyd MR (2001) A novel anti-HIV macrocyclic peptide from Palicourea condensata. J Nat Prod 64:249–250

    Article  PubMed  CAS  Google Scholar 

  44. Gustafson KR, Sowder RC, Henderson LE, Parsons IC, Kashman Y, Cardellina JH, McMahon JB, Buckheit RW, Pannell LK, Boyd MR (1994) Circulins A and B. Novel human immunodeficiency virus (HIV)-inhibitory macrocyclic peptides from the tropical tree Chassalia parvifolia. J Am Chem Soc 116:9337–9338

    Article  CAS  Google Scholar 

  45. Hallock YF, Sowder RC 2nd, Pannell LK, Hughes CB, Johnson DG, Gulakowski R, Cardellina JH 2nd, Boyd MR (2000) Cycloviolins A-D, anti-HIV macrocyclic peptides from Leonia cymosa. J Org Chem 65:124–128

    Article  PubMed  CAS  Google Scholar 

  46. Ireland DC, Colgrave ML, Nguyencong P, Daly NL, Craik DJ (2006) Discovery and characterization of a linear cyclotide from Viola odorata: implications for the processing of circular proteins. J Mol Biol 357:1522–1535

    Article  PubMed  CAS  Google Scholar 

  47. Gruber CW (2010) Global cyclotide adventure: a journey dedicated to the discovery of circular peptides from flowering plants. Biopolymers 94:565–572

    Article  PubMed  CAS  Google Scholar 

  48. Craik DJ, Daly NL, Mulvenna J, Plan MR, Trabi M (2004) Discovery, structure and biological activities of the cyclotides. Curr Protein Pept Sci 5:297–315

    Article  PubMed  CAS  Google Scholar 

  49. Daly NL, Clark RJ, Plan MR, Craik DJ (2006) Kalata B8, a novel antiviral circular protein, exhibits conformational flexibility in the cystine knot motif. Biochem J 393:619–626

    Article  PubMed  CAS  Google Scholar 

  50. Wu WJ, Raleigh DP (1998) Local control of peptide conformation: stabilization of cis proline peptide bonds by aromatic proline interactions. Biopolymers 45:381–394

    Article  PubMed  CAS  Google Scholar 

  51. Heitz A, Hernandez JF, Gagnon J, Hong TT, Pham TT, Nguyen TM, Le-Nguyen D, Chiche L (2001) Solution structure of the squash trypsin inhibitor MCoTI-II. A new family for cyclic knottins. Biochemistry 40:7973–7983

    Article  PubMed  CAS  Google Scholar 

  52. Thongyoo P, Roque-Rosell N, Leatherbarrow RJ, Tate EW (2008) Chemical and biomimetic total syntheses of natural and engineered MCoTI cyclotides. Org Biomol Chem 6:1462–1470

    Article  PubMed  CAS  Google Scholar 

  53. Gunasekera S, Daly NL, Clark RJ, Craik DJ (2009) Dissecting the oxidative folding of circular cystine knot miniproteins. Antioxid Redox Signal 11:971–980

    Article  PubMed  CAS  Google Scholar 

  54. Clark RJ, Daly NL, Craik DJ (2006) Structural plasticity of the cyclic-cystine-knot framework: implications for biological activity and drug design. Biochem J 394:85–93

    Article  PubMed  CAS  Google Scholar 

  55. Herrmann A, Svangard E, Claeson P, Gullbo J, Bohlin L, Goransson U (2006) Key role of glutamic acid for the cytotoxic activity of the cyclotide cycloviolacin O2. Cell Mol Life Sci 63:235–245

    Article  PubMed  CAS  Google Scholar 

  56. Cudic M, Fields GB (2009) Extracellular proteases as targets for drug development. Curr Protein Pept Sci 10:297–307

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centro de Análises Proteômicas e Bioquímicas, Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, SGAN, Quadra 916, Módulo B, Av. W5 Norte, CEP 70.790-160, Brasília, DF, Brazil

    Michelle F. S. Pinto, Isabel C. M. Fensterseifer & Octavio L. Franco

Authors
  1. Michelle F. S. Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Isabel C. M. Fensterseifer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Octavio L. Franco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Octavio L. Franco .

Editor information

Editors and Affiliations

  1. , Gr. d'Etude Subst. Vég. à Act. Biolog., Institut des Sciences de la Vigne et du, Chemin de Leysotte 210, Villenave d'Ornon, 33882, France

    Jean Michel Mérillon

  2. , Botany, University College of Science, M.L. Sukhadia University, Durga Nursery Road, Udaipur, 313002, Rajasthan, India

    Kishan Gopal Ramawat

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Pinto, M.F.S., Fensterseifer, I.C.M., Franco, O.L. (2012). Plant Cyclotides: An Unusual Protein Family with Multiple Functions. In: Mérillon, J., Ramawat, K. (eds) Plant Defence: Biological Control. Progress in Biological Control, vol 12. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-1933-0_14

Download citation

Publish with us

Policies and ethics

Search

Navigation