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IN BRIEF

Cyclotides: Cyclical Miniproteins with a Cystine Knot Configuration

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jmach{at}aspb.org

Proteins that operate in challenging environments must be stable to both harsh conditions and vigorous proteolysis. Cystine knot miniproteins are found in diverse phyla and are characterized by three conserved disulfide bonds that stabilize their structure. Some of these miniproteins have further "circled the wagons," as it were, by being processed into a cyclical form where the N and C termini are joined by a peptide bond (reviewed in Trabi and Craik, 2002; Craik et al., 2007). These cyclical proteins are found in many species, from bacteria to Rhesus macaques, and are characterized by high structural and proteolytic stability. Cyclotides, a plant-specific family of cyclical cystine knot miniproteins, are usually 28 to 37 amino acids in size and are transcribed as larger propeptides which are then cleaved and circularized. The first cyclotide was discovered as the active ingredient in an infusion used to hasten childbirth by causing uterine contractions. Other cyclotides are insecticidal or have other functions; indeed, the diversity of functions of natural and engineered cyclotides is just beginning to be explored. So far, cyclotides have been found only in two plant families, the Violaceae (Violet family) and some members of the Rubiaceae (Coffee family), although related proteins are found in grass plants, including rice and barley.

To examine the distribution and evolution of cyclotides, Gruber et al. (pages 2471–2483) exploited the chemical properties of cyclotides (small mass, hydrophobic HPLC elution, and Cys-rich) to assay the number of unique cyclotides in one plant. They screened hundreds of species and found multiple new cyclotide-producing species within the Rubiaceae and in a related family, the Apocynaceae. To examine the mechanism of cyclotide evolution, they compared tribes within the Rubiaceae that express cyclotides to the phylogeny of those tribes and theorized that the ability to make cyclical proteins evolved independently in different plant families, possibly by recruiting a common cellular protease to a novel function. Their research also showed that cyclotides are likely a very large protein family, with individual plant species expressing 15 to 60 distinct cyclotides (see figure ). Moreover, their screen found very few duplicate cyclotides between plant species, based on sequences, elution profiles, and protein mass data. Therefore, multiplying the cyclotides per species by the estimated number of species that produce cyclotides yields a very large protein family. Based on the stability, diversity, and biological activities of cyclotides, this protein family has an amazing breadth of potential applications.

View larger version (38K): [in this window] [in a new window] [as a PowerPoint slide]   The circular structure, three conserved disulfide bonds (yellow), and the amino acid variation at all other positions shown for a collection of 18 cyclotides from a single plant species, Oldenlanida affinis.

www.plantcell.org/cgi/doi/10.1105/tpc.108.200915

REFERENCES

Craik, D.J., Cemazar, M., and Daly, N.L. (2007). The chemistry and biology of cyclotides. Curr. Opin. Drug Discov. Dev. 10: 176–184.[Web of Science][Medline]

Gruber, C.W., Elliott, A.G., Ireland, D.C., Delprete, P.G., Dessein, S., Goransson, U., Trabi, M., Wang, C.K., Kinghorn, A.B., Robbrecht, E., and Craik, D.J. (2008). Distribution and evolution of circular miniproteins in flowering plants. Plant Cell 20: 2471–2483.[Abstract/Free Full Text]

Trabi, M., and Craik, D.J. (2002). Circular proteins – No end in sight. Trends Biochem. Sci. 27: 132–138.[CrossRef][Web of Science][Medline]

Related articles in Plant Cell:

Distribution and Evolution of Circular Miniproteins in Flowering Plants

Christian W. Gruber, Alysha G. Elliott, David C. Ireland, Piero G. Delprete, Steven Dessein, Ulf Göransson, Manuela Trabi, Conan K. Wang, Andrew B. Kinghorn, Elmar Robbrecht, and David J. Craik
Plant Cell 2008 20: 2471-2483. [Abstract] [Full Text]  

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