PROSITE documentation PDOC51052

Cyclotides profile and signatures

Cyclotides (cyclo peptides) are plant peptides of ~30 amino acids with a head-to-tail cyclic backbone and six cysteine residues involved in three disulfide bonds as shown in the schematic representation below. The cyclotides are extremely resistant to proteolysis and are remarkably stable. Cyclotides display a diverse range of biological activities, including uterotonic activity, inhibition of neurotensin binding, hemolytic, anti-HIV and anti-microbial activity. This range of biological activities makes cyclotides amenable to potential pharmaceutical and agricultural applications. Although their precise role in plants has not yet been reported, it appears that they are most likely present as defense molecules [1,2,3,4].

The three-dimensional structure of cyclotides is compact and contains a number of β-turns, three β strands arranged in a distorted triple-stranded β-sheet, a short helical segment, and a network of disulfide bonds which form a cystine knot (see <PDB:1NBJ>). The cystine knot consists of an embedded ring in the structure, formed by two disulfide bonds and their connecting backbone segments is threaded by a third disulfide bond. Although the cystine knot motif is now well known in a wide variety of proteins, the cyclotides remain as the only example in which a cystine knot is embedded within a circular protein backbone, a motif that is referred to as the cyclic cystine knot (CCK) [1,2,3,4].

                          +----------------+
                          |                |
                          **********       |
                      xxxxCxxxCxxxxCxxxxxxxCxCxxxxxCxxx
                      |       |    |         |     |  |
                      |       |    +---------|-----+  |
                      |       +--------------+        |
                      |-------------------------------|

'C': conserved cysteine involved in a disulfide bond.
'*': position of the pattern.

Cyclotides can be separated into two sub-families, one of which tends to contain a larger number of positively charged residues and has a bracelet-like circularization of the backbone. The second subfamily contains a backbone twist due to a cis-Pro peptide bond and may conceptually be regarded as a molecular Moebius strip [1,3]. Bracelet and Moebius families of cyclotides possess Knottin scaffold (see <PDOC60004>) [E2].

The cyclotide family of proteins is abundant in plants from the Rubiaceae and Violaceae families and includes:

• kalata B1 [E1].
• circulins.
• cyclopsychotride A.
• cycloviolacin O1.

We have developed a profile that covers the whole length of cyclotides, and two patterns that contain the first three cysteines and are directed respectively against the bracelet and Moebius subfamilies.