Running rings around proteins: Protease-mediated biosynthesis of circular peptide and proteins Published abstract
Date
2010
Authors
Craik, David J
Colgrave, Michelle L
Mylne, J
Conlan, Brendon
Anderson , Marilyn
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John Wiley & Sons Inc
Abstract
Ribosomally synthesized cyclic peptides ranging in size from 10-80 amino acids have been discovered in bacteria, plants and animals over the last decade [1]. Their head-totail cyclic peptide backbone, which means they are devoid of N- or C-termini, makes them resistant to exoprotease digestion and they are thus exceptionally stable. They have a wide range of biological activities but most are involved in host-defense. The cyclotides [2] are the largest family of plant-derived circular proteins, and occur in plants from the Violaceae (violet), Rubiaceae (coffee) and Cucurbitaceae (cucurbit) families. They have a diverse range of biological activities, including uterotonic, anti-HIV, antimicrobial, and insecticidal activities, the latter consistent with a natural function in plant defense. Individual plants express suites of 10-100 cyclotides. Cyclotides contain ~30 amino acids, and as well as their head-to-tail cyclized backbone, they incorporate three disulfide bonds arranged in a cystine knot topology. The combination of this knotted and strongly braced structure with a circular backbone renders the cyclotides impervious to enzymatic breakdown and makes them exceptionally stable. Their stability and compact structure makes them, and other cyclic peptides, attractive protein frameworks onto which bioactive peptide epitopes can be grafted to stabilize them, thus making them of interest in drug design applications [2]. Cyclotides are matured from larger precursor proteins via a series of processing events, including excision, and head-to-tail peptide ligation via asparaginyl endoproteinase enzyme activity. This mechanism of biosynthesis in which a protease effectively operates in reverse to make rather than break peptide bonds appears to be common to other known classes of ribosomally synthesized cyclic peptides, including sunflower trypsin inhibitor-1 (SFTI-1), a 14-amino acid peptide from sunflower seeds. This presentation will describe the discovery and characterization of the precursor proteins for cyclotides and describe in vitro studies on SFTI-1 which demonstrate the generality of protease-mediated cyclisation.
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Running rings around proteins: Protease-mediated biosynthesis of circular peptide and proteins
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Conference paper