Naturally occurring circular proteins: distribution, biosynthesis and evolution

Circular proteins, i.e., proteins with a backbone comprised of a continuous and seamless circle of amino acids, have been discovered over the last 15 years in bacteria, plants, fungi and animals. They function as defence tools in the organisms in which they are expressed and are exceptionally stable. The cyclotides are the largest known family of circular proteins and are expressed by plants of the Violaceae (violet), Rubiaceae (coffee) and Cucurbitaceae (cucurbit) families, where they have a role in plant defence against insect predation. So far there are fewer examples of cyclic peptides in bacteria or animals but we suggest that cyclic peptides are an underdiscovered class of molecules and that many more will be discovered in the near future. There is much interest in understanding the mechanism of cyclization of circular proteins and the role of the cyclic backbone in defining structure and activity. In this review, the families of ribosomally synthesized cyclic proteins reported to date are described and their common features are examined, providing information on their distribution, biosynthesis and evolution. The unusual structure of circular proteins confers them with high stability, and makes them very interesting as scaffolds for drug design, and this has led to the re-engineering of linear proteins to stabilise them and use them for such applications.