In 1983, David Goldenberg and Thomas Creighton were able to create a circularly permuted version of a protein by chemically ligating the termini to create a cyclic protein, then introducing new termini elsewhere using trypsin. Īfter the discovery of a natural circularly permuted protein, researchers looked for a way to emulate this process. Later work confirmed the circular permutation between the pair and showed that concanavalin A is permuted post-translationally through cleavage and an unusual protein ligation. After determining the peptide sequence of the lectin protein favin, they noticed its similarity to a known protein – concanavalin A – except that the ends were circularly permuted. In 1979, Bruce Cunningham and his colleagues discovered the first instance of a circularly permuted protein in nature. The 3D fold of the two proteins is highly similar however, the N- and C- termini are located on different positions of the protein. The termini of the proteins are highlighted by blue and green spheres, and the sequence of residues is indicated by the gradient from blue (N-terminus) to green (C-terminus).

Concanavalin A (left), from the Protein Data Bank ( PDB: 3cna), and peanut lectin (right), from PDB: 2pel, which is homologous to favin. History Two proteins that are related by a circular permutation. New non-linear approaches have been developed that overcome this and are able to detect topology-independent similarities. Traditional algorithms for sequence alignment and structure alignment are not able to detect circular permutations between proteins. Fission and fusion occurs when partial proteins fuse to form a single polypeptide, such as in nicotinamide nucleotide transhydrogenases.Ĭircular permutations are routinely engineered in the laboratory to improve their catalytic activity or thermostability, or to investigate properties of the original protein. Permutation by duplication occurs when a gene undergoes duplication to form a tandem repeat, before redundant sections of the protein are removed this relationship is found between saposin and swaposin. The two main models proposed to explain the evolution of circularly permuted proteins are permutation by duplication and fission and fusion. In 1979, the first pair of circularly permuted proteins – concanavalin A and lectin – were discovered over 2000 such proteins are now known.Ĭircular permutation can occur as the result of evolutionary events, posttranslational modifications, or artificially engineered mutations. The result is a protein structure with different connectivity, but overall similar three-dimensional (3D) shape. The letters N and C indicate the location of the amino- and carboxy-termini of the protein sequences and how their positions change relative to each other.Ī circular permutation is a relationship between proteins whereby the proteins have a changed order of amino acids in their peptide sequence. After the permutation the second protein (inner circle) has the sequence c-a-b. The first protein (outer circle) has the sequence a-b-c. Arrangement of amino acid sequence Schematic representation of a circular permutation in two proteins.

Circular permutation