Naturally occurring circular permutations in proteins

A pair of proteins is defined to be related by a circular permutation if th e N-terminal region of one protein has significant sequence similarity to t he C-terminal of the other and vice versa. To detect pairs of proteins that might be related by circular permutation, we implemented a procedure based on a combination of a fast screening algorithm that we had designed and ma nual verification of candidate pairs. The screening algorithm is a variatio n of a dynamic programming string matching algorithm, in which one of the s equences is doubled. This algorithm, although not guaranteed to identify al l cases of circular permutation, is a good first indicator of protein pairs related by permutation events. The candidate pairs were further validated first by application of an exhaustive string matching algorithm and then by manual inspection using the dotplot visual tool. Screening the whole Swiss prot database, a total of 25 independent protein pairs were identified. The se cases are presented here, divided into three categories depending on the level of functional similarity of the related proteins. To validate our ap proach and to confirm further the small number of circularly permuted prote in pairs, a systematic search for cases of circular permutation was carried out in the Pfam database of protein domains. Even with this more inclusive definition of a circular permutation, only seven additional candidates wer e found. None of these fitted our original definition of circular permutati ons. The small number of cases of circular permutation suggests that there is no mechanism of local genetic manipulation that can induce circular perm utations; most examples observed seem to result from fusion of functional u nits.