Circular permutation in proteins

Circular permutation is a process during evolution that changes the order of amino acids in a protein sequence, resulting in a protein structure with different connectivity, but overall similar three dimensional shape. As a consequence of the circular permutation, the N-terminus of one protein shows significant sequence similarity to the C-terminus of the other and vice versa. Artificially created permutations have been used for various purposes in protein engineering and design. One of the first naturally occurring circular permutations identified was the swaposin family which are circularly permuted versions of saposins.PubMed

Two proteins that are related by a circular permutation: Concanavalin A (left) PDB 3cna, and Peanut Lectin (right), PDB 2pel. The two proteins are colored using a “rainbow” coloring scheme, showing the N-terminus in red and C-terminus in blue. As can be seen, the 3-dimensional fold is highly similar; however, the N and C- termini are located on different positions of the protein.^[1]

Evolution

A model that can explain how circular permutations can occur during evolution is gene duplication of a precursor gene.^[2] If both genes become fused this leads to a tandem protein. The 5' and 3’ part of the gene can get lost again for example by insertion of a stop codon.

Many protein structures are observed to have their N- and C-termini in close proximity in space.^[3] This characteristic contributes that such permutation events can get tolerated. The amino and carboxy termini of the protein are being fused and different termini introduced, while keeping the overall arrangement of secondary structure elements essentially unmodified.

Role in protein engineering

Artificially constructed circularly permuted proteins are being used in protein engineering to stabilize proteins. They have been show to decrease the proteolytic susceptibility of recombinant proteins,^[4] They have been used to insert domains into green fluorescent protein.^[5] There are several studies that use circular permutations to manipulate protein scaffolds, resulting in improved catalytic activity and altered substrate or ligand binding affinity. Circular permutations have been also used to enable the design of novel biocatalysts and biosensors. For a review on this see.^[3]

References

1. ^ Cunningham et al (1976). "Favin versus concanavalin A: Circularly permuted amino acid sequences". PNAS 76 (7): 3218–3222. doi:10.1073/pnas.76.7.3218. PMC 383795. PMID 16592676. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=383795. 
2. ^ Jeltsch A (1999). "Circular permutations in the molecular evolution of DNA methyltransferases". J. Mol. Evol. 49 (1): 161–164. doi:10.1007/PL00006529. PMID 10368444. 
3. ^ ^{a b} Yu and Lutz (2011). "Circular permutation: a different way to engineer enzyme structure and function.". Trends Biotechnol. 29 (1): 18–25. doi:10.1016/j.tibtech.2010.10.004. PMID 21087800. 
4. ^ Whitehead et al (2009). "Tying up the loose ends: circular permutation decreases the proteolytic susceptibility of recombinant proteins". Prot Eng. Design 22 (10): 607-513. PMID 19622546. 
5. ^ Baird GS, Zacharias DA, Tsien RY. (1999). "Circular permutation and receptor insertion within green fluorescent proteins.". PNAS 96 (20): 11241–11246.. doi:10.1073/pnas.96.20.11241. PMC 18018. PMID 10500161. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=18018. 

Further reading

• David Goodsell (2010) Concanavalin A and Circular Permutation RCSB PDB Molecule of the Month [1]