Circular permutation in proteins

Circular permutation can occur as the result of evolutionary events, posttranslational modifications, or artificially engineered mutations.

Fission and fusion occurs when partial proteins fuse to form a single polypeptide, such as in nicotinamide nucleotide transhydrogenases.

Circular permutations are routinely engineered in the laboratory to improve their catalytic activity or thermostability, or to investigate properties of the original protein.

[5] In 1989, Karolin Luger and her colleagues introduced a genetic method for making circular permutations by carefully fragmenting and ligating DNA.

Chris Ponting and Robert Russell identified a circularly permuted version of a saposin inserted into plant aspartic proteinase, which they nicknamed swaposin.

[7] Hundreds of examples of protein pairs related by a circular permutation were subsequently discovered in nature or produced in the laboratory.

[10] SISYPHUS is a database that contains a collection of hand-curated manual alignments of proteins with non-trivial relationships, several of which have circular permutations.

Saposins are highly conserved glycoproteins, approximately 80 amino acid residues long and forming a four alpha helical structure.

[17] It belongs to the saposin-like protein family (SAPLIP) and has the N- and C- termini "swapped", such that the order of helices is 3-4-1-2 compared with saposin, thus leading to the name "swaposin".

[20] These are membrane-bound enzymes that catalyze the transfer of a hydride ion between NAD(H) and NADP(H) in a reaction that is coupled to transmembrane proton translocation.

They consist of three major functional units (I, II, and III) that can be found in different arrangement in bacteria, protozoa, and higher eukaryotes.

[34] Two examples of frequently used methods that have problems correctly aligning proteins related by circular permutation are dynamic programming and many hidden Markov models.

[34] As an alternative to these, a number of algorithms are built on top of non-linear approaches and are able to detect topology-independent similarities, or employ modifications allowing them to circumvent the limitations of dynamic programming.

[36] Sequence methods are generally fast and suitable for searching whole genomes for circularly permuted pairs of proteins.

[37] They are often slower than sequence-based methods, but are able to detect circular permutations between distantly related proteins with low sequence similarity.

[38] This article was adapted from the following source under a CC BY 4.0 license (2012) (reviewer reports): Spencer Bliven; Andreas Prlić (2012).

Schematic representation of a circular permutation in two proteins. The first protein (outer circle) has the sequence a-b-c. After the permutation the second protein (inner circle) has the sequence c-a-b. 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.
Two proteins that are related by a circular permutation. Concanavalin A (left), from the Protein Data Bank ( PDB : 3cna ​), and peanut lectin (right), from PDB : 2pel ​, which is homologous to favin. 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). The 3D fold of the two proteins is highly similar; however, the N- and C- termini are located on different positions of the protein. [ 1 ]
The permutation by duplication mechanism for producing a circular permutation. First, a gene 1-2-3 is duplicated to form 1-2-3-1-2-3. Next, a start codon is introduced before the first domain 2 and a stop codon after the second domain 1, removing redundant sections and resulting in a circularly permuted gene 2-3-1.
Suggested relationship between saposin and swaposin. They could have evolved from a similar gene. [ 7 ] Both consist of four alpha helices with the order of helices being permuted relative to each other.
The fission and fusion mechanism of circular permutation. Two separate genes arise (potentially from the fission of a single gene). If the genes fuse together in different orders in two orthologues, a circular permutation occurs.
Transhydrogenases in various organisms can be found in three different domain arrangements. In cattle , the three domains are arranged sequentially. In the bacteria E. coli , Rb. capsulatus , and R. rubrum , the transhydrogenase consists of two or three subunits. Finally, transhydrogenase from the protist E. tenella consists of a single subunit that is circularly permuted relative to cattle transhydrogenase. [ 20 ]