Circular permutation in proteins

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.

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. Both consist of four alpha helices with the order of helices being permuted relative to each other.

Circular permutation in proteins refers to a phenomenon where proteins have sequences that can be considered rearranged versions of each other, such that the N-terminus of one protein corresponds to an internal sequence of another, and vice versa. This rearrangement maintains the functionality and three-dimensional structure of the protein, despite the different linear sequence. Circular permutation can occur naturally through evolutionary processes or can be engineered for research and biotechnological applications.

Overview

Circular permutation in proteins is a fascinating aspect of protein structure and evolution. It provides insights into how proteins can evolve new functions, fold into their active forms, and interact with other molecules. In nature, circular permutation may result from events such as genetic recombination, gene duplication, and fusion events, leading to the diversification of protein functions without the need to evolve entirely new structures from scratch.

Mechanisms

The mechanisms behind circular permutation involve several genetic processes:

• Genetic recombination: A process by which pieces of DNA are broken and re-joined to produce new combinations of alleles. This can result in the rearrangement of genetic material, including the sequences encoding proteins.
• Gene duplication: Duplication of a gene can lead to redundancy. Over time, one copy of the gene may undergo mutations that allow for circular permutation without losing the original function.
• Fusion events: Two or more genes, or parts of genes, can fuse together, potentially creating a circularly permuted protein if the fusion alters the original linear sequence of the protein's active site.

Biotechnological Applications

Circular permutation can be exploited in biotechnology for various purposes, including the development of novel enzymes with altered substrate specificities or improved stability, and the creation of new biosensors. By rearranging the sequence of a protein, researchers can introduce new properties or enhance existing ones, such as altering the binding site's accessibility or changing the protein's dynamics.

Examples

Some well-known examples of circularly permuted proteins include:

• Green Fluorescent Protein (GFP): Variants of GFP have been engineered through circular permutation to alter its fluorescence properties or to create biosensors that can report on different aspects of cellular function.
• Tyrosyl-tRNA synthetase: This enzyme, which is crucial for protein synthesis, has been found in circularly permuted forms in certain species, suggesting a natural occurrence of this phenomenon.

Challenges and Future Directions

While circular permutation offers exciting opportunities for protein engineering and understanding protein evolution, it also presents challenges. Predicting how a circular permutation will affect a protein's function and stability is complex and requires a deep understanding of protein structure and dynamics. Future research in this field may focus on developing better computational models to predict the outcomes of circular permutations and exploring the natural roles of circularly permuted proteins in organisms.