Defensin

In animals, they are produced by cells of the innate immune system and epithelial cells, whereas in plants and fungi they are produced by a wide variety of tissues. An organism usually produces many different defensins, some of which are stored inside the cells (e.g. in neutrophil granulocytes to kill phagocytosed bacteria), and others are secreted into the extracellular medium. For those that directly kill microbes, their mechanism of action varies from disruption of the microbial cell membrane to metabolic disruption.

Varieties

The name 'defensin' was coined in the mid-1980s, though the proteins have been called 'Cationic Antimicrobial Proteins,' 'Neutrophil peptides,' 'Gamma thionins' amongst others.

Proteins called 'defensins' are not all evolutionarily related to one another. Instead fall into two broad superfamilies, each of which contains multiple families. One superfamily, the trans-defensins, contains the defensins found in humans and other vertebrates, as well as some invertebrates. The other superfamily, cis-defensins, contains the defensins found in invertebrates, plants, and fungi. The superfamilies and families are determined by the overall tertiary structure, and each family usually has a conserved pattern of disulphide bonds. All defensins form small and compact folded structures, typically with a high positive charge, that are highly stable due to the multiple disulphide bonds. In all families, the underlying genes responsible for defensin production are highly polymorphic.

Trans-defensins

Vertebrate defensins are primarily α-defensins and β-defensins. Some primates additionally have the much smaller θ-defensins. In general, both α- and β-defensins are encoded by two-exon genes, where the first exon encodes for a hydrophobic leader sequence (removed after translation) and the cysteine-rich sequence (the mature peptide). The disulfide linkages formed by the cysteines have been suggested to be essential for activities related to innate immunity in mammals, but are not necessarily required for antimicrobial activity. Theta defensins form a single beta-hairpin structure and represent a distinct group. Only alpha and beta-defensins are expressed in humans.

Although the most well-studied defensins are from vertebrates, a family of trans-defensins called 'big defensins' are found in molluscs, arthropods and lancelets.

Cis-defensins

Arthropod defensins are the best-characterised defensins from invertebrates (especially those from insects). Other invertebrates known to produce defensins from this protein superfamily include molluscs, annelids and cnidaria.

Plant defensins were discovered in 1990 and have subsequently been found in most plant tissues with antimicrobial activities, with both antifungal and antibacterial examples. They have been identified in all major groups of vascular plants, but not in ferns, mosses or algae.

Fungal defensins were first identified in 2005. Studied examples mainly have anti-bacterial activities and have been found in both main divisions of fungi (Ascomycota and Basidiomycota), as well as in the more basal groups of Zygomycota and Glomeromycota.

Bacterial defensins have also been identified, but are by far the least studied. They include variants with only four cysteines, whereas defensins from eukaryote defensins almost all have six or eight.

Related defensin-like proteins

In addition to the defensins involved in host defence, there are a number of related Defensin-Like Peptides (DLPs) that have evolved to have other activities.

Toxins

There appear to have been multiple evolutionary recruitments of defensins to be toxin proteins used in the venoms of animals; they act via a completely different mechanism to their antimicrobial relatives, from binding directly to ion channels to disrupting nerve signals. Examples include the crotamine toxin in snake venom, many scorpion toxins, some sea anemone toxins, and one of the toxins in platypus venom. Indeed, an insect defensin has been experimentally converted into a toxin by deletion of a small loop that otherwise sterically hindered interactions with the ion channels.

Signalling

In vertebrates, some α- and β-defensins are involved in signalling between the innate immune and adaptive immune systems. In plants, a specialised family of DLPs is involved in signalling to detect if self-pollination has occurred and induce self-incompatibility to prevent inbreeding.

Enzyme inhibitors

Some antimicrobial defensins also have enzyme inhibitory activity, and some DLPs function primarily as enzyme inhibitors, acting as antifeedants (discouraging animals from eating them).