Defensin

Monomeric and dimeric structures of human beta-defensin HBD-2

Defensins are small cysteine-rich cationic proteins found in both vertebrates and invertebrates. They have also been reported in plants. They are, and function as, host defense peptides. They are active against bacteria, fungi and many enveloped and nonenveloped viruses. They consist of 18-45 amino acids including six (in vertebrates) to eight conserved cysteine residues. Cells of the immune system contain these peptides to assist in killing phagocytosed bacteria, for example in neutrophil granulocytes and almost all epithelial cells. Most defensins function by binding to the microbial cell membrane, and, once embedded, forming pore-like membrane defects that allow efflux of essential ions and nutrients.

Varieties

The name 'defensin' was coined in the early 1990s, though the proteins had been studied as 'Cationic Antimicrobial Proteins'. The underlying genes responsible for defensin production are highly polymorphic. Some aspects are conserved, however; the hallmarks of a β-defensin are its small size, high density of cationic charge, and six-cysteine-residue motif. In general, they are encoded by two-exon genes, wherein the first exon encodes for a hydrophobic leader sequence and the second for a peptide containing the cysteine motif. All defensins have disulfide linkages. But the role of these highly conserved cysteines is not known. Many reports reveal that disulfide bonds are not necessary for antimicrobial activity of arthropod defensins.[1] Similarly, mammalian defensins also do not require disulfide bonds to exhibit antimicrobial activity. [2] The disulfide linkages have been suggested to be essential for activities related to innate immunity in mammals.

Insect defensins as a group occur in various species and in their three-dimensional structure some are very similar to proteins from scorpion toxins. The venom gland of a Chinese Buthus species yielded complementary DNA encoding a peptide resembling an insect defensin-like peptide. The precursor has an organization similar in various respects to that of insect defensins, for example, the positions of several cysteines and a conserved glycine are common, suggesting that these peptides should share a cysteine-stabilized motif. Phylogenetic analysis suggests closer resemblances between the newly discovered scorpion peptide and ancient insect defensins in the scorpion haemolymph, than to toxins in scorpion venoms. Subsequent investigations confirmed relationships between channel toxins and insect defensins in their conserved three-dimensional structure and their disruption of membrane functions of invasive microbes. Experimental deletion of a small loop of a defensin molecule from a Hymenopteran parasitoid venom that shares attributes of scorpion toxin, removed steric hindrance of interactions between peptides and channels. The resulting peptide was neurotoxin that selectively inhibited potassium channels, binding to the channels in the same manner as scorpion toxins. The results presented structural and functional evidence for the basis of toxin evolution.

Type	Gene Symbol	Gene Name	Protein Name	Description
α-defensins	DEFA1	Defensin, alpha 1	Neutrophil defensin 1	Are expressed primarily in neutrophils as well as in NK cells and certain T-lymphocyte subsets. DEFA5 and DEFA6 are expressed in Paneth cells of the small intestine, where they may regulate and maintain microbial balance in the intestinal lumen.
	DEFA1B	Defensin, alpha 1B	Defensin, alpha 1
	DEFA3	Defensin, alpha 3, neutrophil-specific	Neutrophil defensin 3
	DEFA4	Defensin, alpha 4, corticostatin	Neutrophil defensin 4
	DEFA5	Defensin, alpha 5, Paneth cell-specific	Defensin-5
	DEFA6	Defensin, alpha 6, Paneth cell-specific	Defensin-6
β-defensins	DEFB1	Defensin, beta 1	Beta-defensin 1	Are the most widely distributed, being secreted by leukocytes and epithelial cells of many kinds. For example, they can be found on the tongue, skin, cornea, salivary glands, kidneys, esophagus, and respiratory tract. It has been suggested (but also challenged) that some of the pathology of cystic fibrosis arises from the inhibition of β-defensin activity on the epithelial surfaces of the lungs and trachea due to higher salt content.
	DEFB2	Defensin, beta 2	Beta-defensin 2
	DEFB103A	Defensin, beta 103B	Beta-defensin 103
	...	...	...
	DEFB106A	Defensin, beta 106A	Beta-defensin 106A
	DEFB106B	Defensin, beta 106B	Beta-defensin 106B
	DEFB107B	Defensin, beta 107A	Beta-defensin 107
	DEFB110	Defensin, beta 110	Beta-defensin 110
...	...	...
DEFB136	Defensin, beta 136	Beta-defensin 136
θ-defensins	DEFT1P	Defensin, theta 1 pseudogene	not expressed in humans	Are rare, and thus far have been found only in the leukocytes of the rhesus macaque and the olive baboon, Papio anubis, being vestigial in humans and other primates.

Function

In immature marsupials, because their immune system is underdeveloped at the time of birth, defensins play a major role in defense against pathogens. They are produced in the milk of the mother as well as by the young marsupial in question.

Human genome contains theta-defensin genes, but they have a premature stop codon, hampering their expression. An artificial human theta-defensin, retrocyclin, was created by `fixing' the pseudogene, and it was shown to be effective against HIV and other viruses, including herpes simplex virus and influenza A. They act primarily by preventing these viruses from entering their target cells.

Also interesting is the effect of alpha-defensins on the exotoxin produced by anthrax (Bacillus anthracis). Chun Kim et al. showed how anthrax, which produces a metalloprotease Lethal Factor (LF) protein to target MAPKK, is vulnerable to human neutrophil protein-1 (HNP-1). This group showed HNP-1 to behave as a reversible noncompetitive inhibitor of LF.

Defensin-like proteins are also a component of platypus venom.

Pathology

The alpha defensin peptides are increased in chronic inflammatory conditions.

Alpha defensin are increased in several cancers, including colorectal cancer.

An imbalance of defensins in the skin may contribute to acne.

A reduction of ileal defensins may predispose to Crohn's disease.

In one small study, a significant increase in alpha defensin levels was detected in T cell lysates of schizophrenia patients; in discordant twin pairs, unaffected twins also had an increase, although not as high as that of their ill siblings. The authors suggested that alpha-defensin levels might prove a useful marker for schizophrenia risk.

Defensins are found in the human skin during inflammatory conditions like psoriasis and also during wound healing.

Defensin-mimetics as antibiotics, antifungals, and anti-inflammatories

Defensin-Mimetics, also called host defense peptide (HDP) mimetics, developed at the University of Pennsylvania, are completely synthetic, non-peptide, small molecule structures that mimic defensins in structure and activity. Similar molecules (e.g. Brilacidin formerly PMX-30063) are being developed as antibiotics, anti-inflammatories for Oral Mucositis, and antifungals, especially for Candidiasis.

See also

• Arthropod defensin
• Host defense peptides, to which defensins belong.
• Virtual colony count

External links

• Defensins Database, Singapore
• Innate ( Nonspecific ) Immunity at Western Kentucky University
• UMich Orientation of Proteins in Membranes families/superfamily-56 - Vertebrate defensins and related sea anemone sodium channel toxins
• UMich Orientation of Proteins in Membranes families/superfamily-61 - Defensins from insects and plants and scorpion toxins
• Defensins at the US National Library of Medicine Medical Subject Headings (MeSH)