Defensin

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Defensin
Defensin examples.png
Example defensins with alpha helix in red, beta strands in blue, disulphide bonds in yellow ( PDB: 1MR4, 2KOZ, 1FJN, 2LXZ, 1IJV, 2RNG ​)
Identifiers
SymbolDefensin
Pfam clan CL0075
OPM superfamily 54
OPM protein 6cs9

Defensins are small cysteine-rich cationic proteins across cellular life, including vertebrate [1] and invertebrate [2] animals, plants, [3] [4] and fungi. [5] They are host defense peptides, with members displaying either direct antimicrobial activity, immune signaling activities, or both. They are variously active against bacteria, fungi and many enveloped and nonenveloped viruses. They are typically 18-45 amino acids in length, with three or four highly conserved disulphide bonds.

Contents

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

Characteristic disulphide linkages
Trans-defensin disulphides.svg
Trans-defensin superfamily: In yellow, the two most conserved disulphides link a beta strand to two different secondary structure elements (motif = CC). On the right, an example structure ( PDB: 1IJV ​).
Cis-defensin disulphides.svg
Cis-defensin superfamily: In yellow, the two most conserved disulphides link a beta strand to the same alpha helix (motif = CxC...CxxxC). On the right, an example structure ( PDB: 1MRR4 ​).

The name 'defensin' was coined in the mid-1980s, though the proteins have been called 'Cationic Antimicrobial Proteins,' 'Neutrophil peptides,' 'Gamma thionins' amongst others. [6]

Proteins called 'defensins' are not all evolutionarily related to one another. [7] Instead fall into two broad superfamilies, each of which contains multiple families. [7] [8] One superfamily, the trans-defensins, contains the defensins found in humans and other vertebrates, [9] [10] as well as some invertebrates. [11] [12] The other superfamily, cis-defensins, contains the defensins found in invertebrates, plants, and fungi. [13] [14] [15] The superfamilies and families are determined by the overall tertiary structure, and each family usually has a conserved pattern of disulphide bonds. [9] [16] 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.[ citation needed ]

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. [17] [18] Theta defensins form a single beta-hairpin structure and represent a distinct group. Only alpha and beta-defensins are expressed in humans. [19]

Table of human defensins
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
DEFB3 Defensin, beta 3Beta-defensin 3
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 110Beta-defensin 110
.........
DEFB136 Defensin, beta 136Beta-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 [20] and the olive baboon, Papio anubis, the gene coding for it is corrupted in humans and other primates. [21] [22]

Although the most well-studied defensins are from vertebrates, a family of trans-defensins called 'big defensins' are found in molluscs, arthropods and lancelets. [7] [8]

Cis-defensins

Arthropod defensins are the best-characterised defensins from invertebrates (especially those from insects). [23] Other invertebrates known to produce defensins from this protein superfamily include molluscs, annelids and cnidaria. [24]

Plant defensins were discovered in 1990 and have subsequently been found in most plant tissues with antimicrobial activities, with both antifungal and antibacterial examples. [25] They have been identified in all major groups of vascular plants, but not in ferns, mosses or algae. [25]

Fungal defensins were first identified in 2005. [26] 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. [27]

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. [28]

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; [29] 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, [30] many scorpion toxins, [31] some sea anemone toxins, [10] and one of the toxins in platypus venom. [29] 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. [32]

Signalling

In vertebrates, some α- and β-defensins are involved in signalling between the innate immune and adaptive immune systems. [33] [34] 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. [35]

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). [36] [37] [38]

Function

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

In human breast milk, defensins play a central role in neonate immunity. [39]

The human genome contains theta-defensin genes, but they have a premature stop codon, hampering their expression. An artificial human theta-defensin, [40] retrocyclin, was created by 'fixing' the pseudogene, and it was shown to be effective against HIV [41] 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. [42]

They have generally been considered to contribute to mucosal health; however, it is possible that these peptides can be considered biological factors that can be upregulated by bioactive compounds present in human breast milk. In this sense, the intestinal production of antimicrobial peptides as hBD2 and hBD4 by trefoil from milk might play an important role on neonate colonization, thereby enhancing the immune response of newborns against pathogens with which they may come in contact. [39] [43]

Pathology

The alpha defensin peptides are increased in chronic inflammatory conditions.

Alpha defensin are increased in several cancers, including colorectal cancer. [44]

An imbalance of defensins in the skin may contribute to acne. [45]

A reduction of ileal defensins may predispose to Crohn's disease. [46] [47]

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. [48]

Defensins are found in the human skin during inflammatory conditions like psoriasis [49] and also during wound healing.

Applications

Defensins

At present, the widespread spread of antibiotic resistance requires the search and development of new antimicrobial drugs. From this point of view, defensins (as well as antimicrobial peptides in general) are of great interest. It was shown that defensins have pronounced antibacterial activity against a wide range of pathogens. [50] In addition, defensins can enhance the effectiveness of conventional antibiotics. [50]

Defensin-mimetics

Defensin mimetics, also called host defense peptide (HDP) mimetics, are completely synthetic, non-peptide, small molecule structures that mimic defensins in structure and activity. [51] Similar molecules, such as brilacidin, are being developed as antibiotics, [52] anti-inflammatories for oral mucositis, [53] [54] and antifungals, especially for candidiasis. [55] [56] [57]

See also

Related Research Articles

<span class="mw-page-title-main">Antimicrobial peptides</span> Class of peptides that have antimicrobial activity

Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides. These peptides are potent, broad spectrum antimicrobials which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria, enveloped viruses, fungi and even transformed or cancerous cells. Unlike the majority of conventional antibiotics it appears that antimicrobial peptides frequently destabilize biological membranes, can form transmembrane channels, and may also have the ability to enhance immunity by functioning as immunomodulators.

<span class="mw-page-title-main">Paneth cell</span> Anti-microbial epithelial cell of the small intestine

Paneth cells are cells in the small intestine epithelium, alongside goblet cells, enterocytes, and enteroendocrine cells. Some can also be found in the cecum and appendix. They are located below the intestinal stem cells in the intestinal glands and the large eosinophilic refractile granules that occupy most of their cytoplasm.

Cathelicidin antimicrobial peptide (CAMP) is a polypeptide that is primarily stored in the lysosomes of macrophages and polymorphonuclear leukocytes (PMNs); in humans, the CAMP gene encodes the peptide precursor CAP-18, which is processed by proteinase 3-mediated extracellular cleavage into the active form LL-37. LL-37 is the only peptide in the Cathelicidin family found in the human body.

<span class="mw-page-title-main">Beta-defensin 2</span> Mammalian protein found in humans

Beta-defensin 2 (BD-2) also known as skin-antimicrobial peptide 1 (SAP1) is a peptide that in humans is encoded by the DEFB4 gene.

<span class="mw-page-title-main">Alpha defensin</span>

Alpha defensins are a family of mammalian defensin peptides of the alpha subfamily. In mammals they are also known as cryptdins and are produced within the small bowel. Cryptdin is a portmanteau of crypt and defensin.

<span class="mw-page-title-main">Beta defensin</span>

Beta defensins are a family of vertebrate defensins. The beta defensins are antimicrobial peptides implicated in the resistance of epithelial surfaces to microbial colonization.

<span class="mw-page-title-main">DEFA1</span> Protein-coding gene in the species Homo sapiens

Defensin, alpha 1 also known as human alpha defensin 1, human neutrophil peptide 1 (HNP-1) or neutrophil defensin 1 is a human protein that is encoded by the DEFA1 gene. Human alpha defensin 1 belongs to the alpha defensin family of antimicrobial peptides.

<span class="mw-page-title-main">Beta defensin 1</span> Protein found in humans

Beta-defensin 1 is a protein that in humans is encoded by the DEFB1 gene.

<span class="mw-page-title-main">DEFB103A</span> Protein-coding gene in humans

Beta-defensin 103 is a protein that in humans is encoded by the DEFB103A gene.

<span class="mw-page-title-main">Plant defensin</span>

Plant defensins are a family of primitive, highly stable, cysteine-rich defensins found in plants that function to defend them against pathogens and parasites. Defensins are integral components of the innate immune system and belong to the ancient superfamily of antimicrobial peptides (AMPs). AMPs are also known as host defense peptides (HDPs), and they are thought to have diverged about 1.4 billion years ago before the evolution of prokaryotes and eukaryotes. They are ubiquitous in almost all plant species, functionally diverse, and their primary structure varies significantly from one species to the next, except for a few cysteine residues, which stabilize the protein structure through disulfide bond formation. Plant defensins usually have a net positive charge due to the abundance of cationic amino acids and are generally divided into two classes. Those in the class II category contain a C-terminal pro-peptide domain of approximately 33 amino acids and are targeted to the vacuole, while the class I defensins lack this domain and mature in the cell wall. Unlike their class I counterparts, class II plant defensins are relatively smaller, and their acidic C-terminal prodomain is hypothesized to contribute to their vacuolar targeting. The first plant defensins were discovered in barley and wheat in 1990 and were initially designated as γ-thionins. In 1995, the name was changed to 'plant defensin' when it was identified that they are evolutionarily unrelated to other thionins and were more similar to defensins from insects and mammals.

<span class="mw-page-title-main">Arthropod defensin</span>

Arthropod defensins are a family defensin proteins found in mollusks, insects, and arachnids. These cysteine-rich antibacterial peptides are primarily active against Gram-positive bacteria and fungi in vitro. However Drosophila fruit flies mutant for the fly defensin were more susceptible to infection by the Gram-negative bacteria Providencia burhodogranariea, and resisted infection against Gram-positive bacteria like wild-type flies. It remains to be seen how in vitro activity relates to in vivo function. Mutants for the defensin-like antimicrobial peptide Drosomycin were more susceptible to fungi, validating a role for defensin-like peptides in anti-fungal defence.

<span class="mw-page-title-main">DEFA5</span> Mammalian protein found in Homo sapiens

Defensin, alpha 5 (DEFA5) also known as human alpha defensin 5 (HD5) is a protein that in humans is encoded by the DEFA5 gene. DEFA5 is expressed in the Paneth cells of the ileum.

Protegrins are small peptides containing 16-18 amino acid residues. Protegrins were first discovered in porcine leukocytes and were found to have antimicrobial activity against bacteria, fungi, and some enveloped viruses. The amino acid composition of protegrins contains six positively charged arginine residues and four cysteine residues. Their secondary structure is classified as cysteine-rich β-sheet antimicrobial peptides, AMPs, that display limited sequence similarity to certain defensins and tachyplesins. In solution, the peptides fold to form an anti-parallel β-strand with the structure stabilized by two cysteine bridges formed among the four cysteine residues. Recent studies suggest that protegrins can bind to lipopolysaccharide, a property that may help them to insert into the membranes of gram-negative bacteria and permeabilize them.

<span class="mw-page-title-main">Thionin</span>

Thionins are a family of small proteins found solely in higher plants. Typically, a thionin consists of 45–48 amino acid residues. 6–8 of these are cysteine forming 3–4 disulfide bonds. They include phoratoxins and viscotoxins.

<span class="mw-page-title-main">DEFA6</span> Protein-coding gene in the species Homo sapiens

Defensin, alpha 6 (DEFA6) also known as human alpha defensin 6 (HD6) is a human protein that is encoded by the DEFA6 gene. DEFA6 is expressed in the Paneth cells of the ileum.

<span class="mw-page-title-main">DEFA4</span> Protein-coding gene in the species Homo sapiens

Defensin, alpha 4 (DEFA4), also known as neutrophil defensin 4 or HNP4, is a human defensin peptide that is encoded by the DEFA4 gene. HNP4 is expressed in the granules of the neutrophil where it defends the host against bacteria and viruses.

Theta-defensins are a family of mammalian antimicrobial peptides. They are found in non-human 'Old World' primates, but not in human, gorilla, bonobo, and chimpanzee.

Myticin is a cysteine-rich peptide produced in three isoforms, A, B and C, by Mytilus galloprovincialis, which are found primarily in marine habitats. Myticin is also produced in other species of Mytilus, though the properties of Myticin in Mytilus galloprovincialis is understood to a greater extent. Isoforms A and B show antibacterial activity against Gram-positive bacteria, while isoform C is additionally active against the fungus Fusarium oxysporum and bacterium Escherichia coli. Myticin-prepro is the precursor peptide.

Virtual colony count (VCC) is a kinetic, 96-well microbiological assay originally developed to measure the activity of defensins. It has since been applied to other antimicrobial peptides including LL-37. It utilizes a method of enumerating bacteria called quantitative growth kinetics, which compares the time taken for a bacterial batch culture to reach a threshold optical density with that of a series of calibration curves. The name VCC has also been used to describe the application of quantitative growth kinetics to enumerate bacteria in cell culture infection models. Antimicrobial susceptibility testing (AST) can be done on 96-well plates by diluting the antimicrobial agent at varying concentrations in broth inoculated with bacteria and measuring the minimum inhibitory concentration that results in no growth. However, these methods cannot be used to study some membrane-active antimicrobial peptides, which are inhibited by the broth itself. The virtual colony count procedure takes advantage of this fact by first exposing bacterial cells to the active antimicrobial agent in a low-salt buffer for two hours, then simultaneously inhibiting antimicrobial activity and inducing exponential growth by adding broth. The growth kinetics of surviving cells can then be monitored using a temperature-controlled plate reader. The time taken for each growth curve to reach a threshold change in optical density is then converted into virtual survival values, which serve as a measure of antimicrobial activity.

<span class="mw-page-title-main">Drosomycin</span>

Drosomycin is an antifungal peptide from Drosophila melanogaster and was the first antifungal peptide isolated from insects. Drosomycin is induced by infection by the Toll signalling pathway, while expression in surface epithelia like the respiratory tract is instead controlled by the immune deficiency pathway (Imd). This means that drosomycin, alongside other antimicrobial peptides (AMPs) such as cecropins, diptericin, drosocin, metchnikowin and attacin, serves as a first line defence upon septic injury. However drosomycin is also expressed constitutively to a lesser extent in different tissues and throughout development.

References

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