Beta defensin

Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Beta defensin
Beta defensin
Identifiers
Symbol	Defensin_beta
Pfam	PF00711
InterPro	IPR001855
SCOP2	1bnb / SCOPe / SUPFAM
OPM superfamily	54
OPM protein	1ut3
Pfam
Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Last updated February 22, 2024

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

Defensins are 2-6 kDa, cationic, microbicidal peptides active against many Gram-negative and Gram-positive bacteria, fungi, and enveloped viruses,^[1] containing three pairs of intramolecular disulfide bonds. On the basis of their size and pattern of disulfide bonding, mammalian defensins are classified into alpha, beta and theta categories. Every mammalian species explored thus far has beta-defensins. In cows, as many as 13 beta-defensins exist in neutrophils. However, in other species, beta-defensins are more often produced by epithelial cells lining various organs (e.g. the epidermis, bronchial tree and genitourinary tract).

Human, rabbit and guinea-pig beta-defensins, as well as human beta-defensin-2 (hBD2), induce the activation and degranulation of mast cells, resulting in the release of histamine and prostaglandin D2.^[2]

Genes

β-defensins are coding for genes which impact the function of the innate immune system.^[3] These genes are responsible for production of antimicrobial peptides found in white blood cells such as macrophages, granulocytes and NK-cells, β-defensins are also found in epithelial cells.^[4] Single-nucleotide polymorphisms (SNPs) are found in genes coding for β-defensins.^[5] The presences of SNPs are lower in the coding regions compared to non-coding regions.^[5] The appearance of SNPs in the coding region will highly likely affecting the resistance against infections through changes in the protein sequences which will give rise to different biological functions.^[5]

Initiation

Receptors such as toll-like receptors (TLR) and nod-like receptors (NLR) will activate the immune system by binding of ligands such as lipopolysaccharides and peptidoglycan.^[6] Toll-like receptors are expressed in intestinal epithelial cells ^[7] or antigen presenting cells (APCs) such as dendritic cells, B-lymphocytes and macrophages.^[6] When the receptors are activated a cascade reaction will take place and substances such as cytokines and antimicrobial peptides ^[8] will be released.^[6]

Function

β-defensins are cationic and can therefore interact with the membrane of invading microbes, which are negative due to lipopolysaccharides (LPS) and lipoteichoic acid (LTA) found in the cell membrane.^[1] The peptides have higher affinity to the binding site compared to Ca2+ and Mg2+ ions.^[5] The peptides will therefore exchange place with those ions, thus affecting the stability of the membrane.^[5] The peptides have a greater size compared with the ions which cause changes in the membrane structure.^[5] Due to changes in the electric potential, peptides will pass across the membrane and thus aggregate into dimers.^[9] Pore complex will be created as a result of breaking the hydrogen bonds between the amino acids in the terminal end of the strands connecting defensins monomers.^[9] Formation of pore complex will cause membrane depolarization and cell lysis.^[5]

Defensins not only have the ability to strengthen the innate immune system but can also enhance the adaptive immune system by chemotaxis of monocytes, T-lymphocytes, dendritic cells and mast cells to the infection site.^[5] Defensins will also improve the capacity of macrophage phagocytosis.^[5]

Avian β-defensins

β-defensins are classified in three classes and avian β-defensins constitute for one of the classes.^[3] This division is based on Zhang's classification and both the length, the homology of the peptides and the gene structure are factors affecting the classification.^[9]

Avian β-defensins are separated in avian heterophiles and non-heterophiles. Avian heterophiles can be divided into two sub-classes, depending on the number of present homologous residues in the genome.^[9]

Avian heterophiles lack protective oxidative mechanisms, such as superoxide and myeloperoxidase, making non-oxidative mechanisms, such as lysosomes and cationic peptides, even more important.^[9]

Evolution

β-defensins genes are found across the vertebrates, including mammals, reptiles, birds and fish.^[10] The fact that alpha and theta defensins are absent in older vertebrates, like birds and fishes, indicates that defensins must have evolved from the same ancestral gene coding for β-defensins.^[11] Indeed, these defensins of this superfamily are related to the 'big defensins' which are found in invertebrate animals, indicating even earlier origins.^[10]

In 2001, it was thought that β-defensins were similar to the ancestral defensin from a comparison of sequences of β-defensins, α-defensins and insect defensins.^[12] Subsequent structural analyses have suggested that the β-defensins, α-defensins, θ-defensins and big defensins share an evolutionary origin, but are separate to the defensins found in insects, fungi and plants.^[13]

In addition to other antimicrobial defensins, there are related defensin-like proteins with have evolved other functions. These include toxins found in snakes (e.g. crotamine), bearded lizards and platypus.^[14]

History

The first beta-defensin discovered was Tracheal Antimicrobial Peptide, found in the bovine airway in 1991.^[15] The first human beta-defensin, HBD1, was discovered in 1995,^[2] followed by the HBD2 in 1997.^[16]

Human proteins containing this domain

DEFB1; DEFB103A; DEFB105A; DEFB105B; DEFB106; DEFB108B; DEFB109; DEFB110; DEFB111; DEFB114; DEFB130; DEFB136; DEFB4; SPAG11A;

Related Research Articles

Defensins are small cysteine-rich cationic proteins across cellular life, including vertebrate and invertebrate animals, plants, and fungi. 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.

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.

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.

An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.

Cathelicidin antimicrobial peptide (CAMP) is an antimicrobial peptide encoded in the human by the CAMP gene. The active form is LL-37. In humans, CAMP encodes the peptide precursor CAP-18, which is processed by proteinase 3-mediated extracellular cleavage into the active form LL-37.

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.

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.

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.

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

Trefoil factor 3 is a protein that in humans is encoded by the TFF3 gene.

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

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.

Heat-stable enterotoxins (STs) are secretory peptides produced by some bacterial strains, such as enterotoxigenic Escherichia coli which are in general toxic to animals.

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.

The ocular immune system protects the eye from infection and regulates healing processes following injuries. The interior of the eye lacks lymph vessels but is highly vascularized, and many immune cells reside in the uvea, including mostly macrophages, dendritic cells, and mast cells. These cells fight off intraocular infections, and intraocular inflammation can manifest as uveitis or retinitis. The cornea of the eye is immunologically a very special tissue. Its constant exposure to the exterior world means that it is vulnerable to a wide range of microorganisms while its moist mucosal surface makes the cornea particularly susceptible to attack. At the same time, its lack of vasculature and relative immune separation from the rest of the body makes immune defense difficult. Lastly, the cornea is a multifunctional tissue. It provides a large part of the eye's refractive power, meaning it has to maintain remarkable transparency, but must also serve as a barrier to keep pathogens from reaching the rest of the eye, similar to function of the dermis and epidermis in keeping underlying tissues protected. Immune reactions within the cornea come from surrounding vascularized tissues as well as innate immune responsive cells that reside within the cornea.

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.

The intestinal mucosal barrier, also referred to as intestinal barrier, refers to the property of the intestinal mucosa that ensures adequate containment of undesirable luminal contents within the intestine while preserving the ability to absorb nutrients. The separation it provides between the body and the gut prevents the uncontrolled translocation of luminal contents into the body proper. Its role in protecting the mucosal tissues and circulatory system from exposure to pro-inflammatory molecules, such as microorganisms, toxins, and antigens is vital for the maintenance of health and well-being. Intestinal mucosal barrier dysfunction has been implicated in numerous health conditions such as: food allergies, microbial infections, irritable bowel syndrome, inflammatory bowel disease, celiac disease, metabolic syndrome, non-alcoholic fatty liver disease, diabetes, and septic shock.

Type 3 innate lymphoid cells (ILC3) are immune cells from the lymphoid lineage that are part of the innate immune system. These cells participate in innate mechanisms on mucous membranes, contributing to tissue homeostasis, host-commensal mutualism and pathogen clearance. They are part of a heterogeneous group of innate lymphoid cells, which is traditionally divided into three subsets based on their expression of master transcription factors as well as secreted effector cytokines - ILC1, ILC2 and ILC3.

Peptidoglycan recognition protein 3 is an antibacterial and anti-inflammatory innate immunity protein that in humans is encoded by the PGLYRP3 gene.

References

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