Alpha defensin

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Mammalian defensin
PDB 1dfn EBI.jpg
Structure of defensin HNP-3. [1]
Identifiers
SymbolDefensin_1
Pfam PF00323
InterPro IPR006081
PROSITE PDOC00242
SCOP2 1dfn / SCOPe / SUPFAM
TCDB 1.C.19
OPM superfamily 54
OPM protein 1tv0
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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

Contents

Defensins are 2-6 kDa, cationic, antimicrobial peptides active against many Gram-negative and Gram-positive bacteria, fungi, and enveloped viruses, [2] 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. Alpha-defensins, which have been identified in humans, monkeys and several rodent species, are particularly abundant in neutrophils, certain macrophage populations and Paneth cells of the small intestine.

Defensins are produced constitutively and/or in response to microbial products or proinflammatory cytokines. Some defensins are also called corticostatins because they inhibit corticotropin-stimulated corticosteroid production. The mechanism(s) by which microorganisms are killed and/or inactivated by defensins is not understood completely. However, it is generally believed that killing is a consequence of disruption of the microbial membrane. The polar topology of defensins, with spatially separated charged and hydrophobic regions, allows them to insert themselves into the phospholipid membranes so that their hydrophobic regions are buried within the lipid membrane interior and their charged (mostly cationic) regions interact with anionic phospholipid head groups and water. Subsequently, some defensins can aggregate to form 'channel-like' pores; others might bind to and cover the microbial membrane in a 'carpet-like' manner. The net outcome is the disruption of membrane integrity and function, which ultimately leads to the lysis of microorganisms. Some defensins are synthesized as propeptides which may be relevant to this process. Alpha defensins of the mouse bowel were historically called cryptdins when first discovered.

Structure

HNP-1, HNP-2 and HNP-3 are encoded by two genes DEFA1 and DEFA3 localized at chromosome 8, location 8p23.1. DEFA1 and DEFA3 encode identical peptides except the conversion of the first amino acid from alanine in HNP-1 to aspartic acid in HNP-3; HNP-2 is an N-terminally truncated iso-form lacking the first amino acid. Human neutrophil peptides are found in human atherosclerotic arteries, inhibit LDL metabolism and fibrinolysis and promote Lp(a) binding. [3]

Like other alpha-defensins, cryptdins are small, 32-36 amino acid long cationic peptides. They possess 6 conserved cysteines that form a tridisulfide array with an arrangement of cysteine pairings that typify alpha-defensins. Cryptdins also display a secondary and tertiary structure that is dominated by a three-stranded beta-sheet. The topology that arises from this structure is an amphipathic globular form in which the termini are paired opposite a pole including a cluster of cationic residues. [4]

Sequences of major human α-defensins: [5]

GeneAliasesPeptideSequence
DEFA1 HNP1human neutrophil peptide 1ACYCRIPACIAGERRYGTCIYQGRLWAFCC
HNP2human neutrophil peptide 2  CYCRIPACIAGERRYGTCIYQGRLWAFCC
DEFA3 HNP3human neutrophil peptide 3DCYCRIPACIAGERRYGTCIYQGRLWAFCC
DEFA4 HNP4human neutrophil peptide 4VCSCRLVFCRRTELRVGNCLIGGVSFTYCCTRV
DEFA5 HD5human defensin 5ATCYCRHGRCATRESLSGVCEISGRLYRLCCR
DEFA6 HD6human defensin 6AFTCHCRRSCYSTEYSYGTCTVMGINHRFCCL

Genes encoding cryptdins are located on the proximal arm of mouse chromosome 8. They are similar to other enteric alpha-defensins genes in that they involve a two exon structure. The first exon encodes an N-terminal canonical signal peptide and proregion that is present in the cryptdin precursor. The processed, mature peptide is encoded by the second exon which is separated from the first exon by a ~500 bp intron. [6]

Biosynthesized as precursors possessing an anionic, N-terminal proregion, cryptdins are packaged into the apically directed secretory granules of Paneth cells. During this process and perhaps succeeding it, the precursors are cleaved by matrix metalloproteinase-7 (matrilysin; MMP-7). As a result of this proteolysis, the C-terminal mature form is released from the proregion. [7]

Functional characteristics

With the ability to kill gram-positive and gram-negative bacteria, fungi, spirochetes and some enveloped viruses, cryptdins are classified as broad-spectrum antimicrobial peptides. Although it is the least expressed of the six isoforms, cryptdin-4 is the most bactericidal. Procryptdins, however, are nonbactericidal and thus require degradation of the proregion by MMP-7 for activation. In response to bacterial antigens, Paneth cells release their secretory granules into the lumen of intestinal crypts. There, cryptdins, along with other antimicrobial peptides expressed by Paneth cells, contribute to enteric mucosal innate immunity by clearing the intestinal crypt of potential invading pathogens. [8]

Human defensins

Initially human alpha defensin peptides were isolated from the neutrophils and are thus called human neutrophil peptides. [9] Human neutrophil peptides are also known as α-defensins.

Human neutrophil-derived alpha-defensins (HNPs) are capable of enhancing phagocytosis by mouse macrophages. HNP1-3 have been reported to increase the production of tumor necrosis factor (TNF) and IL-1, while decreasing the production of IL-10 by monocytes. Increased levels of proinflammatory factors (e.g., IL-1, TNF, histamine and prostaglandin D2) and suppressed levels of IL-10 at the site of microbial infection are likely to amplify local inflammatory responses. This might be further reinforced by the capacity of some human and rabbit alpha-defensins to inhibit the production of immunosuppressive glucocorticoids by competing for the binding of adrenocorticotropic hormone to its receptor. Moreover, human alpha-defensins can enhance or suppress the activation of the classical pathway of complement in vitro by binding to solid-phase or fluid-phase complement C1q, respectively. The capacity of defensins to enhance phagocytosis, promote neutrophil recruitment, enhance the production of proinflammatory cytokines, suppress anti-inflammatory mediators and regulate complement activation argues that defensins upregulate innate host inflammatory defenses against microbial invasion.

Human neutrophil defensin-1, -3, and -4 are elevated in nasal aspirates from children with naturally occurring adenovirus infection. [10] 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. [11]

The Virtual Colony Count antibacterial assay was originally developed to measure the activity of all six human alpha defensins on the same microplate. [12]

In human plasma

HNPs have been extensively studied as plasma marker of a range of diseases such as atherosclerosis, rheumatic diseases, [13] infections, [14] cancer, [15] preeclampsia, [16] and schizophrenia. [17] Antibodies directed against fully processed HNP-1 seem to have low affinity for the propeptides, proHNPs. A recent study used antibodies directed against proHNPs to show that the predominant forms of alpha-defensins in plasma are in fact proHNPs. [18] ProHNPs are exclusively synthesized by neutrophil precursors in the bone marrow and appear to be very specific markers of granulopoiesis.

Gut expression

Cryptdins are the protein products of a related family of highly polymorphic genes that are specifically expressed by mouse Paneth cells at the base of intestinal crypts. [19] They were first characterized as products of cDNAs derived from mouse small intestinal RNA. To date, over 25 cryptdin-encoding transcripts have been described. Despite the expression of a relatively large number of cryptdin isoforms, only 6 cryptdins have been isolated at the protein level. Conventional nomenclature labels the isoforms cryptdins-1 through -6 in order of discovery. The primary structures of cryptdin isoforms are highly homologous. Most differences between the isoforms lie in the identity of residues at the N- and C-termini.

See also

Related Research Articles

<span class="mw-page-title-main">Defensin</span> Group of antimicrobial peptides

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.

<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.

<span class="mw-page-title-main">CXCL5</span> Mammalian protein found in Homo sapiens

C-X-C motif chemokine 5 is a protein that in humans is encoded by the CXCL5 gene.

<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">Beta defensin</span> Family of proteins

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> Host-defense peptide family in plants

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">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.

<span class="mw-page-title-main">DEFB106A</span> Protein-coding gene in humans

Beta-defensin 106 is a protein that in humans is encoded by the DEFB106A gene.

<span class="mw-page-title-main">Intestinal epithelium</span> Single-cell layer lining the intestines

The intestinal epithelium is the single cell layer that forms the luminal surface (lining) of both the small and large intestine (colon) of the gastrointestinal tract. Composed of simple columnar epithelium its main functions are absorption, and secretion. Useful substances are absorbed into the body, and the entry of harmful substances is restricted. Secretions include mucins, and peptides.

<span class="mw-page-title-main">DEFB105A</span> Protein-coding gene in humans

Beta-defensin 105 is a protein that is encoded by the DEFB105A gene in humans.

<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.

<span class="mw-page-title-main">DEFA3</span> Protein-coding gene in the species Homo sapiens

Defensin, alpha 3 (DEFA3) also known as human alpha defensin 3, human neutrophil peptide 3 (HNP-3) or neutrophil defensin 3 is a human protein that is encoded by the DEFA3 gene. Human alpha defensin 3 belongs to the alpha defensin family of antimicrobial peptides.

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.

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">Intestinal mucosal barrier</span>

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.

References

  1. ↑ Hill CP, Yee J, Selsted ME, Eisenberg D (March 1991). "Crystal structure of defensin HNP-3, an amphiphilic dimer: mechanisms of membrane permeabilization". Science. 251 (5000): 1481–5. Bibcode:1991Sci...251.1481H. doi:10.1126/science.2006422. PMID   2006422.
  2. ↑ Selsted ME, White SH, Wimley WC (1995). "Structure, function, and membrane integration of defensins". Curr. Opin. Struct. Biol. 5 (4): 521–527. doi:10.1016/0959-440X(95)80038-7. PMID   8528769.
  3. ↑ Nassar H, Lavi E, Akkawi S, Bdeir K, Heyman SN, Raghunath PN, Tomaszewski J, Higazi AA (Oct 2007). "alpha-Defensin: link between inflammation and atherosclerosis". Atherosclerosis. 194 (2): 452–7. doi:10.1016/j.atherosclerosis.2006.08.046. PMID   16989837.
  4. ↑ Satchell DP, Sheynis T, Shirafuji Y, Kolusheva S, Ouellette AJ, Jelinek R (2003). "Interactions of mouse Paneth cell alpha-defensins and alpha-defensin precursors with membranes. Prosegment inhibition of peptide association with biomimetic membranes". J. Biol. Chem. 278 (16): 13838–46. doi: 10.1074/jbc.M212115200 . PMID   12574157.
  5. ↑ Bowdish DM, Davidson DJ, Hancock RE (2006). "Immunomodulatory Properties of Defensins and Cathelicidins". Antimicrobial Peptides and Human Disease. Current Topics in Microbiology and Immunology. Vol. 306. pp. 27–66. doi:10.1007/3-540-29916-5_2. ISBN   978-3-540-29915-8. PMC   7121507 . PMID   16909917.{{cite book}}: |journal= ignored (help)
  6. ↑ Ouellette AJ, Darmoul D, Tran D, Huttner KM, Yuan J, Selsted ME (1999). "Peptide localization and gene structure of cryptdin 4, a differentially expressed mouse paneth cell alpha-defensin". Infect. Immun. 67 (12): 6643–51. doi:10.1128/IAI.67.12.6643-6651.1999. PMC   97078 . PMID   10569786.
  7. ↑ Wilson C, Ouellette A, Satchell D, Ayabe T, López-Boado Y, Stratman J, Hultgren S, Matrisian L, Parks W (1999). "Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense". Science. 286 (5437): 113–7. doi:10.1126/science.286.5437.113. PMID   10506557.
  8. ↑ Ayabe T, Satchell DP, Wilson CL, Parks WC, Selsted ME, Ouellette AJ (2000). "Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria". Nat. Immunol. 1 (2): 113–8. doi:10.1038/77783. PMID   11248802. S2CID   23204633.
  9. ↑ Ganz T, Selsted ME, Szklarek D, Harwig SS, Daher K, Bainton DF, Lehrer RI (Oct 1985). "Defensins. Natural peptide antibiotics of human neutrophils". J Clin Invest. 76 (4): 1427–35. doi:10.1172/JCI112120. PMC   424093 . PMID   2997278.
  10. ↑ V. S. Priyadharshini, F. Ramírez-Jiménez, M. Molina-Macip, et al., “Human Neutrophil Defensin-1, -3, and -4 Are Elevated in Nasal Aspirates from Children with Naturally Occurring Adenovirus Infection,” Canadian Respiratory Journal, vol. 2018, Article ID 1038593, 6 pages, 2018. https://doi.org/10.1155/2018/1038593.
  11. ↑ Craddock RM, Huang JT, Jackson E, et al. (March 2008). "Increased alpha defensins as a blood marker for schizophrenia susceptibility". Mol. Cell. Proteomics . 7 (7): 1204–13. doi: 10.1074/mcp.M700459-MCP200 . PMID   18349140.
  12. ↑ Ericksen B, Wu Z, Lu W, Lehrer RI (2005). "Antibacterial Activity and Specificity of the Six Human α-Defensins". Antimicrob. Agents Chemother. 49 (1): 269–75. doi:10.1128/AAC.49.1.269-275.2005. PMC   538877 . PMID   15616305.
  13. ↑ Vordenbäumen, S; Sander, O; Bleck, E; Schneider, M; Fischer-Betz, R (May–Jun 2012). "Cardiovascular disease and serum defensin levels in systemic lupus erythematosus". Clinical and Experimental Rheumatology. 30 (3): 364–70. PMID   22510487.
  14. ↑ Panyutich, AV; Panyutich, EA; Krapivin, VA; Baturevich, EA; Ganz, T (August 1993). "Plasma defensin concentrations are elevated in patients with septicemia or bacterial meningitis". The Journal of Laboratory and Clinical Medicine. 122 (2): 202–7. PMID   8340706.
  15. ↑ Droin, N; Hendra, JB; Ducoroy, P; Solary, E (Aug 20, 2009). "Human defensins as cancer biomarkers and antitumour molecules". Journal of Proteomics. 72 (6): 918–27. doi:10.1016/j.jprot.2009.01.002. PMID   19186224.
  16. ↑ Prieto, JA; Panyutich, AV; Heine, RP (January 1997). "Neutrophil activation in preeclampsia. Are defensins and lactoferrin elevated in preeclamptic patients?". The Journal of Reproductive Medicine. 42 (1): 29–32. PMID   9018642.
  17. ↑ Craddock, RM; Huang, JT; Jackson, E; Harris, N; Torrey, EF; Herberth, M; Bahn, S (July 2008). "Increased alpha-defensins as a blood marker for schizophrenia susceptibility". Molecular & Cellular Proteomics. 7 (7): 1204–13. doi: 10.1074/mcp.M700459-MCP200 . PMID   18349140.
  18. ↑ Glenthøj, A; Glenthøj, AJ; Borregaard, N (August 2013). "ProHNPs are the principal α-defensins of human plasma". European Journal of Clinical Investigation. 43 (8): 836–43. doi:10.1111/eci.12114. PMID   23718714. S2CID   205092943.
  19. ↑ Ouellette AJ (1997). "Paneth cells and innate immunity in the crypt microenvironment". Gastroenterology. 113 (5): 1779–84. doi: 10.1053/gast.1997.v113.pm9352884 . PMID   9352884.
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