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

Defensins are small cysteine-rich cationic proteins found in both vertebrates and invertebrates. They are active against bacteria, fungi and many enveloped and nonenveloped viruses. They consist of 18-45 amino acids including six (in vertebrates) to 8 conserved cysteine residues. Cells of the immune system contain these peptides to assist in killing phagocytized bacteria, for example in neutrophil granulocytes and almost all epithelial cells. Most defensins function by binding to microbial cell membrane, and once embedded, forming pore-like membrane defects that allow efflux of essential ions and nutrients.

Contents

Varieties

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. Generally they are encoded by two-exon genes, where the first exon encodes for a hydrophobic leader sequence and the second for a peptide containing the cysteine motif.

There are three main (known) forms of mammalian defensins; α-defensins, β-defensins, and θ-defensins.

Type Genes Description
α-defensins DEFA1, DEFA1A3, DEFA3, DEFA4 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.
β-defensins DEFB1, DEFB4, DEFB103A/DEFB103B to DEFB107A/DEFB107B, DEFB110 to DEFB133 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.
θ-defensins DEFT1P Are rare, and thus far have been found only in the leukocytes of the rhesus macaque[1] and the olive baboon, Papio anubis, being vestigial in humans and other primates.[2][3]

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,[4] retrocyclin, was created by `fixing' the pseudogene, and it was shown to be effective against HIV[5] 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.[6]

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

Pathology

An imbalance of defensins in the skin may contribute to acne.[7]

A reduction of ileal defensins may predispose to Crohn's disease.[8][9]

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.[10]

Defensins are found in the human skin during inflammatory conditions like psoriasis[11] and also during wound healing.[12]

References

  1. ^ Microbicidal properties and cytocidal selectivity of rhesus macaque theta defensins. Tran D, Tran P, Roberts K, Osapay G, Schaal J, Ouellette A, Selsted ME. Antimicrob Agents Chemother. 2008 Mar;52(3):944-53. Epub 2007 Dec 26. PMID 18160518
  2. ^ Angie Eva Garcia and Michael Selsted Olive baboon theta-defensins FASEB J. 2008 22:673.11
  3. ^ Isolation, synthesis, and antimicrobial activities of naturally occurring theta-defensin isoforms from baboon leukocytes. Garcia AE, Osapay G, Tran PA, Yuan J, Selsted ME. Infect Immun. 2008 Dec;76(12):5883-91. Epub 2008 Oct 13. PMID 18852242
  4. ^ MeSH retrocyclin
  5. ^ The theta-defensin, retrocyclin, inhibits HIV-1 entry. Münk C, Wei G, Yang OO, Waring AJ, Wang W, Hong T, Lehrer RI, Landau NR, Cole AM. AIDS Res Hum Retroviruses. 2003 Oct;19(10):875-81. PMID 14585219
  6. ^ Kim C, Gajendran N, Mittrücker H, Weiwad M, Song Y, Hurwitz R, Wilmanns M, Fischer G, Kaufmann S (2005). "Human alpha-defensins neutralize anthrax lethal toxin and protect against its fatal consequences". Proc Natl Acad Sci U S A 102 (13): 4830–5. doi:10.1073/pnas.0500508102. PMID 15772169.  
  7. ^ Philpott M (2003). "Defensins and acne". Mol Immunol 40 (7): 457–62. doi:10.1016/S0161-5890(03)00154-8. PMID 14568392.  
  8. ^ Genomics & Genetics Weekly, "Researchers discover a possible cause of chronic inflammations of Crohn Disease." August 11, 2006, page 72
  9. ^ Wehkamp J et al. (2005). "Reduced Paneth cell alpha-defensins in ileal Crohn's disease" (abstract). Proc Natl Acad Sci U S A 102 (50): 18129–34. doi:10.1073/pnas.0505256102. PMID 16330776. http://www.pnas.org/cgi/content/abstract/102/50/18129.  
  10. ^ Craddock RM, Huang JT, Jackson E, et al. (March 2008). "Increased alpha defensins as a blood marker for schizophrenia susceptibility". Mol. Cell Proteomics 7: 1204. doi:10.1074/mcp.M700459-MCP200. PMID 18349140. http://www.mcponline.org/cgi/pmidlookup?view=long&pmid=18349140.  
  11. ^ Harder J, Bartels J, Christophers E, "et al." (1999). "A peptide antibiotic from human skin". Nature 387 (6636): 861. doi:10.1038/43088. PMID 9202117.  
  12. ^ Sorensen OE, Thapa, DR, Roupé KM, "et al." (2006). "Injury-induced innate immune response in human skin mediated by transactivation of the epidermal growth factor receptor". J Clin Invest 116 (7): 1878–1885. doi:10.1172/JCI28422. PMID 16778986.  

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