Defensin

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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 have also been reported in plants.[1][2] 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[edit]

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 arhtropod defensins.[1][3] Similarly, mammalian defensins also do not require disulfide bonds to exhibit antimicrobial activity. [2][4] 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.[5] 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 betweem 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.\[6]

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
... ... ...
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[7] and the olive baboon, Papio anubis, being vestigial in humans and other primates.[8][9]

Function[edit]

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,[10] retrocyclin, was created by `fixing' the pseudogene, and it was shown to be effective against HIV[11] 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.[12]

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

Defensin-mimetics as antibiotics[edit]

Similar molecules (e.g. PMX-30063) are being developed as antibiotics.[13]

Pathology[edit]

The alpha defensin peptides are increased in chronic inflammatory conditions.

Alpha defensin are increased in several cancers, including colorectal cancer.[14]

An imbalance of defensins in the skin may contribute to acne.[15]

A reduction of ileal defensins may predispose to Crohn's disease.[16][17]

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.[18]

Defensins are found in the human skin during inflammatory conditions like psoriasis[19] and also during wound healing.

See also[edit]

References[edit]

  1. ^ Structure–activity studies of AtPep1, a plant peptide signal involved in the innate immune response Peptides Volume 29, Issue 12, December 2008, Pages 2083-2089
  2. ^ Planta. 2002 Dec;216(2):193-202. Epub 2002 Oct 8. Plant defensins.
  3. ^ Jobin Varkey, Shashi Singh, Ramakrishnan Nagaraj. Antibacterial activity of linear peptides spanning the carboxy-terminal β-sheet domain of arthropod defensins
  4. ^ Jobin Varkey, Ramakrishnan Nagaraj. Antibacterial Activity of Human Neutrophil Defensin HNP-1 Analogs without Cysteines
  5. ^ Shunyi Zhu, Wenxin Li, Dahe Jiang, and Xianchun Zeng. Evidence for the Existence of Insect defensin-like Peptide in Scorpion Venom. IUBMB Life, 50: 57–61, 2000
  6. ^ Shunyi Zhu, Steve Peigneur, Bin Gao, Yoshitaka Umetsu, Shinya Ohki, Jan Tytgat. Experimental Conversion of a Defensin into a Neurotoxin: Implications for Origin of Toxic Function. Mol Biol Evol (2014) doi: 10.1093/molbev/msu038
  7. ^ Tran D, Tran P, Roberts K, Osapay G, Schaal J, Ouellette A, Selsted ME (March 2008). "Microbicidal properties and cytocidal selectivity of rhesus macaque theta defensins". Antimicrob. Agents Chemother. 52 (3): 944–53. doi:10.1128/AAC.01090-07. PMC 2258523. PMID 18160518. 
  8. ^ Angie Eva Garcia and Michael Selsted Olive baboon theta-defensins FASEB J. 2008 22:673.11
  9. ^ Garcia AE, Osapay G, Tran PA, Yuan J, Selsted ME (December 2008). "Isolation, synthesis, and antimicrobial activities of naturally occurring theta-defensin isoforms from baboon leukocytes". Infect. Immun. 76 (12): 5883–91. doi:10.1128/IAI.01100-08. PMC 2583559. PMID 18852242. 
  10. ^ retrocyclin at the US National Library of Medicine Medical Subject Headings (MeSH)
  11. ^ Münk C, Wei G, Yang OO, et al. (October 2003). "The theta-defensin, retrocyclin, inhibits HIV-1 entry". AIDS Res. Hum. Retroviruses 19 (10): 875–81. doi:10.1089/088922203322493049. PMID 14585219. 
  12. ^ 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. PMC 555714. PMID 15772169. 
  13. ^ "PMX-30063 The First And Only Defensin Mimetic Systemic Antibiotic Drug In Human Clinical Trials". 2008. 
  14. ^ Albrethsen J; Bøgebo, R; Gammeltoft, S; Olsen, J; Winther, B; Raskov, H (2005). "Upregulated expression of human neutrophil peptides 1, 2 and 3 (HNP 1-3) in colon cancer serum and tumours: a biomarker study". BMC cancer 5: 9. doi:10.1186/1471-2407-5-8. PMC 548152. PMID 15656915. 
  15. ^ Philpott M (2003). "Defensins and acne". Mol Immunol 40 (7): 457–62. doi:10.1016/S0161-5890(03)00154-8. PMID 14568392. 
  16. ^ Genomics & Genetics Weekly, "Researchers discover a possible cause of chronic inflammations of Crohn Disease." August 11, 2006, page 72
  17. ^ 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. PMC 1306791. PMID 16330776. 
  18. ^ 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. 
  19. ^ Harder, J; Bartels, J; Christophers, E; Schroder, JM (Feb 23, 2001). "Isolation and characterization of human beta -defensin-3, a novel human inducible peptide antibiotic.". The Journal of Biological Chemistry 276 (8): 5707–13. doi:10.1074/jbc.M008557200. PMID 11085990. 

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