Alpha defensin

Source: Wikipedia, the free encyclopedia.
Mammalian defensin
TCDB
1.C.19
OPM superfamily54
OPM protein1tv0
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Alpha defensins are a family of mammalian

crypt
and defensin.

Defensins are 2-6 kDa,

Paneth cells
of the small intestine.

Defensins are produced constitutively and/or in response to microbial products or

cryptdins
when first discovered.

Structure

HNP-1, HNP-2 and HNP-3 are encoded by two genes

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

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]

Gene Aliases Peptide Sequence
DEFA1
 HNP1 human neutrophil peptide 1 ACYCRIPACIAGERRYGTCIYQGRLWAFCC
HNP2 human neutrophil peptide 2   CYCRIPACIAGERRYGTCIYQGRLWAFCC
DEFA3 HNP3 human neutrophil peptide 3 DCYCRIPACIAGERRYGTCIYQGRLWAFCC
DEFA4 HNP4 human neutrophil peptide 4 VCSCRLVFCRRTELRVGNCLIGGVSFTYCCTRV
DEFA5 HD5 human defensin 5 ATCYCRHGRCATRESLSGVCEISGRLYRLCCR
DEFA6 HD6 human defensin 6 AFTCHCRRSCYSTEYSYGTCTVMGINHRFCCL

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.

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

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

References

  1. PMID 2006422
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  2. PMID 8528769
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  3. PMID 16989837
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  4. PMID 12574157
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  5. PMID 16909917
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  6. PMID 10569786
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  7. PMID 10506557
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  8. S2CID 23204633
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  9. PMID 2997278
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  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. PMID 18349140
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  12. PMID 15616305
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  13. PMID 22510487
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  14. PMID 8340706
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  15. PMID 19186224
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  16. PMID 9018642
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  17. PMID 18349140
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  18. S2CID 205092943
    .
  19. PMID 9352884
    .
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