Cryptdin

Cryptdin is a term that refers to mammalian defensins of the alpha subfamily that are produced within the mouse small bowel. The word is a portmanteau that combines the terms 'crypt' and 'defensin'. Formally, in the scientific literature they are known as mouse enteric alpha-defensins.

Variation

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 ^[1]. 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 ^[2].

Structural features

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 ^[3].

Gene structure and expression

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 ^[4].

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 ^[5].

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 ^[6].

References

1. ^ 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. 
2. ^ 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. 
3. ^ 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. 
4. ^ 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. PMC 97078. PMID 10569786. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=97078. 
5. ^ 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. 
6. ^ 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.