Defensins

Classical alpha (a)-defensins are small, cysteine- and arginine-rich antimicrobial peptides with a mass of

3.5-4.0 kDa. They contain 29-34 amino acid residues, including six invariant cysteines that form three intramolecular disulfide bonds. Slightly larger antimicrobial peptides, now called beta (p)-dcfensins, were discovered somewhat later in the epithelial cells that line the bovine trachea and tongue and in avian and bovine neutrophils. In humans, a (3-defensin (hBD-1) is produced by cells in the kidney, male and female genitourinary tracts, trachea and small airways, placenta, pancreas and salivary glands. hBD-1 is not produced by neutrophils or other cells derived from the bone marrow. Individual defensin molecules have a triple-stranded 3-sheet structure and form dimers with six-stranded (3 sheets. Assembly of defensins into multimeric structures may be necessary for them to exert their antimicrobial and membrane-perturbing effects.

Defensin genes show extraordinary multiplicity and provide compelling evidence of the rapid evolution of the sequences that encode the mature defensin peptide. The genes for human a- and (3-defensin lie within 150 kb of each other on the short arm of chromosome 8. This observation, and other recent studies suggest that a- and (3-defensins arose, via multiple gene reduplications and mutations, from a common gene existent in a progenitor common to birds and mammals. Myeloid a-defensin genes contain three exons, whereas enteric a-defensin genes contain only two. The primary structures of several a- and (3-defensins are shown in Figure 1.

Defensins are synthesized as 93-100 amino acid long, nonglycosylated prepropeptides. The amino acids destined to form the mature defensin peptides constitute the C-terminal portion of their respective precursors. After cotranslational removal of a highly conserved 19 residue signal sequence, the resulting prodefensin undergoes sequential proteolytic cleavages that yield the mature defensin molecules that are stored within the neutrophil's azurophil granules. The defensin propiece is polyanionic and may protect defensin-producing cells from autocytotoxicity. It also plays a key role in the intracellular trafficking that targets defensins to the azurophil granule compartment of the neutrophil.

Since the first description of 'lysosomal cationic proteins' in rabbit and guinea pig neutrophils, more than 50 different a-defensins and 20 different |3-defensins obtained from avian and mammalian sources have been identified and sequenced. Although a-defensins are exceptionally abundant constituents of human, rabbit, guinea pig and rat neutrophils, they are not found in those of mice, horses, pigs or cattle. Human neutrophils contain four defensins, called HNP-1, -2, -3 and -4 (Figure 1). a-Defensins constitute 5-7% of the total cellular

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