Enteric alpha defensins in norm and pathology

Defensins are short, cysteine-rich, cationic peptides found in vertebrates, invertebrates and plants, which play an important role in innate immunity against bacteria, fungi, protozoa, and viruses [1]. Mammalian defensins are predominantly expressed in epithelial cells of skin, respiratory airways, gastrointestinal and genitourinary tracts, which form physical barriers to external infectious agents [2,3], and also in leukocytes (mostly neutrophils), which kill microbes that have already penetrated the body [4]. Mature defensins contain six cysteine residues (Cys1-6) forming three intramolecular disulphide bonds. Depending on the bonds arrangement they are classified into alpha, beta and theta subfamilies. Alpha defensins secreted by leukocytes and intestinal Paneth cells of mammals [5] contain disulfide bridges between 1-6, 2-4, and 3-5 cysteine residues, while beta defensins produced by epithelial cells and leukocytes of most multicellular organisms [6] are distinguished by pairing of cysteine residues 1-5, 2-4, and 3-6 [7]. Members of the rare theta defensin subfamily (circular minidefensins) are expressed only in leukocytes and bone marrow cells of monkeys. They are produced by the head-to-tail ligation of two different C-terminally truncated pro-alpha defensins (demidefensins), each nine amino acids long [8].The tertiary structure of mature alpha defensins consists of a triple-stranded β-sheet with two β-turns [9]. An amphipathic character of the peptide (i.e., mostly hydrophobic structure with a positively charged hydrophilic part) is essential for the insertion into the microbial membrane and the formation of a pore leading to membrane permeabilization and lysis of the microbe [10]. Initial recognition of numerous microbial targets is a consequence of electrostatic interactions between the defensins arginine residues and the negatively charged phospholipids of the microbial cytoplasmic membrane [2,5]. However, the precise mechanism of target recognition and it