1.C.19 The Defensin (Defensin) Family

Many organisms synthesize proteins (or peptides) which are degraded to relatively small hydrophobic or amphipathic, bioactive peptides. These peptides exhibit antibiotic, fungicidal, virucidal, hemolytic and/or tumoricidal activities by interacting with membranes and forming transmembrane channels that allow the free flow of electrolytes, metabolites and water across the phospholipid bilayers. Most of these peptides appear to function in biological warfare. There are many designations given to these bioactive peptides. They include the magainins, cecropins, melittins, defensins, bacteriocidins, etc. The proteins in each family within this functional superfamily are homologous, but they exhibit little or no significant sequence similarity with members of the other families. Thus, each family may have evolved independently. However, certain common structural features observed between members of distinct families suggest that at least some of these families share a common ancestry.

Several families of eukaryotic channel-forming amphipathic peptides, each from a different group of organisms, are recognized. These families will be listed below and briefly described.

Defensins are produced by mammals. Their precursors vary in size (35-95 amino acyl residues). The active peptides have antibacterial, antifungal and antiviral activities. The three-dimensional structures of defensin-1 have been solved both by x-ray crystallography (1.9 Å resolution) and by NMR. An α-defensin, HNP-1, a β-stranded toxin, forms a dimeric pore (Zhang et al., 2010).

Defensins contribute to innate immunity, including protection of mucosal tissues. Human α-defensin 6 (HD6) is highly expressed by secretory Paneth cells of the small intestine. However, in contrast to the other defensins, it lacks appreciable bactericidal activity. Chu et al. (2012) reported that HD6 affords protection against invasion by enteric bacterial pathogens in vitro and in vivo. After stochastic binding to bacterial surface proteins, HD6 undergoes ordered self-assembly to form fibrils and nanonets that surround and entangle bacteria. This self-assembly mechanism occurs in vivo, requires histidine-27, and is consistent with x-ray crystallography data. These findings support a key role for HD6 in protecting the small intestine against invasion by diverse enteric pathogens and may explain the conservation of HD6 throughout Hominidae evolution (Chu et al., 2012).

The generalized transport reaction catalyzed by channel-forming amphipathic peptides is:

small solutes, electrolytes and water (in) small solutes, electrolytes and water (out).