Molecular Diversity of the Antimicrobial Domain of Beta-Defensin 3 and Homologous Peptides

Human beta-defensin 3 has received great interest for possible pharmaceutical applications. To characterize the biology of this antimicrobial peptide, the mouse beta-defensin 14 has been selected as a prototypical model. This report provides definite evidence of true orthology between these defensins and reveals molecular diversity of a mammalian specific domain responsible for their antimicrobial activity. Specifically, this analysis demonstrates that eleven amino acid residues of the antimicrobial domain have been mutated by positive selection to confer protein niche specialization. These data support the notion that natural selection acts as evolutionary force driving the proliferation and diversification of defensins and introduce a novel strategy for the design of more effective antibiotics.