Evolutionary origin of β-defensins.

β-Defensins are a group of vertebrate-specific antimicrobial peptides (AMPs) with microbicidal and immune regulatory functions. In spite of their conservation across the vertebrate lineage ranging from bony fish to human, the evolutionary origin of these molecules remains unsolved. We addressed this issue by comparing three-dimensional (3D) structure and genomic organization of β-defensins with those of big defensins, a family of invertebrate-derived β-defensin-related peptides with two distinct structural and functional domains. β-Defensins and the carboxyl-terminal domain of big defensins adopt a conserved β-sheet topology stabilized by three identical disulfide bridges. Genomic organization analysis revealed that the defensin domain of these two classes of molecules is encoded by a single exon with a positionally conserved phase-1 intron in its upstream. The genomic and 3D structural conservation provides convincing evidence for their evolutionary relationship, in which β-defensins emerged from an ancestral big defensin through exon shuffling or intronization of exonic sequences. The phylogenetic distribution of big defensins in Arthropoda, Mollusca and Cephalochordata suggests an early origin of the β-defensin domain, which can be traced to the common ancestor of bilateral metazoans.