A fossil antibacterial peptide gives clues to structural diversity of cathelicidin-derived host defense peptides.

摘要

Cathelicidins, a group of vertebrate- specific immune effector molecules, developed into a multigene family through gene duplication in the Cetartiodactyla lineage, in which structural changes of the antimicrobial domains (AMDs) among paralogs during evolution are clearly associated with functional diversification of cathelicidins. However, the evolutionary mechanism for such structural diversity remains largely unsolved. Although at the genomic level, the 3'-exon alone encoding the variable AMD repertoire would favor a role of exon shuffling, the observation that two structurally unrelated subfamilies of AMDs (protegrins and prophenins) display high similarity in some nucleotide regions of the 3'-exons of their genes provides evidence for postduplication sequence remodeling. This opinion is further strengthened by finding a proline-arginine-rich antibacterial peptide of 38 residues (named PR-38) encoded by an open reading frame located in the 3' untranslated region of protegrins, which is in frame with prophenins. The latter appears to have undergone internal motif repeats in the region corresponding to PR-38. PR-38 exhibits similar amino acid sequence and carboxyl-terminal amidation feature to PR-39s, a subfamily of cathelicidin peptides conserved across Cetartiodactyla. Functional assays of the chemically synthesized PR-38 confirmed its antibacterial activity with a similar action mode to PR-39 against both gram-positive and gram-negative bacteria at micromolar concentrations, supporting an ancient functional link among cathelicidin members belonging to different subfamilies. Resurrecting the fossil peptide highlights the evolutionary position of PR-39 in generating structurally variable subfamilies of porcine cathelicidins through postduplication sequence remodeling.