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Positive selection of arginine in α‐defensin: Attenuation of bactericidal activity by Lys→Arg substitutions is dependent on peptide primary structure

Mammalian α‐defensins are endogenous cationic antimicrobial peptides that contain an average of nine times more Arg than Lys. To investigate the functional role of such high Arg content, Arg residues in the mouse Paneth cell α‐defensin cryptdin‐4 (Crp4) and rhesus myeloid α‐defensin RMAD4 were completely replaced with Lys to prepare (R/K)‐Crp4 and (R/K)‐RMAD4, respectively. Arg mutagenesis of Crp4 attenuated peptide bactericidal activity against several species and the kinetics of (R/K)‐Crp4‐mediated E. coli ML35 cell permeabilization were markedly slower than Crp4, needing a 20 min peptide exposure to detect permeabilization. In contrast to the attenuating effects of Arg to Lys replacements on Crp4, corresponding mutations in RMAD4 improved both microbicidal activity against certain bacterial species and the ability to permeabilize live E. coli. Therefore, although Arg→Lys substitutions in Crp4 delay E. coli cell permeabilization and extend exposure times required to induce bacterial cell death, comparable mutagenesis of RMAD4 does not attenuate either activity. Collectively, these findings are inconsistent with the positive selection of Arg in α‐defensins solely to confer selective advantage through superior antibacterial function. Supported by NIH grants DK044632 and AI059346.