Electropositive Charge in α-Defensin Bactericidal Activity: Functional Effects of Lys-for-Arg Substitutions Vary with the Peptide Primary Structure

Author:

Llenado R. Alan1,Weeks Colby S.1,Cocco Melanie J.2,Ouellette André J.13

Affiliation:

1. Departments of Pathology & Laboratory Medicine

2. Molecular Biology & Biochemistry

3. Microbiology & Molecular Genetics, Schools of Medicine and Biological Sciences, University of California, Irvine, California 92697-4800

Abstract

ABSTRACT Cationic amino acids contribute to α-defensin bactericidal activity. Curiously, although Arg and Lys have equivalent electropositive charges at neutral pH, α-defensins contain an average of nine Arg residues per Lys residue. To investigate the role of high α-defensin Arg content, all Arg residues in mouse Paneth cell α-defensin cryptdin 4 (Crp4) and rhesus myeloid α-defensin 4 (RMAD-4) were replaced with Lys to prepare (R/K)-Crp4 and (R/K)-RMAD-4, respectively. Lys-for-Arg replacements in Crp4 attenuated bactericidal activity and slowed the kinetics of Escherichia coli ML35 cell permeabilization, and (R/K)-Crp4 required longer exposure times to reduce E. coli cell survival. In marked contrast, Lys substitutions in RMAD-4 improved microbicidal activity against certain bacteria and permeabilized E. coli more effectively. Therefore, Arg→Lys substitutions attenuated activity in Crp4 but not in RMAD-4, and the functional consequences of Arg→Lys replacements in α-defensins are dependent on the peptide primary structure. In addition, the bactericidal effects of (R/K)-Crp4 and (R/K)-RMAD-4 were more sensitive to inhibition by NaCl than those of the native peptides, suggesting that the high Arg content of α-defensins may be under selection to confer superior microbicidal function under physiologic conditions.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Immunology,Microbiology,Parasitology

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