Schmidt, Nathan W.Nathan W.SchmidtTai, Kenneth P.Kenneth P.TaiKamdar, KarishmaKarishmaKamdarMishra, AbhijitAbhijitMishraLai, Ghee HweeGhee HweeLaiZhao, KunKunZhaoOuellette, André J.André J.OuelletteWong, Gerard C.L.Gerard C.L.Wong2025-08-302025-08-302012-06-2210.1074/jbc.M112.3587212-s2.0-84862646898http://repository.iitgn.ac.in/handle/IITG2025/2104322566697The conserved tridisulfide array of the α-defensin family imposes a common triple-stranded β-sheet topology on peptides that may have highly diverse primary structures, resulting in differential outcomes after targeted mutagenesis. In mouse cryptdin-4 (Crp4) and rhesus myeloid α-defensin-4 (RMAD4), complete substitutions of Arg with Lys affect bactericidal peptide activity very differently. Lys-for-Arg mutagenesis attenuates Crp4, but RMAD4 activity remains mostly unchanged. Here, we show that the differential biological effect of Lys-for- Arg replacements can be understood by the distinct phase behavior of the experimental peptide-lipid system. In Crp4, small-angle x-ray scattering analyses showed that Arg-to-Lys replacements shifted the induced nanoporous phases to a different range of lipid compositions compared with the Arg-rich native peptide, consistent with the attenuation of bactericidal activity by Lys-for-Arg mutations. In contrast, such phases generated by RMAD4 were largely unchanged. The concordance between small-angle x-ray scattering measurements and biological activity provides evidence that specific types of α-defensin-induced membrane curvature-generating tendencies correspond directly to bactericidal activity via membrane destabilization. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.trueArticlehttp://www.jbc.org/article/S0021925820497170/pdf1083351X21866-2187222 June 201258arJournal55WOS:000306418600028