title: Arginine in α-defensins: differential effects on bactericidal activity correspond to geometry of membrane curvature generation and peptide-lipid phase behavior.
abstract: The 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.
authors.affiliation: Department of Bioengineering, UCLA, Los Angeles, California 90095-1600, USA.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Schmidt
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Tai
authors.forename: Karishma
authors.initials: K
authors.lastname: Kamdar
authors.forename: Abhijit
authors.initials: A
authors.lastname: Mishra
authors.forename: Ghee Hwee
authors.initials: GH
authors.lastname: Lai
authors.forename: Kun
authors.initials: K
authors.lastname: Zhao
authors.forename: André J
authors.initials: AJ
authors.lastname: Ouellette
authors.forename: Gerard C L
authors.initials: GC
authors.lastname: Wong
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry; D001120:Arginine / Q000737:chemistry / Q000378:metabolism*; D023082:Defensins / Q000737:chemistry; D004926:Escherichia coli / Q000378:metabolism; D007113:Immunity, Innate; D008055:Lipids / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D051379:Mice; D016011:Normal Distribution; D010455:Peptides / Q000737:chemistry; D011498:Protein Precursors / Q000378:metabolism*; D012542:Scattering, Radiation; D014965:X-Rays; D023084:alpha-Defensins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D023082:Defensins; D008055:Lipids; D010455:Peptides; D011498:Protein Precursors; D023084:alpha-Defensins; C401847:cryptdin 4, mouse; C059569:cryptdin; D001120:Arginine; D008239:Lysine