Year: 2012
Type: article
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.
Source: Journal of Biological Chemistry
Authors: Nathan W. Schmidt, Kenneth P. Tai, Karishma Kamdar, Abhijit Mishra, Ghee Hwee Lai, Kun Zhao, André J. Ouellette, Gerard C.L. Wong
Language: English
Subfield: Microbiology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Funders: National Science Foundation, U.S. Department of Energy, Aspen Center for Physics, USC Norris Comprehensive Cancer Center, Office of Science, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Division of Materials Research, Basic Energy Sciences, California NanoSystems Institute, SLAC National Accelerator Laboratory
Awards: G1199642319, G1286236842, G1286251239, G1451874870, G1863003419, Wet Electrostatics and Biomolecular Self-Assembly, G2880384052, G3062317534, G30714459, G3083819904, G3687380347, G419881185, G42916606, G4501827968, G465867758, G498139845, PEPTIDE EFFECTORS OF ENTERIC HOST DEFENSE, G650090426, CAREER: Geometry of Directed Folding and Soft Packing, Antimicrobial Oligomers for BioDefense and Emerging Food Borne Infectious Disease, STUDIES OF ALPHA-DEFENSINS IN PRIMATE INNATE IMMUNITY, University of Southern California Norris Comprehensive Cancer Center Support Grant (CCSG), G969749505, G969889393
OpenAlex ID: W2017032430