| Autor: |
Andre J. Ouellette, Kun Zhao, Ghee Hwee Lai, Kenneth P. Tai, Nathan W. Schmidt, Abhijit Mishra, Gerard C. L. Wong, Karishma Kamdar |
| Rok vydání: |
2012 |
| Předmět: |
|
| Zdroj: |
Journal of Biological Chemistry. 287:21866-21872 |
| ISSN: |
0021-9258 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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