Structural requirements for antimicrobial versus chemoattractant activities for dermaseptin S9

Abstract

Dermaseptin S9 (Drs S9), GLRSKIWLWVLLMIWQESNKFKKM, isolated from frog skin, does not resemble any of the cationic and amphipathic antimicrobial peptides identified to date, having a highly hydrophobic core sequence flanked at either side by cationic termini. Previous studies [Lequin O, Ladram A, Chabbert A, Bruston F, Convert O, Vanhoye D, Chassaing G, Nicolas P & Amiche M (2006) Biochemistry45, 468-480] demonstrated that this peptide adopted a non-amphipathic alpha-helical conformation in trifluoroethanol/water mixtures, but was highly aggregated in aqueous solutions and in the presence of sodium dodecyl sulfate micelles. Circular dichroism, FTIR and attenuated total reflectance FTIR spectroscopies, combined with a surface plasmon resonance study, show that Drs S9 forms stable and ordered beta-sheet aggregates in aqueous buffers or when bound to anionic or zwitterionic phospholipid vesicles. These structures slowly assembled into amyloid-like fibrils in aqueous environments via spherical intermediates, as revealed by electron microscopy and Congo red staining. Drs S9 induced the directional migration of neutrophils, T lymphocytes and monocytes. Interestingly, the antimicrobial and chemotactic activities of Drs S9 are modulated by its amyloid-like properties. Whereas spherical oligomers of Drs S9 exhibit antimicrobial activity, the soluble, weakly self-associated forms of Drs S9 act on human leukocytes to promote chemotaxis and/or immunological response activation in the same range of concentration as amyloidogenic peptides Abeta(1-42), the most fibrillogenic isoform of amyloid beta peptides, and the prion peptide PrP(106-126).