Membrane activity of the peptide antibiotic clavanin and the importance of its glycine residues

E.J.M. van Kan, A. van der Bent, R.A. Demel, B. de Kruijff

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    The peptide antibiotic clavanin A (VFQFLGKIIHHVGNFVHGFSHVF-NH2) is rich in histidine and glycine residues. In this study the antimicrobial activity and membrane activity of wild-type clavanin A and seven Gly → Ala mutants thereof were investigated. Clavanin A effectively killed the test microorganism Micrococcus flavus and permeabilized its cytoplasmic membrane in the micromolar concentration range, suggesting that the membrane is the target for this molecule. Consistent with this suggestion, it was observed that clavanin A efficiently inserted into different phospholipid monolayers mainly via hydrophobic interactions. Bilayer permeabilization was observed for both low and high molecular mass fluorophores enclosed in unilamellar vesicles and occurred at the same concentration as the antimicrobial activity. It is therefore suggested that the loss of barrier function does not involve specific receptors in the target membrane. Circular dichroism spectroscopy indicated that under membrane mimicking conditions a random coil → helical transition was induced for all clavanin derivatives tested. Observed differences in peptide−membrane interaction and biological activity between the various clavanin derivatives demonstrated the functional importance of Gly at the positions 6 and 13. These two glycines may act as flexible hinges that facilitate the hydrophobic N-terminal end of clavanin to deeply insert into the bilayer. On the contrary, no such role is evident for Gly 18, as its substitution by Ala actually stimulated membrane interaction and biological activity. This study suggests that the combined hydrophobicity, overall state of charge, and conformational flexibility of the peptide determine the (membrane) activity of clavanin A and its Gly → Ala mutants.
    Original languageEnglish
    Pages (from-to)6398-6405
    Issue number21
    Publication statusPublished - 2001

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