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J. Biol. Chem., Vol. 280, Issue 24, 22945-22950, June 17, 2005

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Structure and Mode of Action of the Membrane-permeabilizing Antimicrobial Peptide Pheromone Plantaricin A^*

Per Eugen Kristiansen, Gunnar Fimland, Dimitris Mantzilas, and Jon Nissen-Meyer

From the Department of Molecular Biosciences, University of Oslo, Oslo 0316, Norway

The three-dimensional structure in dodecyl phosphocholine micelles of the 26-mer membrane-permeabilizing bacteriocin-like pheromone plantaricin A (PlnA) has been determined by use of nuclear magnetic resonance spectroscopy. The peptide was unstructured in water but became partly structured upon exposure to micelles. An amphiphilic -helix stretching from residue 12 to 21 (possibly also including residues 22 and 23) was then formed in the C-terminal part of the peptide, whereas the N-terminal part remained largely unstructured. PlnA exerted its membrane-permeabilizing antimicrobial activity through a nonchiral interaction with the target cell membrane because the D-enantiomeric form had the same activity as the natural L-form. This nonchiral interaction involved the amphiphilic -helical region in the C-terminal half of PlnA because a 17-mer fragment that contains the amphiphilic -helical part of the peptide had antimicrobial potency that was similar to that of the L- and D-enantiomeric forms of PlnA. Also the pheromone activity of PlnA depended on this nonchiral interaction because both the L- and D-enantiomeric forms of the 17-mer fragment inhibited the pheromone activity. The pheromone activity also involved, however, a chiral interaction between the N-terminal part of PlnA and its receptor because high concentrations of the L-form (but not the D-form) of a 5-mer fragment derived from the N-terminal part of PlnA had pheromone activity. The results thus reveal a novel mechanism whereby peptide pheromones such as PlnA may function. An initial nonchiral interaction with membrane lipids induces -helical structuring in a segment of the peptide pheromone. The peptide becomes thereby sufficiently structured and properly positioned in the membrane interface, thus enabling it to engage in a chiral interaction with its receptor in or near the membrane water interface. This membrane-interacting mode of action explains why some peptide pheromones/hormones such as PlnA sometimes display antimicrobial activity in addition to their pheromone activity.

Received for publication, February 11, 2005 , and in revised form, April 1, 2005.

^* This work was supported by the Norwegian Research Council and the university funding through EMBIO. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 1YTR) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

To whom correspondence should be addressed: Dept. of Molecular Biosciences, University of Oslo, P. O. box 1041 Blindern, Oslo 0316, Norway. Tel.: 47-2285-6609; Fax: 47-2285-4443; E-mail: eugen{at}kjemi.uio.no.

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