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J. Biol. Chem., Vol. 281, Issue 43, 32089-32094, October 27, 2006

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Synergistic Transmembrane Alignment of the Antimicrobial Heterodimer PGLa/Magainin^*

Pierre Tremouilhac, Erik Strandberg, Parvesh Wadhwani, and Anne S. Ulrich¹

From the Institute for Biological Interfaces, Forschungszentrum Karlsruhe, 76344 Eggenstein-Leopoldshafen, Germany and Institute of Organic Chemistry, University of Karlsruhe, 76131 Karlsruhe, Germany

The antimicrobial activity of amphipathic -helical peptides is usually attributed to the formation of pores in bacterial membranes, but direct structural information about such a membrane-bound state is sparse. Solid state ²H-NMR has previously shown that the antimicrobial peptide PGLa undergoes a concentration-dependent realignment from a surface-bound S-state to a tilted T-state. The corresponding change in helix tilt angle from 98 to 125° was interpreted as the formation of PGLa/magainin heterodimers residing on the bilayer surface. Under no conditions so far, has an upright membrane-inserted I-state been observed in which a transmembrane helix alignment would be expected. Here, we have demonstrated that PGLa is able to assume such an I-state in a 1:1 mixture with magainin 2 at a peptide-to-lipid ratio as low as 1:100 in dimyristoylphosphatidylcholine/dimyristoylphosphatidylglycerol model membranes. This ²H-NMR analysis is based on seven orientational constraints from Ala-3,3,3-d₃ substituted in a non-perturbing manner for four native Ala residues as well as two Ile and one Gly. The observed helix tilt of 158° is rationalized by the formation of heterodimers. This structurally synergistic effect between the two related peptides from the skin of Xenopus laevis correlates very well with their known functional synergistic mode of action. To our knowledge, this example of PGLa is the first case where an -helical antimicrobial peptide is directly shown to assume a transmembrane state that is compatible with the postulated toroidal wormhole pore structure.

Received for publication, May 18, 2006 , and in revised form, July 20, 2006.

^* This work was supported in part by the Deutsche Forschungsgemeinschaft and the Centre for Functional Nanostructures. 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.

¹ To whom correspondence should be addressed: University of Karlsruhe, Inst. of Organic Chemistry, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany. Tel.: 49-721-608-3912; Fax: 49-721-608-4823; E-mail: anne.ulrich{at}ibg.fzk.de.

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