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J. Biol. Chem., Vol. 283, Issue 8, 5195-5207, February 22, 2008

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The Surfactant Peptide KL₄ in Lipid Monolayers

PHASE BEHAVIOR, TOPOGRAPHY, AND CHEMICAL DISTRIBUTION^*

Mohammed Saleem, Michaela C. Meyer, Daniel Breitenstein, and Hans-Joachim Galla¹

From the Institute of Biochemistry, University of Muenster, Muenster 48149, Germany and Tascon GmbH, Muenster 48149, Germany

Studies of different fragments and mutants of SP-B suggest that the function related structural and compositional characteristics in SP-B are its positive charges with intermittent hydrophobic domains. KL₄ ([lysine-(leucine)₄]₄-lysine) is a synthetic peptide based on SP-B structure and is the major constituent of Surfaxin®, a potential therapeutic agent for respiratory distress syndrome in premature infants. There is, however, no clear understanding about the possible lipid-KL₄ interactions behind its function, which is an inevitable knowledge to design improved therapeutic agents. To examine the phase behavior, topography, and lipid specificity of KL₄/lipid systems, we aimed to study different surfactant model systems containing KL₄, neutral dipalmitoylphosphatidylcholine (DPPC) and/or negatively charged dipalmitoylphosphatidylglycerol (DPPG) in the presence of Ca²⁺ ions. Surface pressure-area isotherms, fluorescence microscopic images, scanning force microscopy as well as time-of-flight secondary ion mass spectrometry suggest (i) that KL₄ is not miscible with DPPC and therefore forms peptide aggregates in DPPC/KL₄ mixtures; (ii) that KL₄ specifically interacts with DPPG via electrostatic interactions and induces percolation of DPPG-rich phases; (iii) that existing DPPG-Ca²⁺ interactions are too strong to be overcome by KL₄, the reason why the peptide remains excluded from condensed DPPG domains and passively colocalizes with DPPC in a demixed fluid phase; and (iv) that the presence of negatively charged lipid is necessary for the formation of bilayer protrusions. These results indicate that the capability of the peptide to induce the formation of a defined surface-confined reservoir depends on the lipid environment, especially on the presence of anionic lipids.

Received for publication, July 20, 2007 , and in revised form, December 18, 2007.

^* This work was supported by the North-Rhine Westfalian Graduate School of Chemistry (to M. S.) and the Deutsche Forschungsgemeinschaft (DFG) as a contribution from Sonderforschungsbereich 424/B9 (to H. J. G.). 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: Institute of Biochemistry, University of Muenster, Wilhelm-Klemm-Str. 2, 48149 Muenster, Germany. Tel.: 49-251-8333200; Fax: 49-251-8333206; E-mail: gallah{at}unimuenster.de.

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