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J. Biol. Chem., Vol. 281, Issue 36, 26014-26021, September 8, 2006

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Evidence That Clustered Phosphocholine Head Groups Serve as Sites for Binding and Assembly of an Oligomeric Protein Pore^*

Angela Valeva, Nadja Hellmann, Iwan Walev, Dennis Strand^¶, Markus Plate, Fatima Boukhallouk, Antje Brack, Kentaro Hanada^||, Heinz Decker, and Sucharit Bhakdi¹

From the Institute of Medical Microbiology and Hygiene, Hochhaus am Augustusplatz, D-55101 Mainz, Germany, the Institute of Molecular Biophysics, University of Mainz, D-55099 Mainz, Germany, the ^¶First Medical Clinic, University of Mainz, D-55101 Mainz, Germany, and the ^||Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan

High susceptibility of rabbit erythrocytes toward the poreforming action of staphylococcal -toxin correlates with the presence of saturable, high affinity binding sites. All efforts to identify a protein or glycolipid receptor have failed, and the fact that liposomes composed solely of phosphatidylcholine are efficiently permeabilized adds to the enigma. A novel concept is advanced here to explain the puzzle. We propose that low affinity binding moieties can assume the role of high affinity binding sites due to their spatial arrangement in the membrane. Evidence is presented that phosphocholine head groups of sphingomyelin, clustered in sphingomyelin-cholesterol microdomains, serve this function for -toxin. Clustering is required so that oligomerization, which is prerequisite for stable attachment of the toxin to the membrane, can efficiently occur. Outside these clusters, binding to phosphocholine is too transient for toxin monomers to find each other. The principle of membrane targeting in the absence of any genuine, high affinity receptor may also underlie the assembly of other lipid-inserted oligomers including cytotoxic peptides, protein toxins, and immune effector molecules.

Received for publication, March 1, 2006 , and in revised form, June 28, 2006.

^* This work was supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 490, and the Verband der Chemischen Industrie. 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. Tel.: 49-6131-3937341; Fax: 49-6131-3932359; E-mail: sbhakdi{at}uni-mainz.de.

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