title: Evidence that clustered phosphocholine head groups serve as sites for binding and assembly of an oligomeric protein pore.
abstract: High susceptibility of rabbit erythrocytes toward the pore-forming action of staphylococcal alpha-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 alpha-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.
authors.affiliation: Institute of Medical Microbiology and Hygiene, Hochhaus am Augustusplatz, D-55101 Mainz, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Valeva
authors.forename: Nadja
authors.initials: N
authors.lastname: Hellmann
authors.forename: Iwan
authors.initials: I
authors.lastname: Walev
authors.forename: Dennis
authors.initials: D
authors.lastname: Strand
authors.forename: Markus
authors.initials: M
authors.lastname: Plate
authors.forename: Fatima
authors.initials: F
authors.lastname: Boukhallouk
authors.forename: Antje
authors.initials: A
authors.lastname: Brack
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hanada
authors.forename: Heinz
authors.initials: H
authors.lastname: Decker
authors.forename: Sucharit
authors.initials: S
authors.lastname: Bhakdi
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004912:Erythrocytes / Q000737:chemistry / Q000166:cytology; D006460:Hemolysin Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism; D010767:Phosphorylcholine / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011817:Rabbits; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000737:chemistry / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D008081:Liposomes; D013109:Sphingomyelins; C021091:staphylococcal alpha-toxin; D010767:Phosphorylcholine; D002784:Cholesterol; D013108:Sphingomyelin Phosphodiesterase