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Discoupling the Ca 2+ -activation from the pore-forming function of the bi-component Panton-Valentine leucocidin in human PMNs

Abstract : The consecutive cell activation, including Ca 2+-channel opening, and pore formation leading to human neutrophil lysis were the two functions of the staphylococcal Panton-Valentine leucocidin attempted to be discoupled by site-directed mutagenesis. In a first approach consisting in deletions of the cytoplasmic extremity of the transmembranous domain, we produced a LukF-PV v vSer125-Leu128 with a slightly reduced Ca 2+ induction but with a significantly lowered lytic activity when combined with its synergistic protein LukS-PV. The second approach consisted in the modification of charges and/or introduction of a steric hindrance inside the pore, which also led to interesting mutated proteins: LukF-PV G131D, G131W and G130D. The latter had an intact Ca 2+ induction ability while the lytic one was 20-fold diminished. Binding properties and intrinsic pore diameters of these discoupled toxins remained comparable to the wild-type protein. The mutated proteins promoted interleukin-8 secretion, but they were rather inactive in an experimental model. New insights are brought concerning the role of the two functions in the virulence of this bi-component leucotoxin.
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L. Baba Moussa, S. Werner, D.A. Colin, L. Mourey, J.D. Pëdelacq, et al.. Discoupling the Ca 2+ -activation from the pore-forming function of the bi-component Panton-Valentine leucocidin in human PMNs. FEBS Letters, Wiley, 1999, 461 (3), pp.280-286. ⟨10.1016/s0014-5793(99)01453-2⟩. ⟨hal-03004456⟩

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