6pf0 | pdb_00006pf0
SOLID-STATE NMR STRUCTURE OF PISCIDIN 1 IN ALIGNED 4:1 PHOSPHATIDYLCHOLINE/CHOLESTEROL LIPID BILAYERS
Structural highlights
FunctionMORO_MORSA Exhibits broad spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria as well as against a variety of fungi. Has hemolytic activity. Seems to disrupt the membranes by adopting an alpha helical conformation and forming toroidal pores.[1] [2] Publication Abstract from PubMedThe host-defense peptide (HDP) piscidin 1 (P1), isolated from the mast cells of striped bass, has potent activities against bacteria, viruses, fungi, and cancer cells and also can modulate the activity of membrane receptors. Given its broad pharmacological potential, here we used several approaches to better understand its interactions with multicomponent bilayers representing models of bacterial (phosphatidyl-ethanolamine/phosphatidylglycerol [PE/PG]) and mammalian (phosphatidyl-choline/cholesterol [PC/Chol]) membranes. Using solid-state NMR, we solved the structure of P1 bound to PC/Chol and compared it with that of P3, a less potent homolog. The comparison disclosed that although both peptides are interfacially bound and alpha-helical, they differ in bilayer orientations and depths of insertion, and these differences depended on bilayer composition. Although Chol is thought to make mammalian membranes less susceptible to HDP-mediated destabilization, we found that Chol does not affect the permeabilization effects of P1. X-ray diffraction experiments revealed that both piscidins produce a demixing effect in PC/Chol membranes by increasing the fraction of the Chol-depleted phase. Furthermore, P1 increased the temperature required for the lamellar-to-hexagonal phase transition in PE bilayers, suggesting that it imposes a positive membrane curvature. Patch-clamp measurements on the inner Escherichia coli membrane showed that P1 and P3 at concentrations sufficient for their antimicrobial activity substantially decrease the activating tension for bacterial mechanosensitive channels. This indicated that piscidins can cause lipid redistribution and restructuring in the microenvironment near proteins. We conclude that the mechanism of piscidin's antimicrobial activity extends beyond simple membrane destabilization, helping to rationalize its broader spectrum of pharmacological effects. The host-defense peptide piscidin P1 reorganizes lipid domains in membranes and decreases activation energies in mechanosensitive ion channels.,Comert F, Greenwood A, Maramba J, Acevedo R, Lucas L, Kulasinghe T, Cairns LS, Wen Y, Fu R, Hammer J, Blazyk J, Sukharev S, Cotten ML, Mihailescu M J Biol Chem. 2019 Oct 16. pii: RA119.010232. doi: 10.1074/jbc.RA119.010232. PMID:31619519[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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