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The host-defense peptide piscidin P1 reorganizes lipid domains in membranes and decreases activation energies in mechanosensitive ion channels.

Abstract

The 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 α-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.

Authors+Show Affiliations

Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, United States.Department of Applied Science, College of William and Mary, Williamsburg, VA 23185, United States.Biology Department, University of Maryland, College Park, MD 20742, United States.Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, United States.Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, United States.Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, United States.Department of Biochemistry and Molecular Biology, Johns Hopkins University, Baltimore, MD 21205, United States.Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, United States.National High Magnetic Field Laboratory, Tallahassee, United States.Ohio University, Department of Biomedical Sciences, Athens, OH 45701, United States.Ohio University, Department of Biomedical Sciences, Athens, OH 45701, United States.Biology, University of Maryland, United States.College of William and Mary, United States.Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31619519

Citation

Comert, Fatih, et al. "The Host-defense Peptide Piscidin P1 Reorganizes Lipid Domains in Membranes and Decreases Activation Energies in Mechanosensitive Ion Channels." The Journal of Biological Chemistry, 2019.
Comert F, Greenwood A, Maramba J, et al. The host-defense peptide piscidin P1 reorganizes lipid domains in membranes and decreases activation energies in mechanosensitive ion channels. J Biol Chem. 2019.
Comert, F., Greenwood, A., Maramba, J., Acevedo, R., Lucas, L., Kulasinghe, T., ... Mihailescu, M. (2019). The host-defense peptide piscidin P1 reorganizes lipid domains in membranes and decreases activation energies in mechanosensitive ion channels. The Journal of Biological Chemistry, doi:10.1074/jbc.RA119.010232.
Comert F, et al. The Host-defense Peptide Piscidin P1 Reorganizes Lipid Domains in Membranes and Decreases Activation Energies in Mechanosensitive Ion Channels. J Biol Chem. 2019 Oct 16; PubMed PMID: 31619519.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The host-defense peptide piscidin P1 reorganizes lipid domains in membranes and decreases activation energies in mechanosensitive ion channels. AU - Comert,Fatih, AU - Greenwood,Alexander, AU - Maramba,Joseph, AU - Acevedo,Roderico, AU - Lucas,Laura, AU - Kulasinghe,Thulasi, AU - Cairns,Leah S, AU - Wen,Yi, AU - Fu,Riqiang, AU - Hammer,Janet, AU - Blazyk,Jack, AU - Sukharev,Sergei, AU - Cotten,Myriam L, AU - Mihailescu,Mihaela, Y1 - 2019/10/16/ PY - 2019/10/16/accepted PY - 2019/07/17/received PY - 2019/10/18/entrez KW - MscL KW - MscS KW - antibiotic KW - host defense KW - ion channel KW - lipid bilayer KW - neutron diffraction KW - patch clamp KW - piscidin KW - solid state NMR JF - The Journal of biological chemistry JO - J. Biol. Chem. N2 - The 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 α-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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/31619519/The_host-defense_peptide_piscidin_P1_reorganizes_lipid_domains_in_membranes_and_decreases_activation_energies_in_mechanosensitive_ion_channels L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=31619519 DB - PRIME DP - Unbound Medicine ER -