Phosphatidylserine lipids and membrane order precisely regulate the activity of Polybia-MP1 peptide

Author(s)

Alvares, Dayane S. ; Ruggiero Neto, Joao ; Ambroggio, Ernesto E.

• Document type: Journal article
• Source: BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES; v. 1859, n. 6, p. 1067-1074, JUN 2017.
• Web of Science Citations: 4

Abstract

Polybia-MP1 (IDWKKLLDAAKQIL-NH2) is a lytic peptide from the Brazilian wasp venom with known anti-cancer properties. Previous evidence indicates that phosphatidylserine (PS) lipids are relevant for the lytic activity of MPl. In agreement with this requirement, phosphatidylserine lipids are translocated to the outer leaflet of cells, and are available for MP1 binding, depending on the presence of liquid-ordered domains. Here, we investigated the effect of PS on MP1 activity when this lipid is reconstituted in membranes of giant or large liposomes with different lipid-phase states. By monitoring the membrane and soluble luminal content of giant unilamellar vesicles (GUVs), using fluorescence confocal microscopy, we were able to determine that MP1 has a pore forming activity at the membrane level. Liquid-ordered domains, which were phase-separated within the membrane of GUVs, influenced the pore-forming activity of MPl. Experiments evaluating the membrane-binding and lytic activity of MP1 on large unilamellar vesicles (LUVs), with the same lipid composition as GUVs, demonstrated that there was synergy between liquid-ordered domains and PS, which enhanced both activities. Based on our findings, we propose that the physicochemical properties of cancer cell membranes, which possess a much higher concentration of PS than normal cells, renders them susceptible to MP1 binding and lytic pore formation. These results can be correlated with MP1's potent and selective anti-cancer activity and pave the way for future research to develop cancer therapies that harness and exploit the properties of MP1. (C) 2017 Elsevier B.V. All rights reserved. (AU)

• FAPESP's process: 11/51684-1 - System biology as experimental strategy for discovery of novel natural products in the fauna of venomous arthropods from São Paulo State
• Grantee: Mario Sergio Palma
• Support type: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 11/11640-5 - Interaction of lytic peptides and model membranes: intefacial action and induction of lipid domains
• Grantee: João Ruggiero Neto
• Support type: Regular Research Grants
• FAPESP's process: 12/08147-8 - Study of domains formation in model membranes induced by antimicrobial peptides and their action interfacial
• Grantee: Dayane dos Santos Alvares
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/25619-9 - Effect of aminophospholipids and of the pH on the interfacial activity of the anticancer peptide Polybia-MP1 and analogs in model membranes
• Grantee: João Ruggiero Neto
• Support type: Regular Research Grants
• FAPESP's process: 15/25620-7 - Interaction membrane/peptide: mechanical and electrostatic properties in system with lipid domains
• Grantee: Dayane dos Santos Alvares
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 15/01508-3 - Interaction of the antimicrobial and antitumor peptide, Polybia-MP1, with lipid-domains
• Grantee: Dayane dos Santos Alvares
• Support type: Scholarships abroad - Research Internship - Doctorate