title: Human β-defensin 3 contains an oncolytic motif that binds PI(4,5)P2 to mediate tumour cell permeabilisation.
abstract: Cationic antimicrobial peptides (CAPs), including taxonomically diverse defensins, are innate defense molecules that display potent antimicrobial and immunomodulatory activities. Specific CAPs have also been shown to possess anticancer activities; however, their mechanisms of action are not well defined. Recently, the plant defensin NaD1 was shown to induce tumour cell lysis by directly binding to the plasma membrane phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). The NaD1-lipid interaction was structurally defined by X-ray crystallography, with the defensin forming a dimer that binds PI(4,5)P2 via its cationic β2-β3 loops in a 'cationic grip' conformation. In this study, we show that human β-defensin 3 (HBD-3) contains a homologous β2-β3 loop that binds phosphoinositides. The binding of HBD-3 to PI(4,5)P2 was shown to be critical for mediating cytolysis of tumour cells, suggesting a conserved mechanism of action for defensins across diverse species. These data not only identify an evolutionary conservation of CAP structure and function for lipid binding, but also suggest that PIP-binding CAPs could be exploited for novel multifunction therapeutics.
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
authors.forename: Thanh Kha
authors.initials: TK
authors.lastname: Phan
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
authors.forename: Fung T
authors.initials: FT
authors.lastname: Lay
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
authors.forename: Ivan K H
authors.initials: IK
authors.lastname: Poon
authors.affiliation: Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Hinds
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
authors.forename: Marc
authors.initials: M
authors.lastname: Kvansakul
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Hulett
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D017209:Apoptosis; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism*; D002463:Cell Membrane Permeability; D049109:Cell Proliferation; D005434:Flow Cytometry; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014407:Tumor Cells, Cultured; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism*
chemical_list: C422950:DEFB103A protein, human; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D023083:beta-Defensins; D000255:Adenosine Triphosphate
keywords: HBD-3; PI(4,5)P2; defensin; necrosis; tumour cell lysis