Research ArticleMICROBIOLOGY

Human β-defensin 2 kills Candida albicans through phosphatidylinositol 4,5-bisphosphate–mediated membrane permeabilization

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Science Advances  25 Jul 2018:
Vol. 4, no. 7, eaat0979
DOI: 10.1126/sciadv.aat0979

Abstract

Human defensins belong to a subfamily of the cationic antimicrobial peptides and act as a first line of defense against invading microbes. Their often broad-spectrum antimicrobial and antitumor activities make them attractive for therapeutic development; however, their precise molecular mechanism(s) of action remains to be defined. We show that human β-defensin 2 (HBD-2) permeabilizes Candida albicans cell membranes via a mechanism targeting the plasma membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2). We determined the structure of HBD-2 bound to PIP2, which revealed two distinct PIP2-binding sites, and showed, using functional assays, that mutations in these sites ablate PIP2-mediated fungal growth inhibition by HBD-2. Our study provides the first insight into lipid-mediated human defensin membrane permeabilization at an atomic level and reveals a unique mode of lipid engagement to permeabilize cell membranes.

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