Poster Presentation The 44th Lorne Conference on Protein Structure and Function 2019

Human β-defensin 2 kills Candida albicans through phosphatidylinositol 4,5-bisphosphate–mediated membrane permeabilization (#184)

Michael A Järvå 1 , Kha Phan Thanh 2 , Fung T Lay 2 , Sofia Caria 2 , Marc Kvansakul 2 , Mark D Hulett 2
  1. Department of Chemical Biology, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia
  2. La Trobe Institute for Molecular Science, Bundoora, Victoria, Australia

Human defensins belong to a subfamily of the cationic antimicrobial peptides and act as a first line of defense against invading microbes. Their frequent 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.

 

5bc1456723b2d-lorne+HBD2+small.png