Defensin-lipid interactions in membrane targeting: novel insights into mechanisms of action and therapeutic potential — ASN Events
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  2. SESSION 11: Antiinfectives
  3. Defensin-lipid interactions in membrane targeting: novel insights into mechanisms of action and therapeutic potential

Defensin-lipid interactions in membrane targeting: novel insights into mechanisms of action and therapeutic potential (#60)

Mark D Hulett 1 , Fung T Lay 1 , Scott A Williams 1 , Matthew J Hein 1 , Guneet Bindra 1 , Serenay Demir 1 , Michael Jarva 1 , Kha T Phan 1 , Amy A Baxter 1 , Ivan KH Poon 1 , Marc Kvansakul 1
  1. Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, Bundoora, VIC, Australia

Defensins are an extensive family of host defence peptides found ubiquitously across plant and animal species. In addition to protecting against infection by pathogenic microorganisms, defensins often harbour selective cytotoxicity towards tumour cells. Like many host defence peptides, defensins act at the plasma membrane of cells leading to membrane destabilisation and permeabilisation. We have defined a novel cell lysis mechanism for fungal and tumour cells by plant and human defensins that act via specific recognition membrane phospholipids such as phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid (PA). To understand the structural basis of these interactions, we determined crystal structures of the plant defensins NaD1 and NsD7 in complex with PIP2 and PA, respectively, revealing oligomeric arrangements1-3. Both NaD1 and NsD7 form dimers that cooperatively bind the anionic head groups of PIP2 or PA via unique “cationic grip” configurations and assemble into oligomeric fibrils. Site-directed mutagenesis of NaD1 and NsD7 confirms that phospholipid binding and oligomerisation are critical for fungal and tumor cell permeabilisation. Significantly, this mechanism of membrane targeting and disruption of cellular membranes by defensins is conserved across species. We have shown that the important antimicrobial human beta-defensin HBD-2 also binds PIP2 and forms membrane-disrupting oligomeric complexes4. Interestingly, we have identified that some species, such as crocodilians, have further adapted this conserved mechanism of defensin action with regulatory fine-tuning through pH-dependent cell membrane targeting5. Overall, these observations identify a conserved innate recognition system by defensins for the direct binding of specific phospholipids leading to cell permeabilisation via a novel membrane disrupting mechanism. The potential of using defensins as antimicrobial and anticancer therapeutics is attracting significant interest and these data may be useful for the engineering more effective peptides towards such applications.

  1. 1. IK Poon, AA Baxter, FT Lay…M Kvansakul M and MD Hulett, eLife 3,e01808 (2014).
  2. 2. M Kvansakul, FT Lay IK Poon and MD Hulett. Proc. Natl. Acad. Sci. USA 113,11202 (2016).
  3. 3. M Järvå, F.T. Lay…IK Poon, MD Hulett and M Kvansakul. Nat. Commun. 9,1962 (2018).
  4. 4. M Järvå, K. Phan, FT Lay, M Kvansakul and MD Hulett. Science Advances 4,eaa0979 (2018).
  5. 5. SA Williams, FT Lay…IKH Poon, TK Phan, M Kvansakul and MD Hulett. Nat. Commun. 14,1170 (2023).
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