Binding of phosphatidic acid by NsD7 mediates the formation of helical defensin-lipid oligomeric assemblies and membrane permeabilization

Direct attack of target cell membranes by protein oligomerization is a powerful innate defense mechanism used widely throughout nature. Defensins are ubiquitous innate immunity mediators that are able to recognize certain phospholipids, and subsequently oligomerize to attack target cell membranes. We now show that the plant defensin NsD7 is able to bind the cellular phospholipid, phosphatidic acid (PA), which triggers defensin oligomerization in a unique manner. Our crystal structure of the NsD7-PA oligomer revealed a striking double-helical defensin-lipid oligomer that features a novel phospholipid-binding site mediating PA binding and membrane permeabilization. This demonstrates that defensins use their conserved small fold in a remarkably flexible way to specifically recognize a range of phospholipids during innate defense using different binding sites.