The structure of human beta-defensin-2 shows evidence of higher order oligomerization

Defensins are small cationic peptides that are crucial components of innate immunity, serving as both antimicrobial agents and chemoattractant molecul es. The specific mechanism of antimicrobial activity involves permeabilizat ion of bacterial membranes. It has been postulated that individual monomers oligomerize to form a pore through anionic membranes, although the evidenc e is only indirect. Here, we report two high resolution x-ray structures of human beta -defensin-2 (hBD2). The phases were experimentally determined b y the multiwavelength anomalous diffraction method, utilizing a novel, rapi d method of derivatization with halide ions. Although the shape and charge distribution of the monomer are similar to those of other defensins, an add itional alpha -helical region makes this protein topologically distinct fro m the mammalian alpha- and beta -defensin structures reported previously. h BD2 forms dimers topologically distinct from that of human neutrophil pepti de-3. The quaternary octameric arrangement of hBD2 is conserved in two crys tal forms. These structures provide the first detailed description of dimer ization of beta -defensins, and we postulate that the mode of dimerization of hBD2 is representative of other beta -defensins. The structural and elec trostatic properties of the hBD2 octamer support an electrostatic charge-ba sed mechanism of membrane permeabilization by beta -defensins, rather than a mechanism based on formation of bilayer-spanning pores.