Domain 4 of the anthrax protective antigen maintains structure and binding to the host receptor CMG2 at low pH

Domain 4 of the anthrax protective antigen (PA) plays a key role in cellular receptor recognition as well as in pH‐dependent pore formation. We present here the 1.95 Å crystal structure of domain 4, which adopts a fold that is identical to that observed in the full‐length protein. We have also investigated the structural properties of the isolated domain 4 as a function of pH, as well as the pH‐dependence on binding to the von Willebrand factor A domain of capillary morphogenesis protein 2 (CMG2). Our results provide evidence that the isolated domain 4 maintains structure and interactions with CMG2 at pH 5, a pH that is known to cause release of the receptor on conversion of the heptameric prepore (PA₆₃)₇ to a membrane‐spanning pore. Our results suggest that receptor release is not driven solely by a pH‐induced unfolding of domain 4.