Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin.
Oedema factor, a calmodulin-activated adenylyl cyclase, is important in the pathogenesis of anthrax. Here we report the X-ray structures of oedema factor with and without bound calmodulin. Oedema factor shares no significant structural homology with mammalian adenylyl cyclases or other proteins. In the active site, 3'-deoxy-ATP and a single metal ion are well positioned for catalysis with histidine 351 as the catalytic base. This mechanism differs from the mechanism of two-metal-ion catalysis proposed for mammalian adenylyl cyclases. Four discrete regions of oedema factor form a surface that recognizes an extended conformation of calmodulin, which is very different from the collapsed conformation observed in other structures of calmodulin bound to effector peptides. On calmodulin binding, an oedema factor helical domain of relative molecular mass 15,000 undergoes a 15 A translation and a 30 degrees rotation away from the oedema factor catalytic core, which stabilizes a disordered loop and leads to enzyme activation. These allosteric changes provide the first molecular details of how calmodulin modulates one of its targets.
Drum
Chester L
CL
Ben-May Institute for Cancer Research, The University of Chicago, 924 East 57th Street, Chicago, Illinois 60637, USA.
Yan
Shui-Zhong
SZ
Bard
Joel
J
Shen
Yue-Quan
YQ
Lu
Dan
D
Soelaiman
Sandriyana
S
Grabarek
Zenon
Z
Bohm
Andrew
A
Tang
Wei-Jen
WJ
D000262:Adenylyl Cyclases / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000201:enzymology*; D001427:Bacterial Toxins; D002147:Calmodulin / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D005098:Exotoxins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002147:Calmodulin; D005098:Exotoxins; D046911:Macromolecular Substances; C030325:anthrax toxin; D000262:Adenylyl Cyclases