Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin

• Published in: Nature (London) Vol. 415; no. 6870; pp. 396 - 402
• Main Authors: Tang, Wei-Jen, Drum, Chester L, Yan, Shui-Zhong, Bard, Joel, Shen, Yue-Quan, Lu, Dan, Soelaiman, Sandriyana, Grabarek, Zenon, Bohm, Andrew
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 24.01.2002; Nature Publishing Group
• Subjects: Adenylyl Cyclases - chemistry; Adenylyl Cyclases - metabolism; Amino Acid Sequence; Animals; Anthrax; Antigens, Bacterial; Bacillus anthracis; Bacillus anthracis - enzymology; Bacterial Toxins; Bacteriology; Biological and medical sciences; Calmodulin - chemistry; Calmodulin - pharmacology; Catalysis; Catalytic Domain; Crystallography, X-Ray; edema factor; Enzyme Activation; Exotoxins - chemistry; Exotoxins - metabolism; Fundamental and applied biological sciences. Psychology; Humans; Ions; Macromolecular Substances; Mammals; Metal ions; Microbiology; Models, Molecular; Molecular Sequence Data; Pathogenicity, virulence, toxins, bacteriocins, pyrogens, host-bacteria relations, miscellaneous strains; Peptides; Protein Binding; Protein Conformation; Proteins; Structure-Activity Relationship; Toxicity; X-rays; Bacillus anthracis; Calcium; Enzyme; Phosphorus-oxygen lyases; Lyases; Activation; Bacillaceae; Binding protein; Adenylate cyclase; Toxin; Bacillales; Bacteria; Property structure relationship; Calmodulin
• DOI: 10.1038/415396a
• ISSN: 0028-0836

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.