Structural Basis for the Activation of Anthrax Adenylyl Cyclase Exotoxin by Calmodulin

• NCJ Number: 192923
• Journal: Nature Volume: 415 Dated: January 24, 2002 Pages: 396-402
• Author(s): Chester L. Drum; Shui-Zhong Yan; Joe1 Bard; Yue-Quan Shen; Dan Lu; Sandriyana Soelaiman; Zenon Grabarek; Andrew Bohm; Wei-Jen Tang
• Date Published: 2002
• Length: 7 pages
• Publication Format: Article
• Publication Type: Research Paper
• Language: English
• Country: United States of America
• Note: Downloaded January 30, 2002

Annotation

This article examines the structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin.

Abstract

A number of infectious diseases increase the concentration of cyclic AMP in infected host cells, which disrupt intracellular signaling pathways. While some bacteria achieve this through the chemical modification of heterotrimeric G proteins, three bacteria, Bacilllus anthracis (anthrax), Bordetella pertussis (whooping cough), and Pseudomonas aeruginosa (various nosocomial infections), increase cAMP concentrations by producing exotoxins with adenylyl cyclase activity. Oedema factor (EF), the exotoxin from B. anthracis, is transported to host cells by an anthrax-derived transporter, protective antigen. In conjunction with lethal factor, another transported anthrax toxin that proteolytically inactivates mitogen-activated protein kinase kinase, EF contributes significantly to cutaneous and systematic anthrax. EF is activated by calmodulin (CaM), which is naturally present in host cells. This article reports the 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° 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. References