Bordetella adenylate cyclase toxin: a swift saboteur of host defense

Allosteric Activation of Bordetella pertussis Adenylyl Cyclase by Calmodulin

“…) was decreased significantly compared with the wild-type AC (ϳ15% of the wild type turnover), and its affinity for CaM (K1 ⁄ 2 CaM of 26 nM) was reduced by more than 200 times. These data indicate that the separate single (N347A) and dual (R338A and D360A) modifications had limited effects on the catalytic and CaM-binding properties of AC, whereas their combination in a single enzyme (ACm3A) had strong synergistic effects on both the enzymatic activity and the affinity for CaM.…”

“…The adenylyl cyclase toxin (CyaA) from Bordetella pertussis, the causative agent of whooping cough, plays an essential role in host invasion (1)(2)(3). CyaA is able to invade eukaryotic target cells, where it is activated by interacting with calmodulin (CaM), 5 thereby overproducing cAMP, which disorganizes cellular signaling processes and triggers host cell death (4 -12).…”

Bordetella pertussis adenylate cyclase toxin translocation across a tethered lipid bilayer

“…The adenylate cyclase toxin (CyaA) produced by Bordetella pertussis, the causative agent of whooping cough, is one of the few known toxins able to invade eukaryotic cells through a mechanism of direct translocation across the plasma membrane of the target cells (11)(12)(13). CyaA is an essential virulence factor of B. pertussis that is secreted by virulent bacteria and able to enter into eukaryotic cells, where, on activation by endogenous calmodulin (CaM), it catalyzes high-level synthesis of cAMP, which in turn alters cellular physiology (14)(15)(16).…”

“…The C-terminal part of the molecule (RD; residues 1,000-1,706) is involved in toxin binding to a specific cellular receptor (CD11b/CD18) (22,23). This domain consists of approximately 40 copies of a calcium-binding, glycineand aspartate-rich nonapeptide repeat (residues 1,014-1,613) characteristic of a large family of bacterial cytolysins known as repeat-in-toxin (RTX) toxins (11,13,24,25).…”

“…The most unique property of CyaA is its capability to deliver its N-terminal catalytic domain directly across the plasma membrane of the eukaryotic target cells, a process that occurs independently of the CD11b/CD18 receptor (11)(12)(13). It is believed that CyaA first Significance Many bacterial toxins can cross biological membranes to reach the cytosol of mammalian cells, although how they pass through a lipid bilayer remains largely unknown.…”