title: Structural basis for the interaction of Bordetella pertussis adenylyl cyclase toxin with calmodulin.
abstract: CyaA is crucial for colonization by Bordetella pertussis, the etiologic agent of whooping cough. Here we report crystal structures of the adenylyl cyclase domain (ACD) of CyaA with the C-terminal domain of calmodulin. Four discrete regions of CyaA bind calcium-loaded calmodulin with a large buried contact surface. Of those, a tryptophan residue (W242) at an alpha-helix of CyaA makes extensive contacts with the calcium-induced, hydrophobic pocket of calmodulin. Mutagenic analyses show that all four regions of CyaA contribute to calmodulin binding and the calmodulin-induced conformational change of CyaA is crucial for catalytic activation. A crystal structure of CyaA-calmodulin with adefovir diphosphate, the metabolite of an approved antiviral drug, reveals the location of catalytic site of CyaA and how adefovir diphosphate tightly binds CyaA. The ACD of CyaA shares a similar structure and mechanism of activation with anthrax edema factor (EF). However, the interactions of CyaA with calmodulin completely diverge from those of EF. This provides molecular details of how two structurally homologous bacterial toxins evolved divergently to bind calmodulin, an evolutionarily conserved calcium sensor.
authors.affiliation: Ben-May Institute for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Guo
authors.forename: Yuequan
authors.initials: Y
authors.lastname: Shen
authors.forename: Young-Sam
authors.initials: YS
authors.lastname: Lee
authors.forename: Craig S
authors.initials: CS
authors.lastname: Gibbs
authors.forename: Milan
authors.initials: M
authors.lastname: Mrksich
authors.forename: Wei-Jen
authors.initials: WJ
authors.lastname: Tang
mesh_terms: D037361:Adenylate Cyclase Toxin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001886:Bordetella pertussis / Q000201:enzymology* / Q000235:genetics; D002147:Calmodulin / Q000737:chemistry* / Q000378:metabolism*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009711:Nucleotides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D014757:Viper Venoms / Q000737:chemistry / Q000378:metabolism
chemical_list: D037361:Adenylate Cyclase Toxin; D002147:Calmodulin; D009711:Nucleotides; D014757:Viper Venoms; C416405:edema factor