Conformational Plasticity of the Adenylyl Cyclase CyaA from Bordetella Pertussis

Conformational plasticity of the adenylyl cyclase CyaA from Bordetella pertussisThe toxin CyaA from Bordetella pertussis is activated by calmodulin (CaM), and catalyses the production of cAMP in an uncontrolled way, that will damage the host immune system. The crystallographic structure of the complex between CyaA and the C terminal domain of calmodulin (C-CaM) was determined recently (Guo et al, 2005), the structures of isolated CyaA and of CyaA/CaM being undetermined up to date. As other adenylyl cyclases (Drum et al, 2002; Laine et al, 2008), CyaA/CaM is a good example of interaction associated to conformational transitions. Besides, CyaA represents a good target for the understanding of the B. pertussis action and for the search of whopping cough inhibitors.The conformational tendencies of the isolated CyaA and of the CyaA bound to C-CaM in the presence and in the absence of Calcium, were monitored along molecular dynamics trajectories. The isolated CyaA shows an important conformational drift, in agreement with independent hydrodynamic measures. Besides, the principal component analysis of the three system dynamics, reveals a permanent kink motion of CyaA around the catalytic site, this motion being only amplified in the absence of Calcium or C-CaM. The energetic influences between complex domains (Laine et al, 2009) concern only the domains Switch A and C-CaM.Drum C.L., Yan S.Z., Bard J., Shen Y.Q., Lu D., Soelaiman S., Grabarek Z., Bohm A., Tang W.J. Nature, 415:396-402 (2002)Guo Q, Shen Y, Lee YS, Gibbs CS, Mrksich M, and Tang WJ. The EMBO Journal. 24,3190-3201 (2005)Laine E., Yoneda J.D., Blondel A. and Malliavin T.E. Proteins, 71:1813-29 (2008)Laine E., Blondel A. and Malliavin T.E. Biophysical J., 96:1249-63 (2009)