Figure 7.

Steps in PDE-mediated cAMP signal termination pathway. (A) cAMP binding at CNB:A of R_D (in gray surface representation) results in an allosteric relay (green arrow) that stabilizes structural transitions in CNB:B. This presents an interaction interface for RegA (green surface representation) binding. (B) In the first step of the cAMP termination pathway, with high local cAMP (in yellow spheres) concentrations, R_D and RegA form a stable catalytic complex. cAMP from the local environment binds at the R_D CNB:B cAMP binding pocket and subsequently is channeled into the active site of RegA, as an example for substrate channeling in a signaling complex. (C) Once free cAMP is depleted by substrate channeling, RegA and R_D form transient complexes (indicated by the black arrow). RegA binding also results in an allosteric relay (red arrow) that results in dissociation of cAMP from CNB:A. Thus RegA hydrolyzes all cAMP bound to the receptor and results in apo R_D. (D) RegA dissociates from R_D and subsequently primes R_D to reassociate with PKAC resulting in termination of the cAMP signaling pathway. RegA, cAMP, and PKAC serve to regulate R_D through unique allosteric pathways.