Allosteric communication pathways routed by Ca ²⁺/Mg ²⁺ exchange in GCAP1 selectively switch target regulation modes

Abstract

GCAP1 is a neuronal calcium sensor protein that regulates the phototransduction cascade in vertebrates by switching between activator and inhibitor of the target guanylate cyclase (GC) in a Ca ²⁺-dependent manner. We carried out exhaustive molecular dynamics simulations of GCAP1 and determined the intramolecular communication pathways involved in the specific GC activator/inhibitor switch. The switch was found to depend on the Mg ²⁺/Ca ²⁺ loading states of the three EF hands and on the way the information is transferred from each EF hand to specific residues at the GCAP1/GC interface. Post-translational myristoylation is fundamental to mediate long range allosteric interactions including the EF2-EF4 coupling and the communication between EF4 and the GC binding interface. Some hubs in the identified protein network are the target of retinal dystrophy mutations, suggesting that the lack of complete inhibition of GC observed in many cases is likely due to the perturbation of intra/intermolecular communication routes.