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 Ca2+-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 Mg2+/Ca2+ 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.
Highlights
Conformational changes adopted by calcium-sensor proteins in response to Ca2+-binding allow them to selectively recognize and regulate their targets, thereby contributing to the control of several biological processes[1]
We present a thorough structural analysis of both myristoylated and nonmyristoylated GCAP1 based on exhaustive Molecular Dynamics (MD) simulations that unveiled intramolecular communication pathways involved in the specific switch between guanylate cyclase (GC) activator/inhibitor states
Understanding the mechanism by which relatively small protein conformational changes result in such diverse biochemical properties is not trivial, and yet it would be crucial to shed light on the molecular basis of some inherited retinal diseases caused by the deregulation of second messenger homeostasis in photoreceptors
Summary
Conformational changes adopted by calcium-sensor proteins in response to Ca2+-binding allow them to selectively recognize and regulate their targets, thereby contributing to the control of several biological processes[1]. Other Ca2+-sensors, are selectively expressed in specific cell types and regulate only a few, sometimes even unique biological targets. This is the case for the neuronal calcium sensors (NCS) family[4,5]. Guanylate cyclase activating proteins (GCAPs) are NCS involved in the early steps of vertebrate vision, which shape the photoresponse of rods and cones under different light conditions, contributing to the second messenger-controlled recovery of the phototransduction machinery following light stimulation[6]. A dynamic connection between the myristoyl moiety and EF4 was proposed, which implies a finely regulated allosteric communication between the N and C domains of GCAP1, the mechanism by which Mg2+/ Ca2+ exchange determines the fate of GCAP1 as a Ca2+ sensor and GC-regulator remains largely unknown
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