Structural Insights into Retinal Guanylate Cyclase Activator Proteins (GCAPs)

Retinal guanylate cyclases (RetGCs) promote the Ca(2+)-dependent synthesis of cGMP that coordinates the recovery phase of visual phototransduction in retinal rods and cones. The Ca(2+)-sensitive activation of RetGCs is controlled by a family of photoreceptor Ca(2+) binding proteins known as guanylate cyclase activator proteins (GCAPs). The Mg(2+)-bound/Ca(2+)-free GCAPs bind to RetGCs and activate cGMP synthesis (cyclase activity) at low cytosolic Ca(2+) levels in light-activated photoreceptors. By contrast, Ca(2+)-bound GCAPs bind to RetGCs and inactivate cyclase activity at high cytosolic Ca(2+) levels found in dark-adapted photoreceptors. Mutations in both RetGCs and GCAPs that disrupt the Ca(2+)-dependent cyclase activity are genetically linked to various retinal diseases known as cone-rod dystrophies. In this review, I will provide an overview of the known atomic-level structures of various GCAP proteins to understand how protein dimerization and Ca(2+)-dependent conformational changes in GCAPs control the cyclase activity of RetGCs. This review will also summarize recent structural studies on a GCAP homolog from zebrafish (GCAP5) that binds to Fe(2+) and may serve as a Fe(2+) sensor in photoreceptors. The GCAP structures reveal an exposed hydrophobic surface that controls both GCAP1 dimerization and RetGC binding. This exposed site could be targeted by therapeutics designed to inhibit the GCAP1 disease mutants, which may serve to mitigate the onset of retinal cone-rod dystrophies.