Abstract
Retinal guanylate cyclases (RetGCs) promote the Ca2+-dependent synthesis of cGMP that coordinates the recovery phase of visual phototransduction in retinal rods and cones. The Ca2+-sensitive activation of RetGCs is controlled by a family of photoreceptor Ca2+ binding proteins known as guanylate cyclase activator proteins (GCAPs). The Mg2+-bound/Ca2+-free GCAPs bind to RetGCs and activate cGMP synthesis (cyclase activity) at low cytosolic Ca2+ levels in light-activated photoreceptors. By contrast, Ca2+-bound GCAPs bind to RetGCs and inactivate cyclase activity at high cytosolic Ca2+ levels found in dark-adapted photoreceptors. Mutations in both RetGCs and GCAPs that disrupt the Ca2+-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 Ca2+-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 Fe2+ and may serve as a Fe2+ 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.
Highlights
I will provide an overview of the known atomic-level structures of various guanylate cyclase activator proteins (GCAPs) proteins to understand how protein dimerization and Ca2+ dependent conformational changes in GCAPs control the cyclase activity of retina-specific guanylate cyclases (RetGCs)
Visual excitation of retinal rod and cone photoreceptors is triggered by a phototransduction cascade in which light excitation activates a photoreceptor-specific phosphodiesterase that in turn hydrolyzes cGMP
The Ca2+ -dependent activity of RetGC is controlled by intracellular domains [10,11] that interact with soluble EF-hand Ca2+ sensor proteins, called guanylate cyclase activator proteins (GCAP1-5, see Figure 1) [8,12,13,14,15,16]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. A photoreceptor cell exhibits a more than 10-fold increase in cGMP production due to the Ca2+ -sensitive activation of RetGC by GCAPs [5,22]. At least one Mg binds to GCAP1 in the activatorthan state [26], 2+-sensitive activation of RetGC by GCAPs increase in cGMP production due to the and NMR studies reveal that Mg is bound to GCAP1 at the second EF-hand (EF2 in 2+ -free). In light-adapted rods, GCAPs are bound to free its protein structure to promote activation of RetGC [8,25,30]. In. GCAP1 (in place of Mg binding) stabilizes a distinct structure important for the inhibiphotoreceptors turn on thebinds synthesis of cGMP to help restore theand dark-adapted photoreception of RetGC [21]. 500 nM [18], which implies that GCAPs are nearly saturated with Ca2+ in dark-adapted
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