Structural basis of retinal membrane guanylate cyclase regulation by GCAP1 and RD3

Abstract

Retinal membrane guanylate cyclases (RetGC1 and RetGC2) are expressed in photoreceptor rod and cone cells, where they promote the onset of visual recovery during phototransduction. The catalytic activity of RetGCs is regulated by their binding to regulatory proteins, guanylate cyclase activating proteins (GCAP1-5) and the retinal degeneration 3 protein (RD3). RetGC1 is activated by its binding to Ca2+-free/Mg2+-bound GCAP1 at low cytosolic Ca2+ levels in light-activated photoreceptors. By contrast, RetGC1 is inactivated by its binding to Ca2+-bound GCAP1 and/or RD3 at elevated Ca2+ levels in dark-adapted photoreceptors. The Ca2+ sensitive cyclase activation helps to replenish the cytosolic cGMP levels in photoreceptors during visual recovery. Mutations in RetGC1, GCAP1 or RD3 that disable the Ca2+-dependent regulation of cyclase activity are genetically linked to rod/cone dystrophies and other inherited forms of blindness. Here I review the structural interaction of RetGC1 with GCAP1 and RD3. I propose a two-state concerted model in which the dimeric RetGC1 allosterically switches between active and inactive conformational states with distinct quaternary structures that are oppositely stabilized by the binding of GCAP1 and RD3. The binding of Ca2+-free/Mg2+-bound GCAP1 is proposed to activate the cyclase by stabilizing RetGC1 in an active conformation (R-state), whereas Ca2+-bound GCAP1 and/or RD3 inhibit the cyclase by locking RetGC1 in an inactive conformation (T-state). Exposed hydrophobic residues in GCAP1 (residues H19, Y22, M26, F73, V77, W94) are essential for cyclase activation and could be targeted by rational drug design for the possible treatment of rod/cone dystrophies.

Chemical shift assignments of retinal guanylyl cyclase activating protein 5 (GCAP5) with a mutation (R22A) that abolishes dimerization and enhances cyclase activation

“…The GCAP5 mutations H18E, M25E and V76E each abolish GCAP5 dimerization and prevent activation of RetGC (Cudia et al 2021 ). These results suggested that GCAP5 dimerization might be essential for RetGC activation (Ames 2021 , 2022 ). However, this hypothesis was refuted by the discovery that the R22A mutation of GCAP5 not only abolishes GCAP5 dimerization but also causes a 300% increase in RetGC activation compared to that of wild type (Cudia et al 2021 ).…”

Clinicopathological characteristics of pheochromocytoma/paraganglioma and screening of prognostic markers

“…And also, NRXN3 is involved in the regulation of tumor proliferation, migration and invasion 25 . The RD3 encodes a retinal protein, which is associated with eye disease 26 . As a protein‐coding gene, SPOCK3 is related to the extracellular matrix organization and integrin pathway.…”

“…25 The RD3 encodes a retinal protein, which is associated with eye disease. 26 As a protein-coding gene, SPOCK3 is related to the extracellular matrix organization and integrin pathway. It has been reported that SPOCK3…”

Retinal degeneration protein 3 mutants are associated with cell-cycle arrest and apoptosis

“…A Nuclear Magnetic Resonance (NMR) spectroscopy study indicated that RD3 folds into a three-dimensional structure of a four-helix bundle showing the following arrangement: helix α1: P21-V51; α2: P75-K87; α3: P90-Q107; α4: V111-T139. Point mutations in the central helix α3 of RD3 weaken the RD3 affinity for GC-E [1,7,8]. Genetic deficiencies and mutations of RD3 cause early-onset photoreceptor degeneration in patients with Leber congenital amaurosis type 12 (LCA 12) [4,5,9,10,11].…”