Activation mechanism of photoreceptor membrane-bound Guanylate Cyclase

Photoreceptor guanylate cyclase-E (GC-E) is regulated by GCAP proteins that sense intracellular calcium changes and adjust cGMP synthesis during light adaptation. Mutations that disturb this regulatory loop can cause inherited retinal disease, yet the molecular steps that guide GC-E into its active state remain unclear. In this work I combined biochemical assays with computational modelling to examine the conformational changes underlying activation. The data argue against a helical rotation mechanism and instead support a swinging motion within the dimerization domain. The disease-linked GC-E variant V902L remains active without GCAP and shows Ca2+-dependent modulation consistent with a two-metal catalytic model. Mutational analysis at L804 reveals long-range allostery that subtly tunes catalytic output. Structural studies of zebrafish GCAP5 further illustrate how dimerization, metal sensitivity, and sequence variation contribute to the diversity of photoreceptor signaling mechanisms.