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Updated: Jun 15, 2026

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Published on: March 16, 2020
Calcium binding, structural stability and guanylate cyclase activation in GCAP1 variants associated with human cone
Daniele Dell'Orco1, Petra Behnen, Sara Linse
1Institute of Biology and Environmental Sciences, University of Oldenburg, Germany.
Abstract:
Guanylate cyclase activating protein 1 (GCAP1) is a neuronal Ca(2+) sensor (NCS) that regulates the activation of rod outer segment guanylate cyclases (ROS-GCs) in photoreceptors. In this study, we investigated the Ca(2+)-induced effects on the conformation and the thermal stability of four GCAP1 variants associated with hereditary human cone dystrophies. Ca(2+) binding stabilized the conformation of all the GCAP1 variants independent of myristoylation. The myristoylated wild-type GCAP1 was found to have the highest Ca(2+) affinity and thermal stability, whereas all the mutants showed decreased Ca(2+) affinity and significantly lower thermal stability in both apo and Ca(2+)-loaded forms. No apparent cooperativity of Ca(2+) binding was detected for any variant. Finally, the non-myristoylated mutants were still capable of activating ROS-GC1, but the measured cyclase activity was shifted toward high, nonphysiological Ca(2+) concentrations. Thus, we conclude that distorted Ca(2+)-sensor properties could lead to cone dysfunction.
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