Model of activation of ROS-GC1 by GCAP-1. Decrease of cytoplasmic [Ca²⁺] leads first to dissociation of Ca²⁺ from EF-hand 3 in GCAP-1. This induces a conformational change in GCAP-1 and subsequently in ROS-GC1, which facilitates a reorientation in the DD. Formation of a correct dimer interface then increases the catalytic efficiency. Further release of Ca²⁺ from EF-hand 2 and 4 (EF-hand 1 is nonfunctional) might then stabilize this transition state of cGMP synthesis.