Crystal structure of human guanylate cyclase activating protein‐3

Abstract

Absorption of light by rhodopsin initiates the phototransduction pathway and results in the closing of cGMP-gated cation channels and consequent hyperpolarization of rod and cone photoreceptor cell membranes. Guanylate Cyclase Activating Protein-3 (GCAP3) is one of a family of calcium binding proteins that regulate retinal guanylate cyclase activity in photoreceptor cells. At low calcium concentrations (~50 nM), GCAPs activate retinal guanylate cyclase to replenish dark state cGMP levels and at high calcium concentrations (~500 nM) they inhibit retinal guanylate cyclase. Here we report the crystal structure of human GCAP3 with calcium bound. GCAP3 is a compact EF-hand protein with EF-hand 1 disabled by a Tyr-Pro sequence and EF-hands 2, 3, and 4 binding calcium. The overall structure of GCAP3 is similar to GCAP2 and recoverin family members such as neurocalcin, frequenin, calcineurin,and the calcium-integrin binding protein. Unlike recoverin, GCAP3 does not have a large hydrophobic pocket to accommodate its myristoyl group. Conserved residues between GCAP3 and GCAP1 offer insight into autosomal dominant cone dystrophies that lead to partial blindness. This research is supported by University of Colorado and the American Heart Association.