High-resolution structure of RGS17 suggests a role for Ca²⁺ in promoting the GTPase-activating protein activity by RZ subfamily members.

Regulator of G protein signaling (RGS) proteins are negative regulators of G protein-coupled receptor (GPCR) signaling through their ability to act as GTPase-activating proteins (GAPs) for activated Gα subunits. Members of the RZ subfamily of RGS proteins bind to activated Gα_o, Gα_z, and Gα_i1-3 proteins in the nervous system and thereby inhibit downstream pathways, including those involved in Ca²⁺-dependent signaling. In contrast to other RGS proteins, little is known about RZ subfamily structure and regulation. Herein, we present the 1.5-Å crystal structure of RGS17, the most complete and highest-resolution structure of an RZ subfamily member to date. RGS17 cocrystallized with Ca²⁺ bound to conserved positions on the predicted Gα-binding surface of the protein. Using NMR chemical shift perturbations, we confirmed that Ca²⁺ binds in solution to the same site. Furthermore, RGS17 had greater than 55-fold higher affinity for Ca²⁺ than for Mg²⁺ Finally, we found that Ca²⁺ promotes interactions between RGS17 and activated Gα and decreases the K for GTP hydrolysis, potentially by altering the binding mechanism between these proteins. Taken together, these findings suggest that Ca²⁺ positively regulates RGS17, which may represent a general mechanism by which increased Ca²⁺ concentration promotes the GAP activity of the RZ subfamily, leading to RZ-mediated inhibition of Ca²⁺ signaling.

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