High-resolution structure of RGS17 suggests a role for Ca 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, Gα, and Gα proteins in the nervous system and thereby inhibit downstream pathways, including those involved in Ca-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 Ca bound to conserved positions on the predicted Gα-binding surface of the protein. Using NMR chemical shift perturbations, we confirmed that Ca binds in solution to the same site. Furthermore, RGS17 had greater than 55-fold higher affinity for Ca than for Mg Finally, we found that Ca promotes interactions between RGS17 and activated Gα and decreases the for GTP hydrolysis, potentially by altering the binding mechanism between these proteins. Taken together, these findings suggest that Ca positively regulates RGS17, which may represent a general mechanism by which increased Ca concentration promotes the GAP activity of the RZ subfamily, leading to RZ-mediated inhibition of Ca signaling.

© 2019 Sieng et al.