Identifying structural determinants of Gαz towards RGS RZ subfamily

Heterotrimeric (αβγ) G proteins are molecular switches that mediate signaling initiated by G protein coupled receptors (GPCRs) and play central roles in numerous cellular signaling cascades. G proteins are inactivated by regulator of G protein Signaling (RGS) proteins, which determine the lifetime of the activated G protein switch. Gαz is unique among Gα subunits as its intrinsic GTPase activity is much slower than all other family members. Moreover, previous studies suggested the RZ subfamily of RGS proteins, which inactivate Gαz by accelerating its GTPase activity, as particularly specific to this Gα subunit. However, the molecular and structural basis for these unique attributes is unknown.

We used structure-based computational methods, combined with experiments, to identify the residue-level determinants of the unique activity and specificity of Gαz. We show that the same motif is responsible for both the lower GTPase activity of Gαz and the specificity towards the RZ subfamily. Moreover substitution of single residue in this motif found in oncogenic G proteins. Our results therefore provide a mechanistic understanding for these unique biochemical properties of Gαz and can guide the development of directed therapeutics towards G proteins.