Human regulator of G-protein signalling 16 in complex with the activated state of Galpha1

Regulators of G-protein signalling (RGS) are domains that terminate the signal emanating from G-protein coupled receptors (GPCR). When a GPCR binds a specific ligand a signal is generated that is transmitted to the G-proteins that consist of the Gα and Gβγ subunits. In the inactive state Gα and Gβγ exist as a complex with the Gα GTPase in an inactive GDP bound state. Upon activation GDP is replaced with GTP which induces Gα and Gβγ complex disassociation. At this stage both Gα and Gβγ proteins are active. Gα does have an intrinsic GTPase activity but this is greatly enhanced by the association with an RGS domain. Hence RGS proteins act as GTPase activating proteins (GAPs). Once GTP hydrolysis has taken place the GDP-Gα protein can recombine with Gβγ thus terminating the signal.

RGS16 is a member of the B/R4 subfamily of RGS proteins. All of these subfamily members have an N-terminal amphipathic helix which enhances the localisation of the protein to the membrane surface (Bernstein et al, 2000; Chen et al, 1999) where it is ideally placed to interact with the G-proteins.

RGS16 is abundant in the retina (Snow et al, 1998) and also highly expressed in the lung (Larminie et al, 2004). At a cellular level RGS16 along with other RGS proteins is expressed in T lymphocytes (Beading et al, 1999). These cells play a central role in the inflammatory response of asthma. T cell activation and migration to an inflammatory stimulus in the lung appears to be regulated by RGS16 (Lippert et al, 2003). Expression of RGS16 is also increased by TNFa (Patten et al, 2003). As TNFa is also known to participates in inflammatory disorders this implies that RGS16 may function as a regulator of the inflammatory response.

Here we present the crystal structure of RGS16 in complex with the activated state of Galpha1.