The heterotrimeric G protein Gαq is a central player in signal transduction, relaying signals from activated G protein-coupled receptors (GPCRs) to effectors and other proteins to elicit changes in intracellular Ca2+, the actin cytoskeleton, and gene transcription. Gαq functions at the surface of the plasma membrane, as do its best characterized targets phospholipase C-β, p63RhoGEF, and GPCR kinase 2 (GRK2). Recent insights into the structure and function of these signaling complexes reveals several recurring themes, including complex multivalent interactions between Gαq, its protein target, and the membrane, that are likely essential for allosteric control and maximum efficiency in signal transduction. Thus, the plasma membrane is not only a source of substrates, but also a key player in the scaffolding of Gαq-dependent signaling pathways.

Regulator of G protein signaling (RGS) proteins interact with activated G␣ subunits via their RGS domains and accelerate the hydrolysis of GTP. Although the R4 subfamily of RGS proteins generally accepts both G␣ i/o and G␣ q/11 subunits as substrates, the R7 and R12 subfamilies select against G␣ q/11 . In contrast, only one RGS protein, RGS2, is known to be selective for G␣ q/11 . The molecular basis for this selectivity is not clear. Previously, the crystal structure of RGS2 in complex with G␣ q revealed a non-canonical interaction that could be due to interfacial differences imposed by RGS2, the G␣ subunit, or both. To resolve this ambiguity, the 2.6 Å crystal structure of RGS8, an R4 subfamily member, was determined in complex with G␣ q . RGS8 adopts the same pose on G␣ q as it does when bound to G␣ i3 , indicating that the non-canonical interaction of RGS2 with G␣ q is due to unique features of RGS2. Based on the RGS8-G␣ q structure, residues in RGS8 that contact a unique ␣-helical domain loop of G␣ q were converted to those typically found in R12 subfamily members, and the reverse substitutions were introduced into RGS10, an R12 subfamily member. Although these substitutions perturbed their ability to stimulate GTP hydrolysis, they did not reverse selectivity. Instead, selectivity for G␣ q seems more likely determined by whether strong contacts can be maintained between ␣6 of the RGS domain and Switch III of G␣ q , regions of high sequence and conformational diversity in both protein families.Many transmembrane signaling events are transduced inside the cell by heterotrimeric G proteins, which are activated by cell surface G protein-coupled receptors. G protein-coupled receptors stimulate the exchange of bound GDP for GTP on the G␣ subunit, which then separates from the G␤␥ subunits and interacts with downstream effectors (1). After hydrolyzing GTP to GDP, the G␣ subunit is deactivated and is rapidly sequestered by G␤␥. In biological processes, such as the visual response, deactivation of G␣ has been observed at much faster rates than those measured for isolated G␣ subunits in vitro (2, 3). This discrepancy helped lead to the discovery of a family of GTPaseactivating proteins (GAPs), 2 now known as regulator of G protein signaling (RGS) proteins (4 -6). RGS proteins contain a conserved helical domain called the RGS domain that directly binds to the three switch regions (SwI-III) of the G␣ subunit and stabilizes them in a transition state conformation (7).RGS domains are divided into four subfamilies based on sequence homology and substrate preference: RZ, R4, R7, and R12 (8). All utilize G␣ i/o subunits as substrates, although some RZ members seem selective for G␣ z subunits (9). A recent study using surface plasmon resonance indicated that the RGS domains that belong to the R7 and R12 subfamilies bind weakly or not at all to G␣ q , whereas the RZ and R4 subfamilies tend to interact with both G␣ i/o and G␣ q/11 (10). The exception is RGS2, an R4 subfamily member that is uniquely selective for G␣ q/11 (11). ...

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Cover illustration by Stephen Leacock-leacockdesign.com Front inside cover created by Andrew Maynard using weighted keywords selected by the steering committee and scribes to describe the dialogue at the conference. Conference photographs courtesy of Mark Bialek, Day 1 (http:// markbialek .com) and Mike Gould, Days 2 and 3 (http:// www .mondodyne .com). Photograph of Jane Lubchenco courtesy of Joy Leighton. Organizational affiliations are for identification purposes only. The opinions expressed in this report are the sole responsibility of the participants quoted.

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