G-protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors that endow cells with an ability to detect and respond to a vast array of extracellular stimuli including neurotransmitters, hormones, ions, and light (Shoichet and Kobilka, 2012). GPCR signaling systems are involved in virtually all essential physiological processes and their dysregulation is firmly linked to a number of human diseases (Gutierrez, 2018; Insel et al., 2007; Iyinikkel and Murray, 2018). Accordingly, an estimated one-third of all FDA approved and marketed drugs target GPCRs for therapeutic benefits (Hauser et al., 2017). Therefore, understanding how GPCRs transmit their signal and how this process is regulated is of paramount importance.

Ligand-bound GPCRs transmit signals by catalyzing the exchange of GDP for GTP on the heterotrimeric G proteins thereby releasing active GαGTP and free Gβγ subunits, which in turn engage a wide range of the intracellular effectors to produce a cellular response (Pierce et al., 2002). A wealth of accumulated evidence indicates that the key role in regulating this process belongs to a conserved family of regulators of G-protein signaling (RGS) proteins (Hollinger and Hepler, 2002; Ross and Wilkie, 2000; Kimple et al., 2011). RGS proteins act as GTPase-activating proteins (GAPs) by interacting directly with activated Gα and accelerating GTP hydrolysis thereby promoting G-protein inactivation upon reassembly of the inactive Gαβγ heterotrimer. The action of the RGS proteins is essential in providing control over both the extent and duration of signaling (Hollinger and Hepler, 2002; Ross and Wilkie, 2000) and deficits in this control results in severe dysregulation of GPCR signaling causing a number of human pathophysiological conditions (Woodard et al., 2015; Salaga et al., 2016; Druey, 2017; Sjögren, 2017).

More than 30 RGS proteins have been identified and grouped into six subfamilies (Zheng et al., 1999). Among them, the R7 family (RGS6, RGS7, RGS9, and RGS11) stands out for its evolutionary conservation in all animals from worm to man and crucial roles in multiple processes and organ systems including nervous and cardiovascular system function, vision, movement control, and cellular proliferation with ever growing causal connection to many diseases from blindness to cancer (Ahlers et al., 2016; Qutob et al., 2018; Yang et al., 2013; Anderson et al., 2009b). A unique hallmark of R7 RGS proteins is their modular architecture encompassing several domains and subunits. The catalytic RGS domain at the C-terminus is the site for the interaction with the Gα subunits (Hooks et al., 2003). The central GGL domain forms an obligatory heterodimer with type 5 G-protein β-subunit (Gβ5) which stabilizes the complex and docks it onto effectors (Snow et al., 1998; Xie et al., 2010). In addition, the molecule contains the N-terminal interwoven DEP (Dishevelled, Egl10, Pleckstrin) and DHEX (DEP helical extension) domains, a site for major allosteric regulation of the complex via association with GPCRs (Orlandi et al., 2012; Sandiford and Slepak, 2009; Kovoor et al., 2005) and small SNARE-like membrane proteins: the R7-binding protein (R7BP) and/or RGS9-anchor protein (R9AP) (Hu and Wensel, 2002; Drenan et al., 2005; Song et al., 2006; Martemyanov et al., 2005). This complexity of organization is thought to reflect regulatory precision and flexibility adapting R7 RGS proteins to universally meet diverse needs of multiple GPCR pathways in changing molecular landscape of different cells. Yet, our understanding of the structural basis underlying functional diversity is limited. The only structure reported to date is that of the RGS9-Gβ5 dimer, a specialized R7 RGS member with expression limited to striatal neurons and photoreceptors. Furthermore, no structural information exists for the regulation of RGS proteins by R7BP/R9AP subunits.

RGS7 is a prototypic member of the family, broadly expressed in the nervous system and periphery and involved in regulation of multiple GPCR systems with key roles in physiology. A few documented examples include regulation of mGluR in retina bipolar (Cao et al., 2012), GABA(B) in hippocampal CA1 (Fajardo-Serrano et al., 2013; Ostrovskaya et al., 2014), µ-opioid in striatal neurons (Sutton et al., 2016; Anderson et al., 2010; Masuho et al., 2013), and M3 muscarinic receptors in the pancreatic β-cells (Wang et al., 2017). Given these roles, perhaps not surprisingly, the RGS7 complex has been found to play a critical role in vision, learning and memory, drug addiction, insulin production, and cancer progression (Qutob et al., 2018; Sutton et al., 2016; Wang et al., 2017). Furthermore, there is a growing appreciation that the RGS7 complex can be exploited as a target for drug development with the hopes of increasing efficacy, selectivity, and the side effect profile of existing GPCR medications (Muntean et al., 2018). Thus, so far the lack of structural information on organization and regulation of the RGS7 complex has been a major bottleneck in understanding basic biology of GPCR signaling regulation and rational design of small molecule modulators.

Here, we report the high-resolution crystal structure of the RGS7-Gβ5 dimer and the structural basis for its association with R7BP revealed by hydrogen-deuterium exchange as detected by mass spectrometry (HDX-MS) analyses. In combination with molecular dynamics simulations, our data reveal unique structural features of the RGS7 complex that make it suitable for the regulation of diverse GPCR target pathways. These include the long-range rearrangement in the complex induced by R7BP binding and of the complex providing structural basis for its allosteric regulation. Together our findings reconcile a wealth of biochemical observations pertaining to the function of RGS7 thereby providing crucial insights into the biology of this essential GPCR signaling regulator.

The structure of the RGS7 complex and analysis of its conformational dynamics presented here provide critical insights into its mechanisms in regulating GPCR signaling and explains a wealth of biochemical observations. Overall, the structure supports a model of modular organization of the R7 RGS proteins highlighting distinct interfaces that integrate separate elements into a coordinated complex. Our RGS7 structure displays a distinct organization compared to the RGS9 structure.

One of the most striking features of the R7 RGS proteins is their constitutive recruitment of the outlier G-protein β subunit, Gβ5, a central organizational hallmark of the complexes. The present structure shows a unique mode of Gβ5 integration into the complex providing the first example of Gβγ like complexes in which N-terminal α-helices of both Gβ subunit and GGL are protruding away from β-propeller fold of Gβ subunit. These features point to the importance of the RGS-Gβ5 interactions in controlling conformational transitions in the complex. One of the key interfaces formed by Gβ5 involves interaction of its top ‘hot-spot’ surface with the DEP-DHEX module, which forms a major regulatory hub of the molecule.

The DEP domain is found in many signaling proteins and has been shown to be involved in membrane anchoring and protein-protein interactions with regulatory proteins (Consonni et al., 2014; Paclíková et al., 2017; Ballon et al., 2006) while the DHEX domain is a unique feature of the R7 family. In the R7 RGS proteins, both DEP and DHEX domains are indispensable for binding to membrane anchors R7BP and R9AP (Anderson et al., 2007). Our HDX data reveal that the DEP domain indeed forms a major binding site for R7BP that further engages the Gβ5 and the GGL domains. These observations are in good agreement with site-directed mutagenesis data that indicate requirement of both DEP-DHEX and Gβ5 for R7BP/R9AP binding (Masuho et al., 2011). Interestingly, organization of the DEP-DHEX module in the RGS7 complex shows marked differences from that seen in RGS9-Gβ5 including a distinct conformation of the β-hairpin and Eα1Eα2 loops, the DHEX orientation relative to DEP and clustering of basic residues on the surface. These differences likely underlie selectivity and strength of the RGS interaction with membrane anchors restricting RGS7 to interact only with R7BP while increasing the affinity of RGS9 for R7BP and allowing it to additionally bind R9AP. One particularly interesting structural feature in this regard is the β-hairpin known for its involvement in protein-protein interactions sensitive to mutations that affect its conformation (Figure 2—figure supplement 2) (Wong et al., 2000; Yu et al., 2010). Reminiscent of this, we find that the dynamic β-hairpin of RGS7 is stabilized upon R7BP binding, suggesting it role in binding and likely undergoing conformational rearrangements. Curiously, a pathogenic mutation (R44C) in the β-hairpin of RGS7 that causes melanoma reduces the stability of RGS7 and its catalytic activity, further supporting the importance of conformational transitions in this region in regulating RGS7 function (Qutob et al., 2018).

Our MD simulations, HDX data, and comparison of the RGS7 and RGS9 complexes structures suggest that the interaction of the DEP domain with Gβ5 forms a critical hotspot for communication in the complex, which propagates the conformational signal to the GGL-linker and RGS domain. The DEP/Gβ5 interface undergoes large changes in HDX upon R7BP binding that result in shielding constituent residues from solvent accessibility consistent with the stabilization of this region. These observations are consistent with the dynamic nature of the DEP-DHEX-Gβ5 interface organization which was proposed to exist in ‘open’ and ‘closed’ states (Narayanan et al., 2007). There are several biological implications of this regulation that also explain noted differences between RGS9 and RGS7 complexes.

First, we believe it serves as a major determinant of proteolytic stability of the complexes, which is a major point for controlling their expression levels and resultant negative pressure on GPCR signaling. RGS9 is notably more susceptible to proteolytic degradation than RGS7 and relies to a greater extent on R7BP binding for stability (Anderson et al., 2009a). Accordingly, we find that the DEP-Gβ5 interface of RGS7 is more extensive, and thus less dynamic, than that of RGS9. The mutations that weaken the DEP-Gβ5 interface increase susceptibility of the complex to proteolytic degradation (Porter et al., 2010). Taken together, this suggests a model whereby R7BP acts to promote the ‘closed’ conformation, stabilizing the DEP-DHEX interactions with Gβ5 to hide degradation determinants and increase proteolytic stability of the complex.

Second, our model supports a role of the DEP-DHEX-Gβ5 interface in regulating the association of RGS complexes with components of G-protein signaling cascades. The ‘hot spot’ of the G-protein β subunits is well known to engage in interactions with effectors, modulatory proteins, and Gα subunits. Interestingly, residues involved in effector contacts show high levels of conservation (80–90%) in Gβ5; thus, it is possible that it serves a similar function in docking signaling molecules. While the exact structural determinants mediating this binding are not known, the occlusion of the ‘hotspot’ interface by the DEP-DHEX domain suggests that the recruitment of R7 RGS complexes to effectors via Gβ5 could be impossible without re-arrangement of the DEP-DHEX module opening up this interface. Thus, modulation of this interface by R7BP/R9AP may play a role in controlling effector association. One notable exception is the Gβ5-mediated association of the RGS7 complex with the GIRK channel, that is promoted by R7BP (Ostrovskaya et al., 2014; Zhou et al., 2012). Interestingly, based on the crystal structure of the Gβ1-GIRK complex, the analogous surface in Gβ5 possibly involved in GIRK interaction is not occluded by the DEP-DHEX module and RGS7/Gβ5 binding to GIRK could be accommodated with minimal repositioning of cytoplasmic domain of GIRK channel (Figure 7a). Comparison of interfaces of RGS7 DEP-Gβ5 and GIRK2-Gβ1γ2 further shows poor conservation of amino acids with only one shared residue (W107 in Gβ5, W99 in Gβ1) (Figure 3—figure supplement 3 and Figure 3—figure supplement 1). This suggests the distinct binding mode of RGS7 and GIRK2 on Gβ subunits and likely explains why binding of RGS7-Gβ5 does not activate GIRK the way Gβγ association does. The hotspot surface of Gβ5 further features conservation of many residues which in canonical Gβ subunits mediate binding to Gα (Figure 3—figure supplement 1). Indeed, Gβ5 has been shown to be interacting with Gα subunits when complexed with Gγ instead of RGS (Yoshikawa et al., 2000). Furthermore, RGS9-Gβ5-R9AP complex co-purifies with tightly bound Gα-GDP from endogenous tissues (Hu and Wensel, 2002). However, the extensive shielding of the putative Gα binding interface by the DEP-DHEX module makes such association unlikely without ‘uncapping’ requiring conformational re-arrangement that would swing the DEP-DHEX module away from Gβ5 (Cheever et al., 2008). Given our finding that R7BP stabilizes this interface in the RGS7-Gβ5 complex, we suggest that such uncapping would further require the severing of the association with R7BP. Based on these considerations, our model suggests that at the ground state, the hotspot binding surface of Gβ5 in the context of a stable complex with R7BP and RGS7 is inaccessible to Gα-GDP. Thus, association of R7 RGS proteins with Gα-GDP at the hotspot interface, if it occurs, likely requires extensive rearrangement of the complex possibly triggered by yet undiscovered events.

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Another intriguing consideration involves the role of the DEP-DHEX-Gβ5 interface in the association with GPCRs. One of the key roles of conventional Gβ subunits is its interfacing with GPCRs and recent crystal structures reveal the mode of the Gβ association with receptors (Liang et al., 2017; Liang et al., 2018; Zhang et al., 2017). The RGS7-Gβ5 complex is also well documented to associate with several GPCRs including the M3 muscarinic receptor and the orphan receptors GPR158 and GPR179. This association is impacted by R7BP (Orlandi et al., 2012; Sandiford and Slepak, 2009) suggesting involvement of the Gβ5 and DEP-DHEX interface. Interestingly, the amino acids of Gβ subunit involved in GPCR contacts are also reasonably well preserved in Gβ5 (3 out of 5 are conserved) and RGS7-Gβ5 can be confidently docked to accommodate GPCR interactions (Figure 7b). However, as in the case of Gα-GDP binding to the Gβ5, docking of RGS7-Gβ5 onto GPCR based on interactions of the canonical Gβγ complexes requires rearranging of the DEP-DHEX module away from the hotspot surface of Gβ5. This fuels a tempting speculation that interactions with GPCR may in fact provide the conformational trigger for the re-arrangement in RGS7-Gβ5-R7BP complex that leads to the opening of the interface between DEP-DHEX and the hotspot surface of Gβ5 much in the same way GPCRs promote swinging of α-helical domain in Gα (Rasmussen et al., 2011).

Third, a major implication of dynamic interfacing of Gβ5 with multiple domains of RGS7 concerns regulation of the catalytic activity on its Gα-GTP substrates. To better understand the possible mechanisms, we modeled the association of RGS7-Gβ5 with activated Gα by superposing the structures of RGS7-Gβ5 and the RGS9 RGS domain-Gαt/i1 complex (PDB entry 1fqk; Figure 7—figure supplement 1a). The Gα subunit docks well and supports the canonical interaction of Rα3-α4, Rα5-α6, and Rα7-α8 of RGS7 directly with switch I and II residues of Gα observed in several many RGS-Gα complexes (Figure 7—figure supplement 1b,c). These loops of the RGS domain move closer to switch regions to facilitate the stabilization of the Gα transition state and increases GTP hydrolysis (Slep et al., 2001). Comparison of Gα binding residues of RGS9 with RGS7 shows conservation of residues with minor variations (Figure 7—figure supplement 1d). However, the αB-αC residues of the helical domain sterically clash with residues of the GGL α−helices and the N-terminus of Gβ5 (Figure 7—figure supplement 1a). These clashes are consistent with noted inhibitory effects of Gβ5 on binding of the RGS domain to activated Gα (Levay et al., 1999) and suggest that recognition of Gα-GTP by RGS7-Gβ5 could be improved by structural rearrangement of the RGS domain relative to Gβ5. The HDX-MS analysis shows stabilization of the region (GGL α-helices and the N-terminus of Gβ5) clashing with Gα residues (Figure 6b and Figure 7—figure supplement 1a) suggesting that conformational rearrangement of this region upon R7BP binding could alleviate this steric hindrance and improve Gα binding. When considered with our MD simulations, these data suggest that R7BP binding exerts its effects via remodeling contacts initiated at the top surface of Gβ5 which are translated by the S7β1 blade of the WD6 β-propeller to the opposite side and impact the network of the RGS domain contacts with the Gβ5 to allow changes in their relative orientations. Thus, Gβ5 may serve as a conduit of the conformational changes triggered at the N-terminus of the molecule to impact the organization of the RGS domain at the C-terminus of the RGS7 molecule. This model could explain biochemical observations that the GAP activity of RGS7-Gβ5 can be markedly enhanced upon association with R7BP (Masuho et al., 2013; Drenan et al., 2006). Although membrane recruitment of RGS7-Gβ5 by itself plays a major role in augmenting the catalytic activity of RGS7-Gβ5 (Muntean and Martemyanov, 2016), rearrangement of the RGS domain triggered by R7BP likely further contributes to fine tuning this process, possibly in coordination with GPCRs.

To obtain further insights, we modeled R7BP based on its homology with SNARE proteins (PDB entries 1fio, 2xhe, 1hs7). An iterative structural assembly simulation by the I-TASSER algorithm predicts R7BP to form a four-helix bundle (Figure 7—figure supplement 2). The resulting model was docked onto the RGS7-Gβ5 structure guided by our HDX data (Figure 7c). We further docked the Gα−GTP onto the RGS domain guided by the structure of the RGS domain of RGS9 in complex with the Gαt/i1 chimera (PDB entry 1fqk). The resulting model illustrates the possible orientation of the tetramer on the membrane constrained by the positively charged patch in DEP-DHEX, C-terminal palmitoylation on R7BP, and N-terminal lipidation of Gα (Figure 7c). Notably, the orientation of the complex involving R7BP on the membrane is also compatible with the predicted macromolecular assemblies involving the GPCR and the GIRK.

In summary, our study reveals the versatile nature underlying the organization of the macromolecular complex that exploits several interfaces and mechanisms for interaction with GPCR signaling components undergoing conformational transitions that adjust its function allowing it to serve its critical needs in precise regulation of key neuro-modulatory reactions in the nervous system.

Coordinate and structure factor have been deposited in the protein data bank with accession codes 6N9G. Raw HDX data are deposited at https://doi.org/10.6084/m9.figshare.7316462.v2

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Author details

1. Dipak N Patil

   Department of Neuroscience, The Scripps Research Institute, Jupiter, United States

   Contribution

   Data curation, Formal analysis, Visualization, Writing—original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1112-5557

2. Erumbi S Rangarajan

   Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States

   Contribution

   Data curation, Formal analysis, Methodology

   Competing interests

   No competing interests declared

3. Scott J Novick

   Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

4. Bruce D Pascal

   Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States

   Contribution

   Software, Formal analysis

   Competing interests

   No competing interests declared

5. Douglas J Kojetin

   Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8058-6168

6. Patrick R Griffin

   1. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States
   2. Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Visualization, Writing—review and editing

   Competing interests

   No competing interests declared

7. Tina Izard

   Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States

   Contribution

   Data curation, Formal analysis, Supervision, Project administration, Writing—review and editing

   For correspondence

   izard@scripps.edu

   Competing interests

   No competing interests declared

8. Kirill A Martemyanov

   Department of Neuroscience, The Scripps Research Institute, Jupiter, United States

   Contribution

   Conceptualization, Funding acquisition, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   kirill@scripps.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9925-7599

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