Structural diversity in the RGS domain and its interaction with heterotrimeric G protein α-subunits

Soundararajan, M.; Willard, Francis S.; Kimple, Adam J.; Turnbull, A.P.; Ball, Linda; Schoch, Guillaume A.; Gileadi, C.; Fedorov, O.; Dowler, Elizabeth F.; Higman, Victoria Ann; Hutsell, Stephanie Q.; Sundström, M.; Doyle, D.A.; Siderovski, David P.

doi:10.1073/pnas.0801508105

Cited by 182 publications

(261 citation statements)

References 42 publications

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“…Additionally, stabilization was observed in helix 7/8, regions known to interact with and stabilize G protein switch regions. These results are consistent with previous reports of G protein interactions with RGS domains (40,41). Somewhat surprisingly, the differential HDX map for RGS14⅐G␣ o -AlF 4 Ϫ did not show significant changes in other protein regions, suggesting that RGS14 interactions with activated G␣-GTP do not regulate the function of other RGS14 domains.…”

Section: Volume 290 • Number 14 • April 3 2015supporting

confidence: 83%

“…Within the RGS domain, peptide fragments corresponding to the ␣5-␣6 loop (residues 127-142) showed high exchange, indicating a highly dynamic region. These results are consistent with the solution structure of the RGS domain of RGS10 (PDB ID: 2I59), a close relative of RGS14 and a member of the R12 subfamily of RGS proteins (40).…”

Section: And D) Following Activation Of Hela Cells With Alfsupporting

confidence: 78%

“…As a scaffolding protein capable of integrating signals from different G␣ proteins and H-Ras, RGS14 flexibility in the interdomain regions would allow for the adoption of different conformations when binding different proteins. The GPR motif exhibited considerable flexibility, consistent with a previous report showing that a short peptide corresponding to the RGS14 GPR motif utilizes an ␣-helix to contact the Ras-like lobe and irregular secondary structure to contact the ␣-helical lobe of G␣ i1 -GDP (40,44). As such, many residues within this motif must remain accessible to solvent in order to bind G␣.…”

Section: Rgs14 Subcellular Localization-our Previous Work Hassupporting

confidence: 72%

“…We modeled the observed solvent exchange onto a solution structure of the RGS domain of human RGS14 (PDB ID: 2JNU) (40). As seen in Fig.…”

Section: And D) Following Activation Of Hela Cells With Alfmentioning

confidence: 99%

“…Peptides corresponding to the ␣2-, ␣3-, ␣4-, and ␣7-helices were most stable and are known to contribute to the hydrophobic core in homologous RGS domain structures (41). Peptides corresponding to the ␣3-␣4 and ␣5-␣6 loops were least stable, reflecting the solventaccessible G protein binding site where the RGS domain contacts and stabilizes the switch regions of the G protein to promote GTP hydrolysis (40,41). In summary, apo-RGS14 exhibited dynamic structural properties typical of scaffolding proteins that integrate signals from many binding partners.…”

Section: Volume 290 • Number 14 • April 3 2015mentioning

confidence: 99%

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Integration of G Protein α (Gα) Signaling by the Regulator of G Protein Signaling 14 (RGS14)

Brown¹,

Goswami

Branch³

et al. 2015

Journal of Biological Chemistry

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Background: RGS14 binds distinct forms of active and inactive G␣ proteins through its RGS domain and GPR motif. Results: Inactive G␣ i1 -GDP binding of the GPR motif does not preclude RGS action on active G␣ o -GTP. Conclusion: RGS14 simultaneously binds active G␣ o and inactive G␣ i1 while retaining GAP activity. Significance: These findings clarify our understanding of how RGS14 integrates signaling by distinct G protein subunits.

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Section: Volume 290 • Number 14 • April 3 2015supporting

confidence: 83%

Section: And D) Following Activation Of Hela Cells With Alfsupporting

confidence: 78%

Section: Rgs14 Subcellular Localization-our Previous Work Hassupporting

confidence: 72%

“…We modeled the observed solvent exchange onto a solution structure of the RGS domain of human RGS14 (PDB ID: 2JNU) (40). As seen in Fig.…”

Section: And D) Following Activation Of Hela Cells With Alfmentioning

confidence: 99%

Section: Volume 290 • Number 14 • April 3 2015mentioning

confidence: 99%

See 3 more Smart Citations

Integration of G Protein α (Gα) Signaling by the Regulator of G Protein Signaling 14 (RGS14)

Brown¹,

Goswami

Branch³

et al. 2015

Journal of Biological Chemistry

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G Proteins

Willardson

Tensmeyer

2017

Encyclopedia of Life Sciences

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Cells respond to many hormones, neurotransmitters, bioactive peptides and sensory molecules through G protein signalling. The process begins with the binding of the signalling molecule to the extracellular face of a G‐protein‐coupled receptor (GPCR) that initiates binding of the G protein heterotrimer on the intracellular side of the receptor. This interaction causes exchange of GDP for GTP on the G protein α subunit, triggering a conformational change that dissociates the Gα‐GTP from Gβγ. These G protein subcomplexes then interact with effector enzymes and ion channels and elicit a cellular response to the signal. GPCRs constitute the largest class of transmembrane receptors, with 800 genes in the human genome. Consequently, G protein signalling contributes to almost all aspects of human physiology, and GPCRs are the single most common class of drug targets. Key Concepts G protein signalling contributes to almost all aspects of human physiology, including sensory perception, neuronal transmission and hormone secretion. Agonist binding to a G‐protein‐coupled receptor initiates an interaction with the G protein heterotrimer that triggers nucleotide exchange on the G protein α subunit (Gα). The binding of GTP to Gα causes its dissociation from the receptor and the G protein βγ dimer (Gβγ), allowing Gα‐GTP and Gβγ to interact with effector enzymes and ion channels. Effector enzymes and ion channels change the concentration of second messenger molecules or the membrane potential to elicit the cellular response to the agonist. The rate of GTP hydrolysis by Gα, which determines the duration of the G protein signal, is controlled by GTPase‐accelerating proteins called regulators of G protein signalling. To function, the G protein heterotrimer must be assembled from its individual subunits by molecular chaperones.

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Invited review: Activation of G proteins by GTP and the mechanism of Gα‐catalyzed GTP hydrolysis

Sprang¹

2016

Biopolymers

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This review addresses the regulatory consequences of the binding of GTP to the alpha subunits (Gα) of heterotrimeric G proteins, the reaction mechanism of GTP hydrolysis catalyzed by Gα and the means by which GTPase activating proteins (GAPs) stimulate the GTPase activity of Gα. The high energy of GTP binding is used to restrain and stabilize the conformation of the Gα switch segments, particularly switch II, to afford stable complementary to the surfaces of Gα effectors, while excluding interaction with Gβγ, the regulatory binding partner of GDP‐bound Gα. Upon GTP hydrolysis, the energy of these conformational restraints is dissipated and the two switch segments, particularly switch II, become flexible and are able to adopt a conformation suitable for tight binding to Gβγ. Catalytic site pre‐organization presents a significant activation energy barrier to Gα GTPase activity. The glutamine residue near the N‐terminus of switch II (Glncat) must adopt a conformation in which it orients and stabilizes the γ phosphate and the water nucleophile for an in‐line attack. The transition state is probably loose with dissociative character; phosphoryl transfer may be concerted. The catalytic arginine in switch I (Argcat), together with amide hydrogen bonds from the phosphate binding loop, stabilize charge at the β‐γ bridge oxygen of the leaving group. GAPs that harbor “regulator of protein signaling” (RGS) domains, or structurally unrelated domains within G protein effectors that function as GAPs, accelerate catalysis by stabilizing the pre‐transition state for Gα‐catalyzed GTP hydrolysis, primarily by restraining Argcat and Glncat to their catalytic conformations. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 449–462, 2016.

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Structural diversity in the RGS domain and its interaction with heterotrimeric G protein α-subunits

Cited by 182 publications

References 42 publications

Integration of G Protein α (Gα) Signaling by the Regulator of G Protein Signaling 14 (RGS14)

Integration of G Protein α (Gα) Signaling by the Regulator of G Protein Signaling 14 (RGS14)

G Proteins

Invited review: Activation of G proteins by GTP and the mechanism of Gα‐catalyzed GTP hydrolysis

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