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Title: Structure of the Regulator of G Protein Signaling 8 (RGS8)-Gαq Complex: Molecular Basis for Gα Selectivity

Journal Article · · Journal of Biological Chemistry
 [1];  [1];  [1]
  1. Univ. of Michigan, Ann Arbor, MI (United States)
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Regulator of G protein signaling (RGS) proteins interact with activated Gα subunits via their RGS domains and accelerate the hydrolysis of GTP. Although the R4 subfamily of RGS proteins generally accepts both Gαi/o and Gαq/11 subunits as substrates, the R7 and R12 subfamilies select against Gαq/11. In contrast, only one RGS protein, RGS2, is known to be selective for Gαq/11. The molecular basis for this selectivity is not clear. Previously, the crystal structure of RGS2 in complex with Gαq revealed a non-canonical interaction that could be due to interfacial differences imposed by RGS2, the Gα subunit, or both. To resolve this ambiguity, the 2.6 Å crystal structure of RGS8, an R4 subfamily member, was determined in complex with Gαq. RGS8 adopts the same pose on Gαq as it does when bound to Gαi3, indicating that the non-canonical interaction of RGS2 with Gαq is due to unique features of RGS2. Here, based on the RGS8-Gαq structure, residues in RGS8 that contact a unique α-helical domain loop of Gαq 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 Gαq seems more likely determined by whether strong contacts can be maintained between α6 of the RGS domain and Switch III of Gαq, regions of high sequence and conformational diversity in both protein families.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of Health; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor
Grant/Contract Number:
HL086865; HL122416; T32GM008270; AC02-06CH11357; 085P1000817
OSTI ID:
1243106
Journal Information:
Journal of Biological Chemistry, Vol. 291, Issue 10; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 27 works
Citation information provided by
Web of Science

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Cited By (8)

High-resolution structure of RGS17 suggests a role for Ca 2+ in promoting the GTPase-activating protein activity by RZ subfamily members journal April 2019
An Interhelical Salt Bridge Controls Flexibility and Inhibitor Potency for Regulators of G-protein Signaling Proteins 4, 8, and 19 journal September 2019
Structural design principles that underlie the multi-specific interactions of Gαq with dissimilar partners journal May 2019
A highly conserved δ‐opioid receptor region determines RGS4 interaction journal September 2019
Tracing the evolution of the heterotrimeric G protein α subunit in Metazoa journal April 2018
Regulators of G protein signaling in cardiovascular function during pregnancy journal August 2018
Structure of the C-terminal guanine nucleotide exchange factor module of Trio in an autoinhibited conformation reveals its oncogenic potential journal February 2019
Tracking the Cartoon mouse phenotype: Hemopexin domain–dependent regulation of MT1-MMP pericellular collagenolytic activity journal April 2018

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
crystal structure
GTPase-activating protein (GAP)
heterotrimeric G protein
regulator of G protein signaling (RGS)
structure-function
X-ray crystallography
Gq
RGS10
RGS8
selectivity
cell signaling
protein structure
cardiovascular disease
protein complex
GTPase activation assays
Gαq