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

Abstract

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 Gα_i/o and Gα_q/11 subunits as substrates, the R7 and R12 subfamilies select against Gα_q/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 Gα_q 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 Gα_q. RGS8 adopts the same pose on Gα_q as it does when bound to Gα_i3, indicating that the non-canonical interaction of RGS2 with Gα_q is due to unique features of RGS2. Here, based on the RGS8-Gα_q structure, residues in RGS8 that contact a unique α-helical domain loop of Gα_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, theymore » did not reverse selectivity. Instead, selectivity for Gα_q seems more likely determined by whether strong contacts can be maintained between α6 of the RGS domain and Switch III of Gα_q, regions of high sequence and conformational diversity in both protein families.« less

Authors:

Taylor, Veronica G. ^[1]; Bommarito, Paige A. ^[1]; Tesmer, John J. G. ^[1]

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+ Show Author Affiliations

1. Univ. of Michigan, Ann Arbor, MI (United States)

Publication Date:

Mon Jan 11 00:00:00 EST 2016

Research Org.:

Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Org.:

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

OSTI Identifier:

1243106

Grant/Contract Number:  

HL086865; HL122416; T32GM008270; AC02-06CH11357; 085P1000817

Resource Type:

Accepted Manuscript

Journal Name:

Journal of Biological Chemistry

Additional Journal Information:

Journal Volume: 291; Journal Issue: 10; Journal ID: ISSN 0021-9258

Publisher:

American Society for Biochemistry and Molecular Biology

Country of Publication:

United States

Language:

ENGLISH

Subject:

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