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Structural design principles that underlie the multi-specific interactions of G?q with dissimilar partners.

ABSTRACT: G?q is a ubiquitous molecular switch that activates the effectors phospholipase-C-?3 (PLC-?3) and Rho guanine-nucleotide exchange factors. G?q is inactivated by regulators of G protein signaling proteins, as well as by PLC-?3. G?q further interacts with G protein-coupled receptor kinase 2 (GRK2), although the functional role of this interaction is debated. While X-ray structures of G?q bound to representatives of these partners have revealed details of their interactions, the mechanistic basis for differential G?q interactions with multiple partners (i.e., G?q multi-specificity) has not been elucidated at the individual residue resolution. Here, we map the structural determinants of G?q multi-specificity using structure-based energy calculations. We delineate regions that specifically interact with GTPase Activating Proteins (GAPs) and residues that exclusively contribute to effector interactions, showing that only the G?q "Switch II" region interacts with all partners. Our analysis further suggests that G?q-GRK2 interactions are consistent with GRK2 functioning as an effector, rather than a GAP. Our multi-specificity analysis pinpoints G?q residues that uniquely contribute to interactions with particular partners, enabling precise manipulation of these cascades. As such, we dissect the molecular basis of G?q function as a central signaling hub, which can be used to target G?q-mediated signaling in therapeutic interventions.

SUBMITTER: Navot S

PROVIDER: S-EPMC6499889 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Structural design principles that underlie the multi-specific interactions of Gαq with dissimilar partners.

Navot Shir S Kosloff Mickey M

Scientific reports 20190503 1

Gαq is a ubiquitous molecular switch that activates the effectors phospholipase-C-β3 (PLC-β3) and Rho guanine-nucleotide exchange factors. Gαq is inactivated by regulators of G protein signaling proteins, as well as by PLC-β3. Gαq further interacts with G protein-coupled receptor kinase 2 (GRK2), although the functional role of this interaction is debated. While X-ray structures of Gαq bound to representatives of these partners have revealed details of ...[more]

PMID: 31053791

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Project description:Background & aimsProliferation, differentiation, and morphogenesis of the intestinal epithelium are tightly regulated by a number of molecular pathways. Coordinated action of intestine is achieved by gastrointestinal hormones, most of which exert these actions through G-protein-coupled receptors. We herein investigated the role of Gαq/11-mediated signaling in intestinal homeostasis.MethodsIntestinal tissues from control (Gnaqflox/floxGna11+/+ ), Int-Gq knock-out (KO) (VilCre+/-Gnaqflox/floxGna11+/+ ), G11 KO (Gnaqflox/floxGna11-/- ), and Int-Gq/G11 double knock-out (DKO) (VilCre+/-Gnaqflox/floxGna11-/- ) mice were examined by microscopy, transmission electron microscopy, and immunohistochemistry. The effect of Gαq/11-mediated signaling was studied in the cell lineage, proliferation, and apoptosis. Dextran sodium sulfate (DSS) colitis was induced to study the role of Gαq/11 in colon.ResultsPaneth cells were enlarged, increased in number, and mislocalized in Int-Gq/G11 DKO small intestine. Paneth cells also reacted with PAS and Muc2 antibody, indicating an intermediate character of Paneth and goblet cells. The nuclear β-catenin, T-cell factor 1, and Sox9 expression were reduced severely in the crypt base of Int-Gq/G11 DKO intestine. Proliferation was activated in the crypt base and apoptosis was enhanced along the crypt. Int-Gq/G11 DKO mice were susceptible to DSS colitis. Proliferation was inhibited in the crypt of unaffected and regenerative areas. Cystic crypts, periodic acid-Schiff-positive cells, and Muc2-positive cells were unusually observed in the ulcerative region.ConclusionsThe Gαq/11-mediated pathway plays a pivotal role in the preservation of intestinal homeostasis, especially in Paneth cell maturation and positioning. Wnt/β-catenin signaling was reduced significantly in the crypt base in Gαq/G11-deficient mice, resulting in the defective maturation of Paneth cells, induction of differentiation toward goblet cells, and susceptibility to DSS colitis.

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Structural design principles that underlie the multi-specific interactions of G?q with dissimilar partners.

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Structural design principles that underlie the multi-specific interactions of Gα<sub>q</sub> with dissimilar partners.

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