Structural basis for GPCR-independent activation of heterotrimeric Gi proteins
Year: 2019
Type: article
Abstract: Heterotrimeric G proteins are key molecular switches that control cell behavior. The canonical activation of G proteins by agonist-occupied G protein-coupled receptors (GPCRs) has recently been elucidated from the structural perspective. In contrast, the structural basis for GPCR-independent G protein activation by a novel family of guanine-nucleotide exchange modulators (GEMs) remains unknown. Here, we present a 2.0-Å crystal structure of Gαi in complex with the GEM motif of GIV/Girdin. Nucleotide exchange assays, molecular dynamics simulations, and hydrogen-deuterium exchange experiments demonstrate that GEM binding to the conformational switch II causes structural changes that allosterically propagate to the hydrophobic core of the Gαi GTPase domain. Rearrangement of the hydrophobic core appears to be a common mechanism by which GPCRs and GEMs activate G proteins, although with different efficiency. Atomic-level insights presented here will aid structure-based efforts to selectively target the noncanonical G protein activation.
Institutions: University of California San Diego, Moores Cancer Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, National Institutes of Health, National Health and Medical Research Council, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: G1081931513, G122547126, G1359535963, G1625166284, G1638849993, Synapt G2-S System with HXMS Automation, G250925262, G2752339580, The structural plasticity of chemokine and gp120 recognition by CCR5, Trimeric G proteins as Novel Targets in Cancer Progression, Graduate Training in Cellular and Molecular Pharmacology, Center for Research on Plant Transporters (CROPS) - A Plant Community Resource for the Structure and Function of Plant Membrane Transporters Underlying Important Crop Traits, Spatial Regulation of RGS and G Protein Signaling, Integrators of Metastatic Potential, Training Grant in Gastroenterology, Computational and structural studies of protein-GPCR interactions underlying HIV infection, G819730897, G825010248, MOLECULAR BIOPHYSICS TRAINING PROGRAM, Cancer Biology, Informatics & Omics (CBIO) Training Program, Modulation of G proteins by Growth Factors
OpenAlex ID: W2964586900