6mhf | pdb_00006mhf
Galphai3 co-crystallized with GIV/Girdin
Structural highlights
Disease[GRDN_HUMAN] PEHO-like syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function[GNAI3_RAT] Heterotrimeric guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding. The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal (PubMed:2159473). Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins. Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels. Stimulates the activity of receptor-regulated K(+) channels. The active GTP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[UniProtKB:P08754][1] [GRDN_HUMAN] Plays a role as a key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Enhances phosphoinositide 3-kinase (PI3K)-dependent phosphorylation and kinase activity of AKT1/PKB, but does not possess kinase activity itself (By similarity). Phosphorylation of AKT1/PKB thereby induces the phosphorylation of downstream effectors GSK3 and FOXO1/FKHR, and regulates DNA replication and cell proliferation (By similarity). Essential for the integrity of the actin cytoskeleton and for cell migration (PubMed:16139227). Required for formation of actin stress fibers and lamellipodia (PubMed:15882442). May be involved in membrane sorting in the early endosome (PubMed:15882442). Plays a role in ciliogenesis and cilium morphology and positioning and this may partly be through regulation of the localization of scaffolding protein CROCC/Rootletin (PubMed:27623382).[UniProtKB:Q5SNZ0][2] [3] [4] Publication Abstract from PubMedHeterotrimeric 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-A crystal structure of Galphai 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 Galphai 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. Structural basis for GPCR-independent activation of heterotrimeric Gi proteins.,Kalogriopoulos NA, Rees SD, Ngo T, Kopcho NJ, Ilatovskiy AV, Sun N, Komives EA, Chang G, Ghosh P, Kufareva I Proc Natl Acad Sci U S A. 2019 Jul 30. pii: 1906658116. doi:, 10.1073/pnas.1906658116. PMID:31363053[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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