6mhf

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Galphai3 co-crystallized with GIV/Girdin

Structural highlights

6mhf is a 2 chain structure with sequence from Homo sapiens and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2Å
Ligands:GDP, GOL
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GRDN_HUMAN PEHO-like syndrome. The disease is caused by mutations affecting the gene represented in this entry.

Function

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][1] [2] [3]

Publication Abstract from PubMed

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-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[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Simpson F, Martin S, Evans TM, Kerr M, James DE, Parton RG, Teasdale RD, Wicking C. A novel hook-related protein family and the characterization of hook-related protein 1. Traffic. 2005 Jun;6(6):442-58. doi: 10.1111/j.1600-0854.2005.00289.x. PMID:15882442 doi:http://dx.doi.org/10.1111/j.1600-0854.2005.00289.x
  2. ↑ Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K, Murakumo Y, Usukura J, Kaibuchi K, Takahashi M. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell. 2005 Sep;9(3):389-402. PMID:16139227 doi:S1534-5807(05)00295-9
  3. ↑ Nechipurenko IV, Olivier-Mason A, Kazatskaya A, Kennedy J, McLachlan IG, Heiman MG, Blacque OE, Sengupta P. A Conserved Role for Girdin in Basal Body Positioning and Ciliogenesis. Dev Cell. 2016 Sep 12;38(5):493-506. doi: 10.1016/j.devcel.2016.07.013. PMID:27623382 doi:http://dx.doi.org/10.1016/j.devcel.2016.07.013
  4. ↑ Kalogriopoulos NA, Rees SD, Ngo T, Kopcho NJ, Ilatovskiy AV, Sun N, Komives EA, Chang G, Ghosh P, Kufareva I. Structural basis for GPCR-independent activation of heterotrimeric Gi proteins. Proc Natl Acad Sci U S A. 2019 Jul 30. pii: 1906658116. doi:, 10.1073/pnas.1906658116. PMID:31363053 doi:http://dx.doi.org/10.1073/pnas.1906658116

Contents


PDB ID 6mhf

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