PUBLICATION
Molecular basis for Gβγ-mediated activation of phosphoinositide 3-kinase γ
- Authors
- Chen, C.L., Syahirah, R., Ravala, S.K., Yen, Y.C., Klose, T., Deng, Q., Tesmer, J.J.G.
- ID
- ZDB-PUB-240403-8
- Date
- 2024
- Source
- Nature structural & molecular biology 31(8): 1198-1207 (Journal)
- Registered Authors
- Deng, Qing, Syahirah Mohd Sabri, Ramizah
- Keywords
- none
- MeSH Terms
-
- Binding Sites
- Neutrophils/metabolism
- GTP-Binding Protein beta Subunits*/chemistry
- GTP-Binding Protein beta Subunits*/metabolism
- Protein Binding
- Enzyme Activation
- Animals
- Humans
- Allosteric Regulation
- Class Ib Phosphatidylinositol 3-Kinase*/chemistry
- Class Ib Phosphatidylinositol 3-Kinase*/metabolism
- Zebrafish
- GTP-Binding Protein gamma Subunits*/chemistry
- GTP-Binding Protein gamma Subunits*/metabolism
- Models, Molecular
- Protein Conformation
- Cryoelectron Microscopy*
- PubMed
- 38565696 Full text @ Nat. Struct. Mol. Biol.
Citation
Chen, C.L., Syahirah, R., Ravala, S.K., Yen, Y.C., Klose, T., Deng, Q., Tesmer, J.J.G. (2024) Molecular basis for Gβγ-mediated activation of phosphoinositide 3-kinase γ. Nature structural & molecular biology. 31(8):1198-1207.
Abstract
The conversion of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate by phosphoinositide 3-kinase γ (PI3Kγ) is critical for neutrophil chemotaxis and cancer metastasis. PI3Kγ is activated by Gβγ heterodimers released from G protein-coupled receptors responding to extracellular signals. Here we determined cryo-electron microscopy structures of Sus scrofa PI3Kγ-human Gβγ complexes in the presence of substrates/analogs, revealing two Gβγ binding sites: one on the p110γ helical domain and another on the p101 C-terminal domain. Comparison with PI3Kγ alone reveals conformational changes in the kinase domain upon Gβγ binding that are similar to Ras·GTP-induced changes. Assays of variants perturbing the Gβγ binding sites and interdomain contacts altered by Gβγ binding suggest that Gβγ recruits the enzyme to membranes and allosterically regulates activity via both sites. Studies of zebrafish neutrophil migration align with these findings, paving the way for in-depth investigation of Gβγ-mediated activation mechanisms in this enzyme family and drug development for PI3Kγ.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping