Molecular basis for Gβγ-mediated activation of phosphoinositide 3-kinase γ.
Chun-Liang ChenRamizah SyahirahSandeep K RavalaYu-Chen YenThomas KloseQing DengJohn Joseph Grubb TesmerPublished in: Nature structural & molecular biology (2024)
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.
Keyphrases
- protein kinase
- electron microscopy
- endothelial cells
- high resolution
- tyrosine kinase
- high glucose
- papillary thyroid
- molecular dynamics
- high throughput
- copy number
- single molecule
- binding protein
- optical coherence tomography
- molecular dynamics simulations
- dna binding
- squamous cell
- oxidative stress
- molecular docking
- squamous cell carcinoma
- drug induced
- lymph node metastasis
- young adults
- mass spectrometry
- case control