Proteomics

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HDX analysis of PI3K oncogenic mutants

ABSTRACT: We used Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) to examine the dynamic structural changes caused by oncogenic mutations. We performed HDX-MS comparing the full-length complex against the catalytic core which suggest that addition of pY leads to mixed two state population where the state 1 consists of iSH2 bound p110α and the state 2 consists of p110α where the iSH2 is completely disengaged.Therefore, we propose that the non-kinase domain mutations push the equilibrium towards state 2 leading to enhanced enzyme activity.We also propose that the kinase domain mutations lead to the re-orientation of the c-terminal tail leading to exposure of the activation loop and enhanced membrane binding.

INSTRUMENT(S): impact HD

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: John Burke  

LAB HEAD: John Burke

PROVIDER: PXD031080 | Pride | 2023-02-22

REPOSITORIES: Pride

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Publications

Oncogenic mutations of PIK3CA lead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus.

Jenkins Meredith L ML   Ranga-Prasad Harish H   Parson Matthew A H MAH   Harris Noah J NJ   Rathinaswamy Manoj K MK   Burke John E JE  

Nature communications 20230112 1

PIK3CA encoding the phosphoinositide 3-kinase (PI3K) p110α catalytic subunit is frequently mutated in cancer, with mutations occurring widely throughout the primary sequence. The full set of mechanisms underlying how PI3Ks are activated by all oncogenic mutations on membranes are unclear. Using a synergy of biochemical assays and hydrogen deuterium exchange mass spectrometry (HDX-MS), we reveal unique regulatory mechanisms underlying PI3K activation. Engagement of p110α on membranes leads to dis  ...[more]

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