Biophysical Society Conference | Tahoe 2024

Molecular Biophysics of Membranes

Wednesday Speaker Abstracts

PI3KA MEMBRANE BINDING IS ASSOCIATED WITH ALTERED MEMBRANE PROPERTIES Jane Allison 1 ; Anjali Krishna 1 ; Jack U Flanagan 2 ; 1 University of Auckland, School of Biological Sciences, Auckland, New Zealand 2 University of Auckland, Department of Pharmacology and Clinical Pharmacology, Auckland, New Zealand The class IA phosphatidyl-inositide-3’- kinase PI3Kα is frequently mutated in cancers and tumours, so understanding its function and malfunction is important for development of new therapeutics. PI3Kα is a lipid kinase that phosphorylates the inositol ring at the 3’-OH position in phosphatidyl-inositides (PIs), with the most significant reaction being the phosphorylation of PI(4,5)P 2 (PIP 2 ), converting it to PI(3,4,5)P 3 (PIP 3 ). PIP 3 is a secondary lipid messenger that acts as a recruitment site for effector proteins that contain a pleckstrin homology domain, which further leads to the downstream signalling of the PI3K/Akt/mTOR signalling pathway that governs crucial cellular functions such as cell growth, metabolism, motility and survival. To access the lipid substrate PIP 2 and carry out its catalysis, PI3Kα must bind to the plasma membrane in its activated state. While there have been several molecular dynamics (MD) studies of PI3Kα, none have included the plasma membrane. Here, we present the results of MD s imulations of PI3Kα and its cellular partner HRas in the presence of a model plasma membrane. We show that the presence of membrane- anchored HRas is crucial for PI3Kα to bind to the membrane in a catalytically-competent orientation, and that regardless of the presence of HRas, PI3Kα membrane binding is associated with altered membrane properties such as thickness, curvature and PIP 2 spatial distribution.

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