The Mechanism of Full Activation of Tumor Suppressor PTEN at the Phosphatidylinositol-Enriched Membrane

Abstract

Tumor suppressor PTEN dephosphorylates signaling lipid PIP3 produced by PI3Ks. Abundant PIP3 promotes cell growth and proliferation. PTEN is the second most highly mutated protein in cancer and is drugless. The detailed mechanism at the membrane of this pivotal phosphatase is unknown hindering understanding and drug discovery. Here for the first time, exploiting explicit solvent simulations, we tracked full-length PTEN trafficking from the cytosol to the membrane, its interaction with membranes composed of zwitterionic phosphatidylcholine and anionic phosphatidylserine and phosphatidylinositol, including signaling lipids PIP2 and PIP3, and moving away from the zwitterionic and getting absorbed onto the anionic membrane that harbors the PIP3. PIP3 then allosterically unfolds the N-terminal PIP2 binding domain, translocating it to the membrane where its polybasic motif interacts with PIP2, localizing on microdomains enriched in signaling lipids, as PI3K does. Finally, we determined PTEN catalytic action at the membrane, all in line with available experimental observations.