The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane

Tumor suppressor PTEN, the second most highly mutated protein in cancer, dephosphorylates signaling lipid PIP(3) produced by PI3Ks. Excess PIP(3) promotes cell proliferation. The mechanism at the membrane of this pivotal phosphatase is unknown hindering drug discovery. Exploiting explicit solvent simulations, we tracked full-length PTEN trafficking from the cytosol to the membrane. We observed its interaction with membranes composed of zwitterionic phosphatidylcholine, anionic phosphatidylserine, and phosphoinositides, including signaling lipids PIP(2) and PIP(3). We tracked its moving away from the zwitterionic and getting absorbed onto anionic membrane that harbors PIP(3). We followed it localizing on microdomains enriched in signaling lipids, as PI3K does, and observed PIP(3) allosterically unfolding the N-terminal PIP(2) binding domain, positioning it favorably for the polybasic motif interaction with PIP(2). Finally, we determined PTEN catalytic action at the membrane, all in line with experimental observations, deciphering the mechanisms of how PTEN anchors to the membrane and restrains cancer.