Tumor suppressor PTEN, the second most highly mutated protein in cancer, dephosphorylates signaling lipid PIP₃ produced by PI3Ks. Excess PIP₃ 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 PIP₂ and PIP₃. We tracked it's moving away from the zwitterionic and getting absorbed onto anionic membrane that harbors PIP₃. We followed it localizing on microdomains enriched in signaling lipids, as PI3K does, and observed PIP₃ allosterically unfolding the N-terminal PIP₂ binding domain, positioning it favorably for the polybasic motif interaction with PIP₂. 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.

中文翻译：

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在富含磷酸肌醇的膜上完全激活抑癌基因PTEN的机制

抑癌基因PTEN是癌症中突变率第二高的蛋白质，它使PI3K产生的脂质PIP ₃信号去磷酸化。过量的PIP _3会促进细胞增殖。该关键磷酸酶在膜上的机制尚不清楚，这阻碍了药物的发现。利用显式溶剂模拟，我们追踪了从细胞质到膜的全长PTEN转运。我们观察到它与两性离子磷脂酰胆碱，阴离子磷脂酰丝氨酸和磷酸肌醇组成的膜的相互作用，包括信号脂质PIP ₂和PIP ₃。我们跟踪到它正从两性离子移开，并被吸收到带有PIP _3的阴离子膜上。我们跟随它定位在富含信号脂质的微域上，就像PI3K一样，并观察到PIP ₃变构地展开了N末端PIP ₂结合结构域，使其与PIP ₂的多元基序相互作用更为有利。最后，我们确定了PTEN在膜上的催化作用，这与实验观察一致，从而揭示了PTEN如何锚定在膜上并抑制癌症的机制。