The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane.
The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane.
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DOI：
10.1016/j.isci.2021.102438
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发表时间：
2021-05-21
期刊：
影响因子：
5.8
通讯作者：
Nussinov R
中科院分区：
文献类型：
--
作者：
Jang H;Smith IN;Eng C;Nussinov R
肿瘤抑制因子PTEN是癌症中第二高度突变的蛋白质，使PI 3 Ks产生的信号脂质PIP 3去磷酸化。过量的PIP 3促进细胞增殖。这种关键磷酸酶在膜上的作用机制尚不清楚，阻碍了药物的发现。利用明确的溶剂模拟，我们跟踪全长PTEN贩运从细胞质到膜。我们观察到它与膜组成的两性离子磷脂酰胆碱，阴离子磷脂酰丝氨酸，磷酸肌醇，包括信号脂质PIP 2和PIP 3的相互作用。我们追踪到它从两性离子上移动并被吸收到含有PIP 3的阴离子膜上。我们随后将其定位在富含信号脂质的微结构域上，如PI 3 K所做的那样，并观察到PIP 3变构地展开N-末端PIP 2结合结构域，将其有利地定位于与PIP 2的多元基序相互作用。最后，我们确定了PTEN在膜上的催化作用，所有这些都与实验观察一致，破译了PTEN如何锚定到膜上并抑制癌症的机制。PTEN定位在富含磷酸肌醇的膜微区上，如PI 3 K所做的那样。完整的PTEN活化需要两种信号传导脂质，PIP 2和PIP 3。强盐桥相互作用维持稳定的PTEN膜定位。底物诱导的P环构象变化暗示PTEN催化活性。
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 its 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. PTEN localizes on membrane microdomains enriched in phosphoinositides, as PI3K does Full PTEN activation requires both signaling lipids, PIP2 and PIP3 Strong salt bridge interactions sustain stable PTEN membrane localization Substrate-induced P loop conformational change implicates PTEN catalytic activity Structural Biology; Cancer; In Silico Biology
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影响因子：
3.3
作者：
Klauda, Jeffery B.;Venable, Richard M.;Freites, J. Alfredo;O'Connor, Joseph W.;Tobias, Douglas J.;Mondragon-Ramirez, Carlos;Vorobyov, Igor;MacKerell, Alexander D., Jr.;Pastor, Richard W.
通讯作者：
Pastor, Richard W.
影响因子：
4.8
作者：
Jang, Hyunbum;Banerjee, Avik;Nussinov, Ruth
通讯作者：
Nussinov, Ruth
DOI：
10.1002/prot.340230412
发表时间：
1995-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Frishman, D;Argos, P
通讯作者：
Argos, P
影响因子：
5.4
作者：
Kotelevets, Larissa;Trifault, Barbara;Scott, Mark G. H.
通讯作者：
Scott, Mark G. H.
影响因子：
8
作者：
Denning, G.;Jean-Joseph, B.;Vogt, P. K.
通讯作者：
Vogt, P. K.