Membrane association of the PTEN tumor suppressor: electrostatic interaction with phosphatidylserine-containing bilayers and regulatory role of the C-terminal tail.
Membrane association of the PTEN tumor suppressor: electrostatic interaction with phosphatidylserine-containing bilayers and regulatory role of the C-terminal tail.
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DOI：
10.1016/j.jsb.2012.10.003
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发表时间：
2012-12
影响因子：
3
通讯作者：
Loesche, Mathias
中科院分区：
文献类型：
--
作者：
Shenoy, Siddharth S.;Nanda, Hirsh;Loesche, Mathias
磷脂酰肌醇磷酸酶PTEN是人类肿瘤中第二常见的突变蛋白。它的膜结合、变构激活和膜解离还知之甚少。我们最近报道了PTEN与不同组成的膜的结合亲和力，并用中子反射仪(NR)初步研究了蛋白质-膜复合体。在这里，我们使用NR来验证蛋白质的分子动力学(MD)模拟，并研究蛋白质在溶液和阴离子膜上的构象差异。NR表明，全长PTEN大致按照截短的PTEN蛋白晶体结构所示的构象和取向与此类膜结合，而最近提出的模型表明，膜结合主要取决于PTEN C2结构域CBR3环的SUMO化。我们的MD模拟证实，PTEN是外围结合到双层表面的，并且在溶液和膜结合状态下蛋白质结构略有不同，在膜结合状态下，蛋白质体压平在双层表面上。PTEN的C2结构域通过其CBR3环与磷脂酰丝氨酸(PS)紧密结合，其磷酸酶结构域也与PS形成静电相互作用。NR和MD结果一致地表明，PTEN的非结构化、阴离子的C末端尾巴被双层表面排斥。相反，这条尾巴在溶液中被紧紧地拉到C2结构域上，部分阻碍了蛋白质的膜结合界面。通过磷酸化抑制这种构象中的C末端，可能为PTEN的膜结合和活性提供了一种控制机制。
The phosphatidylinositolphosphate phosphatase PTEN is the second most frequently mutated protein in human tumors. Its membrane association, allosteric activation and membrane dissociation are poorly understood. We recently reported PTEN binding affinities to membranes of different compositions and a preliminary investigation of the protein-membrane complex with neutron reflectometry (NR). Here we use NR to validate molecular dynamics (MD) simulations of the protein and study conformational differences of the protein in solution and on anionic membranes. NR shows that full-length PTEN binds to such membranes roughly in the conformation and orientation suggested by the crystal structure of a truncated PTEN protein, in contrast with a recently presented model which suggested that membrane binding depends critically on the SUMOylation of the CBR3 loop of PTEN’s C2 domain. Our MD simulations confirm that PTEN is peripherally bound to the bilayer surface and show slight differences of the protein structure in solution and in the membrane-bound state, where the protein body flattens against the bilayer surface. PTEN’s C2 domain binds phosphatidylserine (PS) tightly through its CBR3 loop, and its phosphatase domain also forms electrostatic interactions with PS. NR and MD results show consistently that PTEN’s unstructured, anionic C-terminal tail is repelled from the bilayer surface. In contrast, this tail is tightly tugged against the C2 domain in solution, partially obstructing the membrane-binding interface of the protein. Arresting the C-terminal tail in this conformation by phosphorylation may provide a control mechanism for PTEN’s membrane binding and activity.
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影响因子：
5.5
作者：
Mallajosyula, Sairam S.;Guvench, Olgun;Hatcher, Elizabeth;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
影响因子：
3.3
作者：
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通讯作者：
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影响因子：
21.3
作者：
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通讯作者：
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影响因子：
3.4
作者：
McGillivray, Duncan J.;Valincius, Gintaras;Kasianowicz, John J.
通讯作者：
Kasianowicz, John J.
影响因子：
64.8
作者：
Cornell, BA;BraachMaksvytis, VLB;Pace, RJ
通讯作者：
Pace, RJ