Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, U.K.
Biochemistry. 2014 Mar 25;53(11):1724-32. doi: 10.1021/bi5000299. Epub 2014 Mar 10.
The phosphatase and tensin homologue (PTEN) and the Ciona intestinalis voltage sensitive phosphatase (Ci-VSP) are both phosphatidylinositol phosphate (PIP) phosphatases that contain a C2 domain. PTEN is a tumor suppressor protein that acts as a phosphatase on PIP3 in mammalian cell membranes. It contains two principal domains: a phosphatase domain (PD) and a C2 domain. Despite detailed structural and functional characterization, less is known about its mechanism of interaction with PIP-containing lipid bilayers. Ci-VSP consists of an N-terminal transmembrane voltage sensor domain and a C-terminal PTEN domain, which in turn contains a PD and a C2 domain. The nature of the interaction of the PTEN domain of Ci-VSP with membranes has not been well established. We have used multiscale molecular dynamics simulations to define the interaction mechanisms of PTEN and of the Ci-VSP PTEN domains with PIP-containing lipid bilayers. Our results suggest a novel mechanism of association of the PTEN with such bilayers, in which an initial electrostatics-driven encounter of the protein and bilayer is followed by reorientation of the protein to optimize its interactions with PIP molecules in the membrane. Although a PIP3 molecule binds close to the active site of PTEN, our simulations suggest a further conformational change of the protein may be required for catalytically productive binding to occur. Ci-VSP interacted with membranes in an orientation comparable to that of PTEN but bound directly to PIP-containing membranes without a subsequent reorientation step. Again, PIP3 bound close to the active site of the Ci-VSP PD, but not in a catalytically productive manner. Interactions of Ci-VSP with the bilayer induced clustering of PIP molecules around the protein.
磷酸酶和张力蛋白同系物（PTEN）和文昌鱼电压敏感磷酸酶（Ci-VSP）都是含有 C2 结构域的磷脂酰肌醇磷酸（PIP）磷酸酶。PTEN 是一种肿瘤抑制蛋白，在哺乳动物细胞膜上作为 PIP3 的磷酸酶发挥作用。它包含两个主要结构域：磷酸酶结构域（PD）和 C2 结构域。尽管对其结构和功能进行了详细的表征，但对其与含有 PIP 的脂质双层相互作用的机制了解较少。Ci-VSP 由 N 端跨膜电压传感器结构域和 C 端 PTEN 结构域组成，后者又包含 PD 和 C2 结构域。Ci-VSP 的 PTEN 结构域与膜的相互作用性质尚未得到很好的确定。我们使用多尺度分子动力学模拟来定义 PTEN 和 Ci-VSP PTEN 结构域与含有 PIP 的脂质双层相互作用的机制。我们的结果表明，PTEN 与这种双层的结合存在一种新的机制，其中蛋白质和双层的初始静电驱动相互作用随后是蛋白质的重新定向，以优化其与膜中 PIP 分子的相互作用。尽管 PIP3 分子靠近 PTEN 的活性位点结合，但我们的模拟表明，可能需要进一步的构象变化才能发生催化有效的结合。Ci-VSP 以与 PTEN 相当的取向与膜相互作用，但直接与含有 PIP 的膜结合，而无需后续的重新定向步骤。同样，PIP3 靠近 Ci-VSP PD 的活性位点结合，但不是以催化有效的方式结合。Ci-VSP 与双层的相互作用诱导了 PIP 分子在蛋白质周围的聚集。
