ASPP 蛋白的灵活连接有助于 PP-1c 的催化。
Flexible Tethering of ASPP Proteins Facilitates PP-1c Catalysis.
机构信息
Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Molecular Biophysics & Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
出版信息
Structure. 2019 Oct 1;27(10):1485-1496.e4. doi: 10.1016/j.str.2019.07.012. Epub 2019 Aug 8.
ASPP (apoptosis-stimulating proteins of p53) proteins bind PP-1c (protein phosphatase 1) and regulate p53 impacting cancer cell growth and apoptosis. Here we determine the crystal structure of the oncogenic ASPP protein, iASPP, bound to PP-1c. The structure reveals a 1:1 complex that relies on interactions of the iASPP SILK and RVxF motifs with PP-1c, plus interactions of the PP-1c PxxPxR motif with the iASPP SH3 domain. Small-angle X-ray scattering analyses suggest that the crystal structure undergoes slow interconversion with more extended conformations in solution. We show that iASPP, and the tumor suppressor ASPP2, enhance the catalytic activity of PP-1c against the small-molecule substrate, pNPP as well as p53. The combined results suggest that PxxPxR binding to iASPP SH3 domain is critical for complex formation, and that the modular ASPP-PP-1c interface provides dynamic flexibility that enables functional binding and dephosphorylation of p53 and other diverse protein substrates.
ASPP（p53 的凋亡刺激蛋白）蛋白与 PP-1c（蛋白磷酸酶 1）结合并调节 p53，从而影响癌细胞的生长和凋亡。在这里，我们确定了与 PP-1c 结合的致癌 ASPP 蛋白 iASPP 的晶体结构。该结构揭示了一个 1:1 的复合物，该复合物依赖于 iASPP SILK 和 RVxF 基序与 PP-1c 的相互作用，以及 PP-1c PxxPxR 基序与 iASPP SH3 结构域的相互作用。小角度 X 射线散射分析表明，晶体结构在溶液中会发生缓慢的互变，形成更伸展的构象。我们表明，iASPP 和肿瘤抑制因子 ASPP2 增强了 PP-1c 对小分子底物 pNPP 以及 p53 的催化活性。综合结果表明，PxxPxR 与 iASPP SH3 结构域的结合对于复合物的形成至关重要，并且 ASPP-PP-1c 界面的模块化提供了动态的灵活性，从而能够实现 p53 和其他多种蛋白质底物的功能结合和去磷酸化。
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