Structural basis of PP2A inhibition by small t antigen.
Structural basis of PP2A inhibition by small t antigen.
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DOI：
10.1371/journal.pbio.0050202
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发表时间：
2007-08
期刊：
影响因子：
9.8
通讯作者：
Xu, Wenqing
中科院分区：
文献类型：
--
作者：
Cho, Uhn Soo;Morrone, Seamus;Sablina, Anna A;Arroyo, Jason D;Hahn, William C;Xu, Wenqing
SV40 小 t 抗原 (ST) 是一种有效的癌蛋白，可扰乱蛋白磷酸酶 2A (PP2A) 的功能。 ST 直接与 PP2A 支架 A 亚基相互作用，并通过替换 A 亚基中的调节 B 亚基来改变 PP2A 活性。我们以 3.1 Å 的分辨率确定了全长 ST 与 PP2A A 亚基复合物的晶体结构。 ST 由一个 N 端 J 结构域和一个包含两个锌结合基序的 C 端独特结构域组成。 J 结构域和第二个锌结合基序均与 A 亚基的 HEAT 重复序列 3-7 的内部 HEAT 重复环相互作用，该重复序列与 PP2A B56 亚基的结合位点重叠。有趣的是，第一个锌结合基序所处的位置可能使其能够直接与 PP2A 催化 C 亚基相互作用并抑制其磷酸酶活性。这些观察结果为理解 ST 的致癌功能提供了结构基础。对 DNA 肿瘤病毒如何诱导恶性转化的研究已经确定了在自发性癌症中也发挥作用的关键途径。其中一种病毒，猿猴病毒 40 (SV40)，产生两种蛋白质，大 T 抗原和小 t 抗原，它们结合并灭活对细胞转化很重要的肿瘤抑制基因。具体来说，SV40 小 t 抗原 (ST) 与丰富的蛋白磷酸酶 2A (PP2A) 结合并扰乱其功能。 PP2A 是异源三聚酶家族，由结构 A 亚基、催化 C 亚基和几个调节 B 亚基之一组成。在这里，我们确定了 SV40 ST 与 PP2A 结构亚基 Aα 复合物的结构。 SV40 ST 由 N 端 J 结构域和 C 端独特结构域组成，其中包含两个独立的锌结合基序。 SV40 ST 与调节亚基 B56 结合到 PP2A 的同一区域，这为 SV40 ST 置换调节 B 亚基提供了结构解释。总而言之，这些观察结果为理解 ST 的致癌功能提供了结构基础。全长 SV40 小 t 抗原 (ST) 与其靶蛋白磷酸酶 2A 的 A 亚基复合的晶体结构有助于我们了解 ST 的致癌功能。
The SV40 small t antigen (ST) is a potent oncoprotein that perturbs the function of protein phosphatase 2A (PP2A). ST directly interacts with the PP2A scaffolding A subunit and alters PP2A activity by displacing regulatory B subunits from the A subunit. We have determined the crystal structure of full-length ST in complex with PP2A A subunit at 3.1 Å resolution. ST consists of an N-terminal J domain and a C-terminal unique domain that contains two zinc-binding motifs. Both the J domain and second zinc-binding motif interact with the intra-HEAT-repeat loops of HEAT repeats 3–7 of the A subunit, which overlaps with the binding site of the PP2A B56 subunit. Intriguingly, the first zinc-binding motif is in a position that may allow it to directly interact with and inhibit the phosphatase activity of the PP2A catalytic C subunit. These observations provide a structural basis for understanding the oncogenic functions of ST. The study of how DNA tumor viruses induce malignant transformation has led to the identification of key pathways that also play a role in spontaneously arising cancers. One such virus, simian virus 40 (SV40), produces two proteins, the large T and small t antigens, that bind and inactivate tumor suppressor genes important for cell transformation. Specifically, SV40 small t antigen (ST) binds to and perturbs the function of the abundant protein phosphatase 2A (PP2A). PP2A is a family of heterotrimeric enzymes, composed of a structural A subunit, a catalytic C subunit, and one of several regulatory B subunits. Here we have determined the structure of SV40 ST in complex with the PP2A structural subunit Aα. SV40 ST consists of an N-terminal J domain and a C-terminal unique domain that contains two separate zinc-binding motifs. SV40 ST binds to the same region of PP2A as the regulatory subunit B56, which provides a structural explanation for the displacement of regulatory B subunits by SV40 ST. Taken together, these observations provide a structural basis for understanding the oncogenic functions of ST. The crystal structure of full-length SV40 small t antigen (ST) in complex with the A subunit of its target, protein phosphatase 2A, contributes to our understanding of the oncogenic functions of ST.