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Nature Structural & Molecular Biology 14, 527–534 (1 June 2007) | doi:10.1038/nsmb1254

Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40

Yu Chen , Yanhui Xu , Qing Bao , Yongna Xing , Zhu Li , Zheng Lin , Jeffry B Stock , Philip D Jeffrey & Yigong Shi

The small t antigen (ST) of DNA tumor virus SV40 facilitates cellular transformation by disrupting the functions of protein phosphatase 2A (PP2A) through a poorly defined mechanism. The crystal structure of the core domain of SV40 ST bound to the scaffolding subunit of human PP2A reveals that the ST core domain has a novel zinc-binding fold and interacts with the conserved ridge of HEAT repeats 3–6, which overlaps with the binding site for the B|[prime]| (also called PR61 or B56) regulatory subunit. ST has a lower binding affinity than B|[prime]| for the PP2A core enzyme. Consequently, ST does not efficiently displace B|[prime]| from PP2A holoenzymes in vitro. Notably, ST inhibits PP2A phosphatase activity through its N-terminal J domain. These findings suggest that ST may function mainly by inhibiting the phosphatase activity of the PP2A core enzyme, and to a lesser extent by modulating assembly of the PP2A holoenzymes.