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

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

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Abstract

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′ (also called PR61 or B56) regulatory subunit. ST has a lower binding affinity than B′ for the PP2A core enzyme. Consequently, ST does not efficiently displace B′ 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.

Original language	English (US)
Pages (from-to)	527-534
Number of pages	8
Journal	Nature Structural and Molecular Biology
Volume	14
Issue number	6
DOIs	https://doi.org/10.1038/nsmb1254
State	Published - Jun 2007

All Science Journal Classification (ASJC) codes

Molecular Biology
Structural Biology

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

abstract = "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′ (also called PR61 or B56) regulatory subunit. ST has a lower binding affinity than B′ for the PP2A core enzyme. Consequently, ST does not efficiently displace B′ 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.",

author = "Yu Chen and Yanhui Xu and Qing Bao and Yongna Xing and Zhu Li and Zheng Lin and Stock, {Jeffry B.} and Jeffrey, {Philip D.} and Yigong Shi",

note = "Funding Information: We thank T. Roberts at Harvard Medical School for the complementary DNA encoding SV40 ST, and A. Saxena at the beamlines of the National Synchrotron Light Source, Brookhaven National Laboratory for help. This work was supported by grant R01-CA123155 from the US National Institutes of Health (Y.S.).",

year = "2007",

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doi = "10.1038/nsmb1254",

language = "English (US)",

volume = "14",

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T1 - Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40

AU - Chen, Yu

AU - Xu, Yanhui

AU - Bao, Qing

AU - Xing, Yongna

AU - Li, Zhu

AU - Lin, Zheng

AU - Stock, Jeffry B.

AU - Jeffrey, Philip D.

AU - Shi, Yigong

N1 - Funding Information: We thank T. Roberts at Harvard Medical School for the complementary DNA encoding SV40 ST, and A. Saxena at the beamlines of the National Synchrotron Light Source, Brookhaven National Laboratory for help. This work was supported by grant R01-CA123155 from the US National Institutes of Health (Y.S.).

PY - 2007/6

Y1 - 2007/6

N2 - 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′ (also called PR61 or B56) regulatory subunit. ST has a lower binding affinity than B′ for the PP2A core enzyme. Consequently, ST does not efficiently displace B′ 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.

AB - 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′ (also called PR61 or B56) regulatory subunit. ST has a lower binding affinity than B′ for the PP2A core enzyme. Consequently, ST does not efficiently displace B′ 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.

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

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