Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40.
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.
Chen
Yu
Y
Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, New Jersey 08544, USA.
Xu
Yanhui
Y
Bao
Qing
Q
Xing
Yongna
Y
Li
Zhu
Z
Lin
Zheng
Z
Stock
Jeffry B
JB
Jeffrey
Philip D
PD
Shi
Yigong
Y
D000595:Amino Acid Sequence; D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000378:metabolism*; D002472:Cell Transformation, Viral / Q000235:genetics / Q000502:physiology*; D003460:Crystallization; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000235:genetics; D013539:Simian virus 40 / Q000276:immunology* / Q000502:physiology
D000957:Antigens, Viral, Tumor; D021122:Protein Subunits; D054648:Protein Phosphatase 2