Structural Basis of PP2A Inhibition by Small t Antigen

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Abstract
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.