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.
Highlights
Simian virus 40 (SV40) is a DNA tumor virus in the polyomavirus family
phosphatase 2A (PP2A) is a family of heterotrimeric enzymes, composed of a structural A subunit, a catalytic C subunit, and one of several regulatory B subunits
We have determined the structure of SV40 small t antigen (ST) in complex with the PP2A structural subunit Aa
Summary
SV40 may play a role in a subset of human cancers, and the study of transformation induced by SV40 has led to many insights into the pathways involved in spontaneously arising cancers [1]. LT binds to a number of host proteins including the retinoblastoma and p53 tumor suppressors. ST, which shares its N terminus with LT but has a unique C-terminal end, is a potent oncoprotein that plays a critical role in the transformation of several human cell types [2,3]. The tumorigenic activity of ST is strictly dependent on its interaction with protein phosphatase 2A (PP2A), since mutant versions of ST that are unable to bind PP2A fail to induce tumorigenic activity [5]
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