Structural basis of PP2A inhibition by small t antigen
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Published on: August 13, 2017
Uhn Soo Cho1, Seamus Morrone, Anna A Sablina
1Department of Biological Structure, University of Washington, Seattle, Washington, United States of America.
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 A 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.
Insights
The SV40 small t antigen (ST) oncoprotein disrupts protein phosphatase 2A (PP2A) function. Structural analysis reveals ST binds the PP2A A subunit, explaining its oncogenic activity.
Area of Science:
- Biochemistry
- Structural Biology
- Oncology
Background:
- The simian virus 40 (SV40) small t antigen (ST) is a known oncoprotein.
- ST modulates the function of protein phosphatase 2A (PP2A), a key cellular regulator.
- PP2A activity is regulated by scaffolding (A), catalytic (C), and regulatory (B) subunits.
Purpose of the Study:
- To elucidate the structural mechanism by which SV40 ST interacts with and perturbs PP2A function.
- To provide a molecular basis for the oncogenic activity of ST.
Main Methods:
- Determined the crystal structure of full-length SV40 ST in complex with the PP2A A subunit.
- Utilized X-ray crystallography at 3.1 Å resolution.
Main Results:
- The crystal structure reveals ST comprises an N-terminal J domain and a C-terminal unique domain with two zinc-binding motifs.
- Both the J domain and the second zinc-binding motif of ST bind to the PP2A A subunit, overlapping with the B56 subunit binding site.
- The first zinc-binding motif of ST is positioned to potentially inhibit the PP2A catalytic C subunit.
Conclusions:
- The determined structure provides a detailed molecular understanding of ST binding to the PP2A A subunit.
- These findings offer a structural basis for the oncogenic properties of SV40 ST by explaining its disruption of PP2A.
- The results highlight potential therapeutic targets for SV40-associated oncogenesis.
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