Structural basis of PP2A inhibition by small t antigen.
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.
Cho
Uhn Soo
US
Department of Biological Structure, University of Washington, Seattle, Washington, United States of America.
Morrone
Seamus
S
Sablina
Anna A
AA
Arroyo
Jason D
JD
Hahn
William C
WC
Xu
Wenqing
W
D000595:Amino Acid Sequence; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004252:DNA Mutational Analysis; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D021122:Protein Subunits / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D013539:Simian virus 40 / Q000276:immunology*
D000957:Antigens, Viral, Tumor; D021122:Protein Subunits; D054648:Protein Phosphatase 2