structural basis of pp2a inhibition by small t antigen抑制pp2a由小t抗原的结构基础.pdfVIP

PLoS BIOLOGY Structural Basis of PP2A Inhibition by Small t Antigen 1 1 2,3 2,3 2,3 1* Uhn Soo Cho , Seamus Morrone , Anna A. Sablina , Jason D. Arroyo , William C. Hahn , Wenqing Xu 1 Department of Biological Structure, University of Washington, Seattle, Washington, United States of America, 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America, 3 Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America 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. Citation: Cho US, Morrone S, Sablina AS, Arroyo JD, Hahn WC