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J. Biol. Chem., Vol. 281, Issue 32, 22434-22438, August 11, 2006

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The Crystal Structure of a Human PP2A Phosphatase Activator Reveals a Novel Fold and Highly Conserved Cleft Implicated in Protein-Protein Interactions^*

Audur Magnusdottir, Pål Stenmark, Susanne Flodin, Tomas Nyman, Martin Hammarström, Maria Ehn, M Amin Bakali H, Helena Berglund, and Pär Nordlund^¶1

From the Department of Biochemistry and Biophysics, Stockholm University 10691 Stockholm, Sweden, the Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden, and the ^¶Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden

Protein phosphatase 2A (PP2A) is a heterotrimeric Ser/Thr phosphatase that is involved in regulating a plethora of signaling pathways in the cell, making its regulation a critical part of the well being of the cell. For example, three of the non-catalytic PP2A subunits have been linked to carcinogenic events. Therefore, the molecular basis for the complicated protein-protein interaction pattern of PP2A and its regulators is of special interest. The PP2A phosphatase activator (PTPA) protein is highly conserved from humans to yeast. It is an activator of PP2A and has been shown to be essential for a fully functional PP2A, but its mechanism of activation is still not well defined. We have solved the crystal structure of human PTPA to 1.6Å. It reveals a two-domain protein with a novel fold comprised of 13 -helices. We have identified a highly conserved cleft as a potential region for interaction with peptide segments of other proteins. Binding studies with ATP and its analogs are not consistent with ATP being a cofactor/substrate for PTPA as had previously been proposed. The structure of PTPA can serve as a basis for structurefunction studies directed at elucidating its mechanism as an activator of PP2A.

Received for publication, April 28, 2006 , and in revised form, June 15, 2006.

^* The Structural Genomics Consortium is a registered charity (number 1097737) funded by the Wellcome Trust, GlaxoSmithKline, Genome Canada, the Canadian Institutes of Health Research, the Ontario Innovation Trust, the Ontario Research and Development Challenge Fund, the Canadian Foundation for Innovation, VINNOVA, The Knut and Alice Wallenberg Foundation, The Swedish Foundation for Strategic Research, and Karolinska Institutet. This work was also supported by grants from the Swedish Research Council and the Swedish Cancer Society. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 2G62) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ To whom correspondence should be addressed. Tel.: 46-852486860; Fax: 46-852486850; E-mail: par.nordlund{at}mbb.ki.se.

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