Volume 23, No 7, Jul 2013

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 23 Issue 7, July 2013: 931-946

ORIGINAL ARTICLES

Structure of the Ca²⁺-dependent PP2A heterotrimer and insights into Cdc6 dephosphorylation

Nathan Wlodarchak^1,*, Feng Guo^1,*, Kenneth A Satyshur¹, Li Jiang¹, Philip D Jeffrey², Tingwan Sun³, Vitali Stanevich¹, Marc C Mumby³ and Yongna Xing¹

¹McArdle Laboratory, Department of Oncology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA
²Department of Molecular Biology, Princeton University, Princeton, NJ, USA
³Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA Correspondence: Yongna Xing(xing@oncology.wisc.edu)

The B″/PR72 family of protein phosphatase 2A (PP2A) is an important PP2A family involved in diverse cellular processes, and uniquely regulated by calcium binding to the regulatory subunit. The PR70 subunit in this family interacts with cell division control 6 (Cdc6), a cell cycle regulator important for control of DNA replication. Here, we report crystal structures of the isolated PR72 and the trimeric PR70 holoenzyme at a resolution of 2.1 and 2.4 Å, respectively, and in vitro characterization of Cdc6 dephosphorylation. The holoenzyme structure reveals that one of the PR70 calcium-binding motifs directly contacts the scaffold subunit, resulting in the most compact scaffold subunit conformation among all PP2A holoenzymes. PR70 also binds distinctively to the catalytic subunit near the active site, which is required for PR70 to enhance phosphatase activity toward Cdc6. Our studies provide a structural basis for unique regulation of B″/PR72 holoenzymes by calcium ions, and suggest the mechanisms for precise control of substrate specificity among PP2A holoenzymes.

10.1038/cr.2013.77

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