title: Structure of the Ca2+-dependent PP2A heterotrimer and insights into Cdc6 dephosphorylation.
abstract: 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.
authors.affiliation: McArdle Laboratory, Department of Oncology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Wlodarchak
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Satyshur
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Philip D
authors.initials: PD
authors.lastname: Jeffrey
authors.forename: Tingwan
authors.initials: T
authors.lastname: Sun
authors.forename: Vitali
authors.initials: V
authors.lastname: Stanevich
authors.forename: Marc C
authors.initials: MC
authors.lastname: Mumby
authors.forename: Yongna
authors.initials: Y
authors.lastname: Xing
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D018360:Crystallography, X-Ray; D020035:Holoenzymes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000737:chemistry* / Q000378:metabolism*; D021122:Protein Subunits / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D018797:Cell Cycle Proteins; D020035:Holoenzymes; D021122:Protein Subunits; D054648:Protein Phosphatase 2; D002118:Calcium