PMC

Activators of PP2A. Several strategies to activate PP2A include: decreasing PP2A Y307 phosphorylation, inhibiting endogenous inhibitors (SET and CIP2A), inhibiting PME-1, and using promethylating agents.

(A) (PDB code: 3C5W) Structure of PP2A and PME-1 complex with scaffold subunit in magenta, catalytic subunit in yellow, and PME-1 in red. (B) (PDB code: 3P71) Structure of PP2A and LCMT complex with catalytic subunit in yellow and LCMT in green (C) (PDB code: 4LAC) Structure of PP2A and PTPA complex with scaffold subunit in magenta, catalytic subunit in yellow, and PTPA in orange.

(A) The C-terminus of the catalytic C subunit undergoes methylation at L309 via LCMT, a SAM-dependent methyltransferase. PME-1 mediates demethylation. (B) Decreased methylation at L309 and increased phosphorylation of Y307 and T304 of the catalytic C subunit are posttranslational modifications that inhibit PP2A.

PP2A is a heterotrimeric complex consisting of a scaffolding subunit (A), a regulatory subunit (B), and a catalytic subunit (C). PP2A A subunit is composed of 15 tandem HEAT repeats in two isoforms α and β. PP2A C subunit also exists in two possible isoforms α and β. PP2A B subunit consists of four classes: B (B55/PR55), B′ (B56/PR61), B″(PR48/PR72/PR130) and B‴(PR93/PR110).

(A) Pie chart of the frequency of PP2A mutations across 9,759 tumor samples. Mutational information was analyzed from Cbioportal.org, which includes 85 different sequencing studies, including TCGA data. Studies with targeted sequencing or expression only data were excluded from the total number. (B) Pie chart of the frequency of PP2A mutations divided by PP2A subunit families: A, B, B′, B″, and C. Bold black lines divide each subunit. Mutational information was analyzed from Cbioportal.org, which includes 85 different sequencing studies, including TCGA data. Studies with targeted sequencing or expression only data were excluded from the total number. The results shown here are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.

Structures of PP2A core enzyme and holoenzyme. (A) (PDB code: 2IE3) Core Enzyme consisting of Aα (in magenta) subunit and Cα (in yellow) subunit. The C subunit binds A at Heat Repeats 11–15. The active site of the C subunit consists of 2 manganese atoms and is positioned away from the ridge of the A subunit HEAT Repeats. Binding with the catalytic subunit shifts HEAT repeats 13–15 by 20–30 Å (B) (PDB code: 3DW8) Core Enzyme binding to B family subunit (in cyan), Bα/PR55α. Members of this subunit family bind the A subunit at two interfaces. The first is via a seven bladed propeller, composed of WD40 repeats. The bottom face of the propeller binds to A subunit HEAT domains 3–7. The second is through a β-hairpin handle that interacts with A subunit HEAT repeats 1 and 2. Upon binding to the holoenzyme, the B subunit substrate binding site lies on the top face proximal to the active site of the catalytic subunit. (C) (PDB code: 2IAE) Core enzyme binding to B′ family subunit (in cyan), Bγ1/PR61γ1. The B′ structures are similar to the A subunit, composed of 8 HEAT-like repeats. These interact with HEAT repeats 2–8 of the A subunit, and with the C subunit. Much like binding to B family subunits, the substrate binding site of B′ is proximal to the active site of the catalytic subunit upon holoenzyme formation. Binding to the B′ subunits forces the N-terminal repeat of the A subunit to twist 50–60 Å, rearranging the hydrophobic core of the scaffolding subunit. (D) (PDB code: 4I5L) Core Enzyme binding to B″ family subunit PR72 (in cyan). B″ subunits consist of a linear arrangement of different functional motifs that include an N-terminal hydrophobic motif and 2 EF hand calcium binding motifs. The N-terminal hydrophobic motif and one EF hand bind to the A subunit at HEAT repeats 1–7 and binds to the catalytic subunit via a helix on the subunit at residues 439–446 near the active site, positioning the substrate binding site near the active site. The resulting conformation of this holoenzyme is wider and taller than that which forms with B or B′ subunits.