PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer

Abstract

PP2A is a highly conserved eukaryotic serine/threonine protein phosphatase of the PPP family of phosphatases with fundamental cellular functions. In cells, PP2A targets specific subcellular locations and substrates by forming heterotrimeric holoenzymes, where a core dimer consisting of scaffold (A) and catalytic (C) subunits complexes with one of many B regulatory subunits. PP2A plays a key role in positively and negatively regulating a myriad of cellular processes, as it targets a very sizable fraction of the cellular substrates phosphorylated on Ser/Thr residues. This review focuses on insights made toward the understanding on how the subunit composition and structure of PP2A holoenzymes mediates substrate specificity, the role of substrate modulation in the signaling of cellular division, growth, and differentiation, and its deregulation in cancer.

Keywords: B55α; Cancer; Cell cycle; PP2A holoenzyme; PPP2R2A; Phosphorylation; Retinoblastoma protein (pRB); Serine/threonine protein phosphatases; Substrate specificity; p107.

Figure 1.. Assembly and composition of trimeric PP2A holoenzymes.

(A) The cartoon depicts the linear pathway for the biogenesis of trimeric PP2A holoenzymes, starting from latent, inactive catalytic C subunit complexed with α4. PTPA displaces α4 and loads catalytic metal ions into the active site, allowing the C subunit to now complex with the scaffold A subunit. The reversible carboxymethylation of L309 of the C-terminal tail of the C subunit is then mediated by the PP2A-specific enzymes LCMT1 and PME1, respectively. The core dimer now complexes with one of four families of B regulatory subunits to form an active, trimeric PP2A holoenzyme. The crystal structures of the core dimer and the trimeric holoenzymes containing B (B55α), B’ (B56γ), B” (PR70), and the coiled coil domain of SG2NA (STRN3) have been solved (see text for details). (B) The cartoon depicts the B regulatory and C catalytic subunit contacts with the 15 HEAT repeats of the scaffold A subunit of PP2A. B55α and PR70 contact HEAT repeats 1–7 of PP2A/A, while B56γ makes contact with HEAT repeats 2–8 of PP2A/A. The catalytic C subunit interacts with HEAT repeats 11–15 of the scaffold A subunit. *The coiled coil domain of SG2NA is known to make contacts with HEAT repeats 1–3 of PP2A/A, although it does not exclude possible contacts with additional HEAT repeats.

Figure 2.. Crystal structures of B55α, B56γ, and PR70-containing PP2A holoenzymes.

Pymol surface structures of trimeric PP2A holoenzymes containing B55α, B56γ, and PR70 are depicted in this figure. The scaffold A subunit is colored light green and the catalytic C subunit is colored light orange with microcystin (bright green) in the active site. Each of the B regulatory subunits are depicted with their electrostatic potentials indicated (red indicates acidic, while blue indicates basic). The surfaces of B55α and B56γ facing the active site are more acidic as compared to PR70, supporting the notion that the pocket created by each B subunit immediately adjacent to the active site of PP2A/C is unique in shape and electrostatic nature. The top surface of B55α also features a deep groove surrounding the central hole of the β-propeller in close proximity to the active site. B56γ makes many contacts with the catalytic C subunit as compared to B55α and PR70. The surface of PR70 appears less proximal to the active site of the enzyme than that of B55α and B56γ.