Protein phosphatase 2
Protein phosphatase 2 , also known as PP2A, is an enzyme that in humans is encoded by the PPP2CA gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in eukaryotic cells. Its serine/threonine phosphatase activity has a broad substrate specificity and diverse cellular functions. Among the targets of PP2A are proteins of oncogenic signaling cascades, such as Raf, MEK, and AKT, where PP2A may act as a tumor suppressor.
Structure and function
PP2A consists of a dimeric core enzyme composed of the structural A and catalytic C subunits, and a regulatory B subunit. When the PP2A catalytic C subunit associates with the A and B subunits several species of holoenzymes are produced with distinct functions and characteristics. The A subunit, a founding member of the HEAT repeat protein family, is the scaffold required for the formation of the heterotrimeric complex. When the A subunit binds it alters the enzymatic activity of the catalytic subunit, even if the B subunit is absent. While C and A subunit sequences show remarkable sequence conservation throughout eukaryotes, regulatory B subunits are more heterogeneous and are believed to play key roles in controlling the localization and specific activity of different holoenzymes. Multicellular eukaryotes express four classes of variable regulatory subunits: B, B′, B″, and B‴, with at least 16 members in these subfamilies. In addition, accessory proteins and post-translational modifications control PP2A subunit associations and activities.The two catalytic metal ions located in PP2A's active site are manganese.
| Function | Protein | Description | Note |
| Structural subunit A | PPP2R1A | PP2A 65 kDa regulatory subunit A alpha isoform | subunit A, PR65-alpha isoform |
| Structural subunit A | PPP2R1B | PP2A 65 kDa regulatory subunit A beta isoform | subunit A, PR65-beta isoform |
| Regulatory subunit B | PPP2R2A | PP2A 55 kDa regulatory subunit B alpha isoform | subunit A, B-alpha isoform |
| Regulatory subunit B | PPP2R2B | PP2A 55 kDa regulatory subunit B beta isoform | subunit B, B-beta isoform |
| Regulatory subunit B | PPP2R2C | PP2A 55 kDa regulatory subunit B gamma isoform | subunit B, B-gamma isoform |
| Regulatory subunit B | PPP2R2D | PP2A 55 kDa regulatory subunit B delta isoform | subunit B, B-delta isoform |
| Regulatory subunit B | PPP2R3A | PP2A 72/130 kDa regulatory subunit B | subunit B, B |
| Regulatory subunit B | PPP2R3B | PP2A 48 kDa regulatory subunit B | subunit B, PR48 isoform |
| Regulatory subunit B | PPP2R3C | PP2A regulatory subunit B | subunit G5PR |
| Regulatory subunit B | PPP2R4 | PP2A regulatory subunit B' | subunit B', PR53 isoform |
| Regulatory subunit B | PPP2R5A | PP2A 56 kDa regulatory subunit alpha isoform | subunit B, B' alpha isoform |
| Regulatory subunit B | PPP2R5B | PP2A 56 kDa regulatory subunit beta isoform | subunit B, B' beta isoform |
| Regulatory subunit B | PPP2R5C | PP2A 56 kDa regulatory subunit gamma isoform | subunit B, B' gamma isoform |
| Regulatory subunit B | PPP2R5D | PP2A 56 kDa regulatory subunit delta isoform | subunit B, B' delta isoform |
| Regulatory subunit B | PPP2R5E | PP2A 56 kDa regulatory subunit epsilon isoform | subunit B, B' epsilon isoform |
| Catalytic subunit C | PPP2CA | catalytic subunit alpha isoform | - |
| Catalytic subunit C | PPP2CB | catalytic subunit beta isoform | - |
s, is shown in rainbow color with the N-terminus in blue at bottom and the C-terminus in red at top. The regulatory subunit B, consisting of irregular pseudo-HEAT repeats, is shown in light blue. The catalytic subunit C is shown in tan. Superposed is the unbound form of the regulatory subunit A in gray, illustrating the flexibility of this alpha solenoid protein. Conformational changes in HEAT repeat 11 result in flexing the C-terminal end of the protein to accommodate binding of the catalytic subunit.
Drug discovery
PP2 has been identified as a potential biological target to discover drugs to treat Parkinson's disease and Alzheimer's disease, however as of 2014 it was unclear which isoforms would be most beneficial to target, and also whether activation or inhibition would be most therapeutic.PP2 has also been identified as a tumor suppressor for blood cancers, and as of 2015 programs were underway to identify compounds that could either directly activate it, or that could inhibit other proteins that suppress its activity.