Protein phosphatase 2

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 (huntingtin, EF3, PP2A, TOR1), 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 (PR55), B′ (B56 or PR61), B″ (PR72), and B‴ (PR93/PR110), with at least 16 members in these subfamilies. In addition, accessory proteins and post-translational modifications (such as methylation) control PP2A subunit associations and activities.

The two catalytic metal ions located in PP2A's active site are manganese.

File:Pp2a 2iae chainABC 1b3u chainA.pngs, 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 (B' gamma), consisting of irregular pseudo-HEAT repeats, is shown in light blue. The catalytic subunit C is shown in tan. (All from {{PDB|2IAE}}.) Superposed is the unbound form of the regulatory subunit A in gray (from {{PDB|1B3U}}), 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.{{cite journal | vauthors = Groves MR, Hanlon N, Turowski P, Hemmings BA, Barford D | title = The structure of the protein phosphatase 2A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs | journal = Cell | volume = 96 | issue = 1 | pages = 99–110 | date = January 1999 | pmid = 9989501 | doi = 10.1016/S0092-8674(00)80963-0 | s2cid = 14465060 | doi-access = free }}]]

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.{{cite journal | vauthors = Braithwaite SP, Voronkov M, Stock JB, Mouradian MM | title = Targeting phosphatases as the next generation of disease modifying therapeutics for Parkinson's disease | journal = Neurochemistry International | volume = 61 | issue = 6 | pages = 899–906 | date = November 2012 | pmid = 22342821 | doi = 10.1016/j.neuint.2012.01.031 | s2cid = 30417962 }}{{cite journal | vauthors = Sontag JM, Sontag E | title = Protein phosphatase 2A dysfunction in Alzheimer's disease | journal = Frontiers in Molecular Neuroscience | volume = 7 | pages = 16 | year = 2014 | pmid = 24653673 | pmc = 3949405 | doi = 10.3389/fnmol.2014.00016 | doi-access = free }}

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.{{cite journal | vauthors = Ciccone M, Calin GA, Perrotti D | title = From the Biology of PP2A to the PADs for Therapy of Hematologic Malignancies | journal = Frontiers in Oncology | volume = 5 | pages = 21 | year = 2015 | pmid = 25763353 | pmc = 4329809 | doi = 10.3389/fonc.2015.00021 | doi-access = free }}

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• {{cite journal | vauthors = Seshacharyulu P, Pandey P, Datta K, Batra SK | title = Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer | journal = Cancer Letters | volume = 335 | issue = 1 | pages = 9–18 | date = July 2013 | pmid = 23454242 | pmc = 3665613 | doi = 10.1016/j.canlet.2013.02.036 }}
• {{cite journal | vauthors = Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E, Yu JW, Strack S, Jeffrey PD, Shi Y | title = Structure of the protein phosphatase 2A holoenzyme | journal = Cell | volume = 127 | issue = 6 | pages = 1239–51 | date = December 2006 | pmid = 17174897 | doi = 10.1016/j.cell.2006.11.033 | s2cid = 18584536 | doi-access = free }}
• {{cite journal | vauthors = Xing Y, Xu Y, Chen Y, Jeffrey PD, Chao Y, Lin Z, Li Z, Strack S, Stock JB, Shi Y | title = Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins | journal = Cell | volume = 127 | issue = 2 | pages = 341–53 | date = October 2006 | pmid = 17055435 | doi = 10.1016/j.cell.2006.09.025 | s2cid = 17264021 | doi-access = free }}
• {{cite journal | vauthors = Ory S, Zhou M, Conrads TP, Veenstra TD, Morrison DK | title = Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites | journal = Current Biology | volume = 13 | issue = 16 | pages = 1356–64 | date = August 2003 | pmid = 12932319 | doi = 10.1016/S0960-9822(03)00535-9 | s2cid = 15865688 | doi-access = free | bibcode = 2003CBio...13.1356O }}

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• {{MeshName|PPP2CA+protein,+human}}
• Rubratoxin

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{{Intracellular signaling peptides and proteins}}

Category:Human proteins

Category:EC 3.1.3