protein phosphatase 2, catalytic subunit, alpha isoform
The catalytic (C) subunit of protein phosphatase 2A. The protein is shown in rainbow color with the N-terminus in blue and the C-terminus in red. The methylated carboxyl group of the C-terminal leucine residue is shown in white. The purple spheres are two catalytically required manganese ions and the dark gray compound at center is a peptidomimetic toxin, microcystin, occupying the active site. From PDB: 2IAE​.[1]
Identifiers
SymbolPPP2CA
NCBI gene5515
HGNC9299
OMIM176915
RefSeqNM_002715
UniProtP67775
Other data
EC number3.1.3.16
LocusChr. 5 q23-q31
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StructuresSwiss-model
DomainsInterPro
protein phosphatase 2, catalytic subunit, beta isoform
Identifiers
SymbolPPP2CB
NCBI gene5516
HGNC9300
OMIM176916
RefSeqNM_001009552
UniProtP62714
Other data
EC number3.1.3.16
LocusChr. 8 p12
Search for
StructuresSwiss-model
DomainsInterPro

Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the PPP2CA gene.[2][3] The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in eukaryotic cells.[4] 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 (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.[1]

FunctionProteinDescriptionNote
Structural subunit APPP2R1APP2A 65 kDa regulatory subunit A alpha isoformsubunit A, PR65-alpha isoform
PPP2R1BPP2A 65 kDa regulatory subunit A beta isoformsubunit A, PR65-beta isoform
Regulatory subunit BPPP2R2APP2A 55 kDa regulatory subunit B alpha isoformsubunit A, B-alpha isoform
PPP2R2BPP2A 55 kDa regulatory subunit B beta isoformsubunit B, B-beta isoform
PPP2R2CPP2A 55 kDa regulatory subunit B gamma isoformsubunit B, B-gamma isoform
PPP2R2DPP2A 55 kDa regulatory subunit B delta isoformsubunit B, B-delta isoform
PPP2R3APP2A 72/130 kDa regulatory subunit Bsubunit B, B''-PR72/PR130
PPP2R3BPP2A 48 kDa regulatory subunit Bsubunit B, PR48 isoform
PPP2R3CPP2A regulatory subunit B'' subunit gammasubunit G5PR
PPP2R4PP2A regulatory subunit B'subunit B', PR53 isoform
PPP2R5APP2A 56 kDa regulatory subunit alpha isoformsubunit B, B' alpha isoform
PPP2R5BPP2A 56 kDa regulatory subunit beta isoformsubunit B, B' beta isoform
PPP2R5CPP2A 56 kDa regulatory subunit gamma isoformsubunit B, B' gamma isoform
PPP2R5DPP2A 56 kDa regulatory subunit delta isoformsubunit B, B' delta isoform
PPP2R5EPP2A 56 kDa regulatory subunit epsilon isoformsubunit B, B' epsilon isoform
Catalytic subunit CPPP2CAcatalytic subunit alpha isoform
PPP2CBcatalytic subunit beta isoform
The assembled heterotrimer of protein phosphatase 2A. The structural subunit A, consisting of 15 HEAT repeats, 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.[1][5]

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.[6][7]

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.[8]

References

  1. 1 2 3 Cho US, Xu W (January 2007). "Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme". Nature. 445 (7123): 53–7. Bibcode:2007Natur.445...53C. doi:10.1038/nature05351. PMID 17086192. S2CID 4408160.
  2. ↑ Jones TA, Barker HM, da Cruz e Silva EF, Mayer-Jaekel RE, Hemmings BA, Spurr NK, Sheer D, Cohen PT (1993). "Localization of the genes encoding the catalytic subunits of protein phosphatase 2A to human chromosome bands 5q23→q31 and 8p12→p11.2, respectively". Cytogenetics and Cell Genetics. 63 (1): 35–41. doi:10.1159/000133497. PMID 8383590.
  3. ↑ Virshup, David M.; Shenolikar, Shirish (2009). "From Promiscuity to Precision: Protein Phosphatases Get a Makeover". Molecular Cell. 33 (5): 537–545. doi:10.1016/j.molcel.2009.02.015. PMID 19285938.
  4. ↑ Mumby M (2007). "PP2A: unveiling a reluctant tumor suppressor". Cell. 130 (1): 21–24. doi:10.1016/j.cell.2007.06.034. PMID 17632053. S2CID 16004039.
  5. ↑ Groves MR, Hanlon N, Turowski P, Hemmings BA, Barford D (January 1999). "The structure of the protein phosphatase 2A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs". Cell. 96 (1): 99–110. doi:10.1016/S0092-8674(00)80963-0. PMID 9989501. S2CID 14465060.
  6. ↑ Braithwaite SP, Voronkov M, Stock JB, Mouradian MM (November 2012). "Targeting phosphatases as the next generation of disease modifying therapeutics for Parkinson's disease". Neurochemistry International. 61 (6): 899–906. doi:10.1016/j.neuint.2012.01.031. PMID 22342821. S2CID 30417962.
  7. ↑ Sontag JM, Sontag E (2014). "Protein phosphatase 2A dysfunction in Alzheimer's disease". Frontiers in Molecular Neuroscience. 7: 16. doi:10.3389/fnmol.2014.00016. PMC 3949405. PMID 24653673.
  8. ↑ Ciccone M, Calin GA, Perrotti D (2015). "From the Biology of PP2A to the PADs for Therapy of Hematologic Malignancies". Frontiers in Oncology. 5: 21. doi:10.3389/fonc.2015.00021. PMC 4329809. PMID 25763353.

Further reading

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