Protein phosphatase 2

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protein phosphatase 2, catalytic subunit, alpha isoform
Pp2a 2iae chainCM.png
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
Symbol PPP2CA
Entrez 5515
HUGO 9299
OMIM 176915
RefSeq NM_002715
UniProt P67775
Other data
EC number 3.1.3.16
Locus Chr. 5 q23-q31
protein phosphatase 2, catalytic subunit, beta isoform
Identifiers
Symbol PPP2CB
Entrez 5516
HUGO 9300
OMIM 176916
RefSeq NM_001009552
UniProt P62714
Other data
EC number 3.1.3.16
Locus Chr. 8 p12

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

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 (huntington-elongation-A subunit-TOR), 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 posttranslational modifications (such as methylation) control PP2A subunit associations and activities.

The two catalytic metal ions located in PP2A's active site are manganese.[1]

Function Protein Description Note
Structural subunit A PPP2R1A PP2A 65 kDa regulatory subunit A alpha isoform subunit A, PR65-alpha isoform
PPP2R1B PP2A 65 kDa regulatory subunit A beta isoform subunit A, PR65-beta isoform
Regulatory subunit B PPP2R2B PP2A 55 kDa regulatory subunit B beta isoform subunit B, B-beta isoform
PPP2R2C PP2A 55 kDa regulatory subunit B gamma isoform subunit B, B-gamma isoform
PPP2R2D PP2A 55 kDa regulatory subunit B delta isoform subunit B, B-delta isoform
PPP2R3A PP2A 72/130 kDa regulatory subunit B subunit B, B''-PR72/PR130
PPP2R3B PP2A 48 kDa regulatory subunit B subunit B, PR48 isoform
PPP2R3C PP2A regulatory subunit B'' subunit gamma subunit G5PR
PPP2R4 PP2A regulatory subunit B' subunit B', PR53 isoform
PPP2R5A PP2A 56 kDa regulatory subunit alpha isoform subunit B, B' alpha isoform
PPP2R5B PP2A 56 kDa regulatory subunit beta isoform subunit B, B' beta isoform
PPP2R5C PP2A 56 kDa regulatory subunit gamma isoform subunit B, B' gamma isoform
PPP2R5D PP2A 56 kDa regulatory subunit delta isoform subunit B, B' delta isoform
PPP2R5E PP2A 56 kDa regulatory subunit epsilon isoform subunit B, B' epsilon isoform
Catalytic subunit C PPP2CA catalytic subunit alpha isoform
PPP2CB catalytic 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, 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][4]

Drug discovery[edit]

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.[5][6]

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.[7]

References[edit]

  1. ^ a b c Cho US, Xu W (January 2007). "Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme". Nature. 445 (7123): 53–7. PMID 17086192. doi:10.1038/nature05351. 
  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. PMID 8383590. doi:10.1159/000133497. 
  3. ^ Mumby M (2007). "PP2A: unveiling a reluctant tumor suppressor". Cell (journal). 130 (1): 21–24. PMID 17632053. doi:10.1016/j.cell.2007.06.034. 
  4. ^ 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. PMID 9989501. doi:10.1016/S0092-8674(00)80963-0. 
  5. ^ 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. PMID 22342821. doi:10.1016/j.neuint.2012.01.031. 
  6. ^ Sontag JM, Sontag E (2014). "Protein phosphatase 2A dysfunction in Alzheimer's disease". Frontiers in Molecular Neuroscience. 7: 16. PMC 3949405Freely accessible. PMID 24653673. doi:10.3389/fnmol.2014.00016. 
  7. ^ 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. PMC 4329809Freely accessible. PMID 25763353. doi:10.3389/fonc.2015.00021. 

Further reading[edit]

External links[edit]