"PP2" redirects here. For the kinase inhibitor, see PP2 (kinase inhibitor). For the movie, see The Pink Panther 2.
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
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.
Contents
1Structure and function
2Drug discovery
3References
4Further reading
5External links
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 (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
PPP2R2A
PP2A 55 kDa regulatory subunit B alpha isoform
subunit A, B-alpha isoform
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
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
^ abcCho US, Xu W (January 2007). "Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme". Nature. 445 (7123): 53–7. doi:10.1038/nature05351. PMID 17086192.
^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.
^Mumby M (2007). "PP2A: unveiling a reluctant tumor suppressor". Cell. 130 (1): 21–24. doi:10.1016/j.cell.2007.06.034. PMID 17632053.
^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.
^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.
^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.
^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
Seshacharyulu P, Pandey P, Datta K, Batra SK (July 2013). "Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer". Cancer Letters. 335 (1): 9–18. doi:10.1016/j.canlet.2013.02.036. PMC 3665613. PMID 23454242.
Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E, Yu JW, Strack S, Jeffrey PD, Shi Y (December 2006). "Structure of the protein phosphatase 2A holoenzyme". Cell. 127 (6): 1239–51. doi:10.1016/j.cell.2006.11.033. PMID 17174897.
Xing Y, Xu Y, Chen Y, Jeffrey PD, Chao Y, Lin Z, Li Z, Strack S, Stock JB, Shi Y (October 2006). "Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins". Cell. 127 (2): 341–53. doi:10.1016/j.cell.2006.09.025. PMID 17055435.
Ory S, Zhou M, Conrads TP, Veenstra TD, Morrison DK (August 2003). "Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites". Current Biology. 13 (16): 1356–64. doi:10.1016/S0960-9822(03)00535-9. PMID 12932319.
External links
PPP2CA+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
β-Arrestin2 Contributes to Cell Viability and Proliferation via the Down-Regulation of FOXO1 in Castration-Resistant Prostate Cancer.
Duan X1, Kong Z1, Liu Y1, Zeng Z2, Li S1, Wu W1, Ji W1, Yang B1, Zhao Z1, Zeng G1.
Journal of cellular physiology.J Cell Physiol.2015 Oct;230(10):2371-81. doi: 10.1002/jcp.24963.
β-Arrestin2 has been identified to act as a corepressor of androgen receptor (AR) signaling by binding to AR and serving as a scaffold to affect the activity and expression of AR in androgen-dependent prostate cancer cells; however, little is known regarding its role in castration-resistant prostat
Cellular signalling.Cell Signal.2015 Sep;27(9):1840-9. doi: 10.1016/j.cellsig.2015.06.001. Epub 2015 Jun 12.
Mitochondria function as the powerhouses of the cell for energy conversion through the oxidative phosphorylation process. Accumulation of dysfunctional mitochondria promotes a bioenergetic crisis and cell death by apoptosis. Yeast cells lacking Isc1p, an orthologue of mammalian neutral sphingomyelin
Journal of virology.J Virol.2015 Sep 1;89(17):8855-70. doi: 10.1128/JVI.03710-14. Epub 2015 Jun 17.
When expressed alone at high levels, the human adenovirus E4orf4 protein exhibits tumor cell-specific p53-independent toxicity. A major E4orf4 target is the B55 class of PP2A regulatory subunits, and we have shown recently that binding of E4orf4 inhibits PP2A(B55) phosphatase activity in a dose-depe
A Protein Phosphatase 2A Catalytic Subunit Modulates Blue Light-Induced Chloroplast Avoidance Movements through Regulating Actin Cytoskeleton in Arabidopsis
Wen Feng,Wang Jinqian,Xing Da
Plant and Cell Physiology 53(8), 1366-1379, 2012-08
PP2A-B’γ (gamma) の機能解析： ・PP2A・・・・ PP2A-B'制御サブユニットの遺伝子変異はパキシリンのリン酸化制御異常 を介して細胞の運動性を亢進する： Ito A, Kataoka TR, Watanabe M, Nishiyama K, Mazaki Y, Sabe H, Kitamura Y ...
