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Protein phosphatase 2

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Class of enzyme complexes

"PP2" redirects here. For the kinase inhibitor, seePP2 (kinase inhibitor). For the movie, seeThe Pink Panther 2. For the other movie, seePitch Perfect 2.

protein phosphatase 2, catalytic subunit, alpha isoform

The catalytic (C) subunit of protein phosphatase 2A. The protein is shown in rainbow color with theN-terminus in blue and theC-terminus in red. Themethylated carboxyl group of the C-terminalleucine residue is shown in white. The purple spheres are two catalytically requiredmanganese ions and the dark gray compound at center is a peptidomimetic toxin,microcystin, occupying theactive site. FromPDB:2IAE.^[1]

Identifiers

Symbol

Other data

Chr. 5q23-q31

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Structures	Swiss-model
Domains	InterPro

protein phosphatase 2, catalytic subunit, beta isoform

Identifiers

Symbol

Other data

Chr. 8p12

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Structures	Swiss-model
Domains	InterPro

Protein phosphatase 2(PP2), also known asPP2A, is anenzyme that in humans is encoded by thePPP2CAgene.^[2]^[3] The PP2Aheterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity ineukaryotic cells.^[4] Itsserine/threonine phosphatase activity has a broad substrate specificity and diverse cellular functions. Among the targets of PP2A are proteins of oncogenic signaling cascades, such asRaf,MEK, andAKT, where PP2A may act as a tumor suppressor.

Structure and function

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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 theHEAT 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. Multicellulareukaryotes 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'sactive site aremanganese.^[1]

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
	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
Catalytic subunit C	PPP2CB	catalytic subunit beta isoform

The assembled heterotrimer of protein phosphatase 2A. The structural subunit A, consisting of 15HEAT 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 fromPDB:2IAE.) Superposed is the unbound form of the regulatory subunit A in gray (fromPDB:1B3U), illustrating the flexibility of thisalpha 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

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PP2 has been identified as a potentialbiological target to discover drugs to treatParkinson's disease andAlzheimer'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 atumor suppressor forblood 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

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^^a ^b ^cCho 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.
^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.
^Virshup DM, Shenolikar S (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.
^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.
^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.
^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.
^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.

External links

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PPP2CA+protein,+human at the U.S. National Library of MedicineMedical Subject Headings (MeSH)
Rubratoxin

Hydrolase:esterases (EC 3.1)

3.1.1:Carboxylic
ester hydrolases

Lipase

Phospholipase
- A1
- A2
- B

3.1.2:Thioesterase

3.1.3:Phosphatase

3.1.4:
Phosphodiesterase

3.1.6:Sulfatase

Nuclease (includes
deoxyribonuclease
andribonuclease)

3.1.11-16:
Exonuclease

Exodeoxyribonuclease	RecBCD
Exoribonuclease	Oligonucleotidase

3.1.21-31:
Endonuclease

Endodeoxyribonuclease	Deoxyribonuclease I Deoxyribonuclease II Deoxyribonuclease IV Restriction enzyme;see{{Restriction enzyme}} UvrABC endonuclease
Endoribonuclease	RNase III Drosha:Microprocessor complex Dicer:RNA-induced silencing complex RNase H 1 2A 2B 2C RNase P RNase A RNase Z RNase E 1 2 3 4/5 RNase T1
either deoxy- or ribo-	Nuclease S1 Mung bean nuclease Serratia marcescens nuclease Micrococcal nuclease

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1Oxidoreductases (list) EC2Transferases (list) EC3Hydrolases (list) EC4Lyases (list) EC5Isomerases (list) EC6Ligases (list) EC7Translocases (list)

Intracellular signaling peptides and proteins

MAP

seeMAP kinase pathway

Calcium

G protein

Heterotrimeric

cAMP:	Heterotrimeric G protein Gs/Gi Adenylate cyclase cAMP 3',5'-cyclic-AMP phosphodiesterase Protein kinase A
cGMP:	Transducin Gustducin Guanylate cyclase cGMP 3',5'-cyclic-GMP phosphodiesterase Protein kinase G
G alpha subunit G_α GNAO1 GNAI1 GNAI2 GNAI3 GNAT1 GNAT2 GNAT3 GNAZ GNAS GNAL GNAQ GNA11 GNA12 GNA13 GNA14 GNA15/GNA16
G beta-gamma complex G_β GNB1 GNB2 GNB3 GNB4 GNB5 G_γ GNGT1 GNGT2 GNG2 GNG3 GNG4 GNG5 GNG7 GNG8 GNG10 GNG11 GNG12 GNG13 BSCL2
G protein-coupled receptor kinase AMP-activated protein kinase

Monomeric

Cyclin

Lipid

Otherprotein kinase

Serine/threonine:	Casein kinase 1 2 eIF-2 kinase EIF2AK3 Glycogen synthase kinase GSK1 GSK2 GSK-3 GSK3A GSK3B IκB kinase CHUK IKK2 IKBKG Interleukin-1 receptor associated kinase IRAK1 IRAK2 IRAK3 IRAK4 Lim kinase LIMK1 LIMK2 p21-activated kinases PAK1 PAK2 PAK3 PAK4 Rho-associated protein kinase ROCK1 ROCK2 Ribosomal s6 kinase RPS6KA1
Tyrosine:	ZAP70 Focal adhesion protein-tyrosine kinase PTK2 PTK2B BTK
Serine/threonine/tyrosine	Dual-specificity kinase DYRK1A DYRK1B DYRK2 DYRK3 DYRK4
Arginine	Arginine kinase McsB

Otherprotein phosphatase

Serine/threonine:	Protein phosphatase 2
Tyrosine:	protein tyrosine phosphatase:Receptor-like protein tyrosine phosphatase Sh2 domain-containing protein tyrosine phosphatase
both:	Dual-specificity phosphatase