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
NCBI gene 5515
HGNC 9299
OMIM 176915
RefSeq NM_002715
UniProt P67775
Other data
EC number 3.1.3.16
Locus Chr. 5 q23-q31
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Structures Swiss-model
Domains InterPro
protein phosphatase 2, catalytic subunit, beta isoform
Identifiers
Symbol PPP2CB
NCBI gene 5516
HGNC 9300
OMIM 176916
RefSeq NM_001009552
UniProt P62714
Other data
EC number 3.1.3.16
Locus Chr. 8 p12
Search for
Structures Swiss-model
Domains InterPro

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.

Contents

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 A PPP2R1A PP2A 65 kDa regulatory subunit A alpha isoformsubunit A, PR65-alpha isoform
PPP2R1B PP2A 65 kDa regulatory subunit A beta isoformsubunit A, PR65-beta isoform
Regulatory subunit B PPP2R2A PP2A 55 kDa regulatory subunit B alpha isoformsubunit A, B-alpha isoform
PPP2R2B PP2A 55 kDa regulatory subunit B beta isoformsubunit B, B-beta isoform
PPP2R2C PP2A 55 kDa regulatory subunit B gamma isoformsubunit B, B-gamma isoform
PPP2R2D PP2A 55 kDa regulatory subunit B delta isoformsubunit B, B-delta isoform
PPP2R3A PP2A 72/130 kDa regulatory subunit Bsubunit B, B''-PR72/PR130
PPP2R3B PP2A 48 kDa regulatory subunit Bsubunit B, PR48 isoform
PPP2R3C PP2A regulatory subunit B'' subunit gammasubunit G5PR
PPP2R4 PP2A regulatory subunit B'subunit B', PR53 isoform
PPP2R5A PP2A 56 kDa regulatory subunit alpha isoformsubunit B, B' alpha isoform
PPP2R5B PP2A 56 kDa regulatory subunit beta isoformsubunit B, B' beta isoform
PPP2R5C PP2A 56 kDa regulatory subunit gamma isoformsubunit B, B' gamma isoform
PPP2R5D PP2A 56 kDa regulatory subunit delta isoformsubunit B, B' delta isoform
PPP2R5E PP2A 56 kDa regulatory subunit epsilon isoformsubunit 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 (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. Pp2a 2iae chainABC 1b3u chainA.png
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.

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]

Related Research Articles

<span class="mw-page-title-main">PRKACA</span> Protein-coding gene in the species Homo sapiens

The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the PRKACA gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catalytic subunit is a member of the AGC kinase family, and contributes to the control of cellular processes that include glucose metabolism, cell division, and contextual memory. PKA Cα is part of a larger protein complex that is responsible for controlling when and where proteins are phosphorylated. Defective regulation of PKA holoenzyme activity has been linked to the progression of cardiovascular disease, certain endocrine disorders and cancers.

<span class="mw-page-title-main">PPP2CA</span> Enzyme

Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform is an enzyme that is encoded by the PPP2CA gene.

<span class="mw-page-title-main">PPP2R1A</span> Enzyme

Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform is an enzyme that in humans is encoded by the PPP2R1A gene. In the plant Arabidopsis thaliana a similar enzyme is encoded by the RCN1 gene (At1g25490).

<span class="mw-page-title-main">PPP2R2B</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform is an enzyme that in humans is encoded by the PPP2R2B gene.

<span class="mw-page-title-main">PPP2CB</span> Enzyme found in humans

Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform is an enzyme that in humans is encoded by the PPP2CB gene.

<span class="mw-page-title-main">PPP2R5A</span> Enzyme found in humans

Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform is an enzyme that in humans is encoded by the PPP2R5A gene.

<span class="mw-page-title-main">PPP2R2A</span> Enzyme found in humans

Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform is an enzyme regulator that in humans is encoded by the PPP2R2A gene.

<span class="mw-page-title-main">PPP2R5C</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform is an enzyme that in humans is encoded by the PPP2R5C gene.

<span class="mw-page-title-main">PPP2R4</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein phosphatase 2A regulatory subunit B is an enzyme that in humans is encoded by the PPP2R4 gene.

<span class="mw-page-title-main">PPP2R1B</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform is an enzyme that in humans is encoded by the PPP2R1B gene.

<span class="mw-page-title-main">PPP2R3A</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit alpha is an enzyme that in humans is encoded by the PPP2R3A gene. Protein phosphatase 2 is one of the four major Ser/Thr phosphatases and is implicated in the negative control of cell growth and division. Protein phosphatase 2 holoenzymes are heterotrimeric proteins composed of a structural subunit A, a catalytic subunit C, and a regulatory subunit B. The regulatory subunit is encoded by a diverse set of genes that have been grouped into the B/PR55, B'/PR61, and B''/PR72 families. These different regulatory subunits confer distinct enzymatic specificities and intracellular localizations to the holozenzyme. The product of this gene belongs to the B'' family. The B'' family has been further divided into subfamilies. The product of this gene belongs to the alpha subfamily of regulatory subunit B''. Alternative splicing results in multiple transcript variants encoding different isoforms.

<span class="mw-page-title-main">PPP2R5D</span> Protein-coding gene in humans

Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform is an enzyme that in humans is encoded by the PPP2R5D gene. Mutations in PPP2R5D cause Jordan's syndrome.

<span class="mw-page-title-main">PPP2R2C</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B gamma isoform is an enzyme that in humans is encoded by the PPP2R2C gene.

<span class="mw-page-title-main">PPP2R5B</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform is an enzyme that in humans is encoded by the PPP2R5B gene.

<span class="mw-page-title-main">PPP2R5E</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform is an enzyme that in humans is encoded by the PPP2R5E gene.

<span class="mw-page-title-main">PPP2R3B</span> Protein-coding gene in humans

Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit beta is an enzyme that in humans is encoded by the PPP2R3B gene.

<span class="mw-page-title-main">Protein phosphatase 1</span>

Protein phosphatase 1 (PP1) belongs to a certain class of phosphatases known as protein serine/threonine phosphatases. This type of phosphatase includes metal-dependent protein phosphatases (PPMs) and aspartate-based phosphatases. PP1 has been found to be important in the control of glycogen metabolism, muscle contraction, cell progression, neuronal activities, splicing of RNA, mitosis, cell division, apoptosis, protein synthesis, and regulation of membrane receptors and channels.

<span class="mw-page-title-main">B56 domain</span>

Protein phosphatase 2A (PP2A) is a major intracellular protein phosphatase that regulates multiple aspects of cell growth and metabolism. Phosphorylation enables the activation or The ability of this widely distributed heterotrimeric enzyme to act on a diverse array of substrates is largely controlled by the nature of its regulatory B subunit. There are multiple families of B subunits, this family is called the B56 family.

Ceramide-activated protein phosphatases (CAPPs) are a group of enzymes that are activated by the lipid second messenger ceramide. Known CAPPs include members of the protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) families. CAPPs are a subset of intracellular serine/threonine phosphatases. Each CAPP consists of a catalytic subunit which confers phosphatase activity and a regulatory subunit which confers substrate specificity. CAPP involvement has been implicated in glycogen metabolism, apoptotic pathways related to cancer and other cellular pathways related to Alzheimer’s disease.

<span class="mw-page-title-main">Small tumor antigen</span>

The small tumor antigen is a protein encoded in the genomes of polyomaviruses, which are small double-stranded DNA viruses. STag is expressed early in the infectious cycle and is usually not essential for viral proliferation, though in most polyomaviruses it does improve replication efficiency. The STag protein is expressed from a gene that overlaps the large tumor antigen (LTag) such that the two proteins share an N-terminal DnaJ-like domain but have distinct C-terminal regions. STag is known to interact with host cell proteins, most notably protein phosphatase 2A (PP2A), and may activate the expression of cellular proteins associated with the cell cycle transition to S phase. In some polyomaviruses - such as the well-studied SV40, which natively infects monkeys - STag is unable to induce neoplastic transformation in the host cell on its own, but its presence may increase the transforming efficiency of LTag. In other polyomaviruses, such as Merkel cell polyomavirus, which causes Merkel cell carcinoma in humans, STag appears to be important for replication and to be an oncoprotein in its own right.

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 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.
  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.

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