PP2A

PPA2. Protein phosphatase type 2A, a major serine/threonine PPase in eukaryotic cells. Ver. 0.1.

Several holoenzyme complexes of PP2A have been isolated from a variety of tissues and have been extensively characterized. The core enzyme is a dimer (PP2AD), consisting of a 36 kDa catalytic subunit (PP2AC) and a regulatory subunit of molecular mass 65 kDa, termed PR65 or the A subunit. A third regulatory B subunit can be associated with this core structure. At present, four different families of B subunits have been identifed, termed the B, B’’, B’’ and B’’’ families (Janssens 2001) [1].

PP2AD was shown to represent at least one-third of the total cellular PP2A (Kremmer 1997) [2].

https://www.genecards.org/cgi-bin/carddisp.pl?gene=PPP2CA Protein Phosphatase 2 Catalytic Subunit Alpha

https://www.genecards.org/cgi-bin/carddisp.pl?gene=PPP2R1A Protein Phosphatase 2 Scaffold Subunit Aalpha

https://www.genecards.org/cgi-bin/carddisp.pl?gene=PPP2R1B Protein Phosphatase 2 Scaffold Subunit Abeta

https://www.genecards.org/cgi-bin/carddisp.pl?gene=PPP2R5A Protein Phosphatase 2 Regulatory Subunit B'Alpha

https://www.genecards.org/cgi-bin/carddisp.pl?gene=PPP2R5B Protein Phosphatase 2 Regulatory Subunit B'Beta

https://www.genecards.org/cgi-bin/carddisp.pl?gene=PPP2R5C Protein Phosphatase 2 Regulatory Subunit B'Gamma

https://www.genecards.org/cgi-bin/carddisp.pl?gene=PPP2R5E Protein Phosphatase 2 Regulatory Subunit B'Epsilon

Structure

Structure of PP2A (Janssens 2001) [1].

Structure of PP2A. C is the catalytic subunit, A is the second regulatory or structural subunit, and B/B’/B’’/B’’’ are the third variable subunits, which are structurally unrelated. In Mammalia, A and C are encoded by two genes (a and b) ; the B/PR55 subunits are encoded by four related genes (a, b, c and d) ; the B’/PR61 family are encoded by five related genes (a, b, c, d and e), some of which give rise to alternatively spliced products ; the B’’ family probably contains three related genes, encoding PR48, PR59 and the splice variants PR72 and PR130; SG2NA and striatin comprise the B’’’ subunit family.

The structure of PP2AC has remained remarkably constant throughout evolution, and may even be the most conserved of all known enzymes (Cohen 1990) [3].

Although approximately one-third of PP2A is estimated to occur as a dimeric complex composed of one catalytic C subunit and one structural A subunit (PP2AD) [5], the majority of these PP2A complexes are heterotrimers, consisting of one catalytic C subunit, one structural A subunit, and one variable regulatory B-type subunit (Sents 2013) [4].

For the B-type subunits, 15 human genes have been described, belonging to four distinct families: PPP2R2 (A to D) (encoding PR55⁄B or B55 subunits), PPP2R5 (A to E) (encoding PR61⁄B’ or B56 subunits), PPP2R3 (A to C) (encoding PR72 ⁄B’’ subunits) and the striatin genes STRN, STRN3 and STRN4 (encoding PR93 ⁄ PR110 ⁄B’’’). Some of these genes generate multiple isoforms arising from alternative splicing or translation [4,10–12], eventually giving rise to at least 23 different B-type subunit isoforms. The final composition of the holoenzyme, resulting from the combinatorial assembly of just one C subunit, one A subunit, and one B-type subunit, eventually provides the essential determinants for subcellular targeting [13], substrate specificity and fine-tuning of phosphatase activity (reviewed in [3,14– 16]), and these holoenzyme properties are mainly determined by the regulatory B-type subunits (Sents 2013) [4].

Action

(Joseph ‎2015) [5]. Protein phosphatase 2A heterotrimer, PP2APpp2r2d, regulates the phosphorylation state of AMP kinase by dephosphorylating Thr-172, a residue that activates kinase activity when phosphorylated. PP2APpp2r2d directly interacted with AMP kinase. PP2APpp2r2d dephosphorylated Thr-172 in human vascular smooth muscle cells.

(Park 2013) [6]. The dephosphorylation of AMPK is associated with the actions of various Ser/Thr protein phosphatases. Protein phosphatase (PP)2C and PP2A are both capable of dephosphorylating AMPK at Thr172 in vitro, whereas protein phosphatase 1 is much less effective [9]. Wang and Unger [10] demonstrated that a decrease in AMPK activity is associated with an increase in PP2C activation, while others indicated that AMPK deactivation is correlative with PP2A activation instead of PP2C [11]. PP2A is ubiquitously expressed in eukaryotic cells.

Kinetics

The concentration of phosphatase was expressed as nmol of PP2Aα per minute per nmol of pAMPK in the reaction (Rajamohan 2016) [7].

Phosphatase (PP2Aα) sensitivity of AMPK isoforms

References

1. Janssens V and Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J. 2001 Feb 1;353(Pt 3):417-39. DOI:10.1042/0264-6021:3530417 |
2. Kremmer E, Ohst K, Kiefer J, Brewis N, and Walter G. Separation of PP2A core enzyme and holoenzyme with monoclonal antibodies against the regulatory A subunit: abundant expression of both forms in cells. Mol Cell Biol. 1997 Mar;17(3):1692-701. DOI:10.1128/MCB.17.3.1692 |
3. Cohen PT, Brewis ND, Hughes V, and Mann DJ. Protein serine/threonine phosphatases; an expanding family. FEBS Lett. 1990 Aug 1;268(2):355-9. DOI:10.1016/0014-5793(90)81285-v |
4. Sents W, Ivanova E, Lambrecht C, Haesen D, and Janssens V. The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity. FEBS J. 2013 Jan;280(2):644-61. DOI:10.1111/j.1742-4658.2012.08579.x |
5. Joseph BK, Liu HY, Francisco J, Pandya D, Donigan M, Gallo-Ebert C, Giordano C, Bata A, and Nickels JT Jr. Inhibition of AMP Kinase by the Protein Phosphatase 2A Heterotrimer, PP2APpp2r2d. J Biol Chem. 2015 Apr 24;290(17):10588-98. DOI:10.1074/jbc.M114.626259 |
6. Park S, Scheffler TL, Rossie SS, and Gerrard DE. AMPK activity is regulated by calcium-mediated protein phosphatase 2A activity. Cell Calcium. 2013 Mar;53(3):217-23. DOI:10.1016/j.ceca.2012.12.001 |
7. Rajamohan F, Reyes AR, Frisbie RK, Hoth LR, Sahasrabudhe P, Magyar R, Landro JA, Withka JM, Caspers NL, Calabrese MF, Ward J, and Kurumbail RG. Probing the enzyme kinetics, allosteric modulation and activation of α1- and α2-subunit-containing AMP-activated protein kinase (AMPK) heterotrimeric complexes by pharmacological and physiological activators. Biochem J. 2016 Mar 1;473(5):581-92. DOI:10.1042/BJ20151051 |