Letunic et al. (2017) Nucleic Acids Res doi: 10.1093/nar/gkx922
Letunic et al. (2020) Nucleic Acids Res doi: 10.1093/nar/gkaa937

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PP2Ac Protein phosphatase 2A homologues, catalytic domain.

SMART accession number:	SM00156
Description:	Large family of serine/threonine phosphatases, that includes PP1, PP2A and PP2B (calcineurin) family members.
Interpro abstract (IPR006186):	Protein phosphorylation plays a central role in the regulation of cell functions [ (PUBMED:2827745) ], causing the activation or inhibition of many enzymes involved in various biochemical pathways [ (PUBMED:2176161) ]. Kinases and phosphatases are the enzymes responsible for this, and may themselves be subject to control through the action of hormones and growth factors [ (PUBMED:2827745) ]. Serine/threonine (S/T) phosphatases ( EC 3.1.3.16 ) catalyse the dephosphorylation of phosphoserine and phosphothreonine residues. In mammalian tissues four different types of PP have been identified and are known as PP1, PP2A, PP2B and PP2C. Except for PP2C, these enzymes are evolutionary related. The catalytic regions of the proteins are well conserved and have a slow mutation rate, suggesting that major changes in these regions are highly detrimental [ (PUBMED:2827745) ]. Protein phosphatase-1 (PP1) and protein phosphatase-2A (PP2A) have a broad specificity and there are two closely related isoforms of each, alpha and beta. PP2A is a trimeric enzyme that consists of a core composed of a catalytic subunit associated with a 65kDa regulatory subunit and a third variable subunit. Protein phosphatase-2B (PP2B or calcineurin), a calcium-dependent enzyme whose activity is stimulated by calmodulin, is composed of two subunits the catalytic A-subunit and the calcium-binding B-subunit. The specificity of PP2B is restricted. Other serine/threonine specific protein phosphatases that have been characterised include mammalian phosphatase-X (PP-X), and Drosophila phosphatase-V (PP-V), which are closely related but yet distinct from PP2A; yeast phosphatase PPH3, which is similar to PP2A, but with different enzymatic properties; and Drosophila phosphatase-Y (PP-Y), and yeast phosphatases Z1 and Z2 which are closely related but yet distinct from PP1.
GO function:	hydrolase activity (GO:0016787)
Family alignment:	View or CHROMA formatHMM/Web logoCLUSTALW formatMSF formatFASTA formatPIR format

There are 25154 PP2Ac domains in 25130 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Taxonomic distribution of proteins containing PP2Ac domain.

  This tree includes only several representative species. The complete taxonomic breakdown of all proteins with PP2Ac domain is also avaliable.

  Click on the protein counts, or double click on taxonomic names to display all proteins containing PP2Ac domain in the selected taxonomic class.

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Egloff MP, Cohen PT, Reinemer P, Barford D
  • Crystal structure of the catalytic subunit of human protein phosphatase 1 and its complex with tungstate.
  • J Mol Biol. 1995; 254: 942-59
  • Display abstract

  • Protein phosphatase 1 (PP1) is a serine/threonine protein phosphatase that is essential in regulating diverse cellular processes. Here we report the crystal structure of the catalytic subunit of human PP1 gamma 1 and its complex with tungstate at 2.5 A resolution. The anomalous scattering from tungstate was used in a multiple wavelength anomalous dispersion experiment to derive crystallographic phase information. The protein adopts a single domain with a novel fold, distinct from that of the protein tyrosine phosphatases. A di-nuclear ion centre consisting of Mn2+ and Fe2+ is situated at the catalytic site that binds the phosphate moiety of the substrate. Proton-induced X-ray emission spectroscopy was used to identify the nature of the ions bound to the enzyme. The structural data indicate that dephosphorylation is catalysed in a single step by a metal-activated water molecule. This contrasts with other phosphatases, including protein tyrosine phosphatases, acid and alkaline phosphatases which form phosphoryl-enzyme intermediates. The structure of PP1 provides insight into the molecular mechanism for substrate recognition, enzyme regulation and inhibition of this enzyme by toxins and tumour promoters and a basis for understanding the expanding family of related phosphatases which include PP2A and PP2B (calcineurin).

  • Kinoshita N, Ohkura H, Yanagida M
  • Distinct, essential roles of type 1 and 2A protein phosphatases in the control of the fission yeast cell division cycle.
  • Cell. 1990; 63: 405-15
  • Display abstract

  • The activities of type 1 protein phosphatase (PP1) and 2A (PP2A) have distinct, essential roles in cell cycle control. Two previously identified PP1 genes (dis2+ and sds21+) and two PP2A genes (ppa1+ and ppa2+), highly homologous to mammalian PP2A, have been isolated from fission yeast. Only double gene disruption of both PP2A genes results in lethality, as is the case for PP1 genes. By fractionating and assaying PPases in wild-type, various deletion, and point mutant strains, the decrease of PP1 or PP2A activity is shown to cause mitotic defects, exhibiting strikingly different cell cycle phenotypes: cold-sensitive mutations in the same amino acid lesion of PP1 and PP2A produce chromosome nondisjunction and premature mitosis, respectively. Consistently, PP1 and PP2A genes cannot be functionally substituted. Although the overall levels of PP1 and PP2A activities do not fluctuate during the cell cycle, subpopulations might be regulated.

  • Berndt N et al.
  • Isolation and sequence analysis of a cDNA clone encoding a type-1 protein phosphatase catalytic subunit: homology with protein phosphatase 2A.
  • FEBS Lett. 1987; 223: 340-6
  • Display abstract

  • A 1.5 kb clone containing the full-length coding sequence of a type-1 protein phosphatase catalytic subunit has been isolated from a rabbit skeletal muscle cDNA library constructed in lambda gt10. The protein sequence deduced from the cDNA contains 311 residues and has a molecular mass of 35.4 kDa. A single mRNA species at 1.6 kb was visualized by Northern blotting. The type-1 protein phosphatase was strikingly homologous to protein phosphatase 2A, 49% of the amino acids between residues 11 and 280 being identical. The first 10 and last 31 residues were dissimilar. Residues 1-101 of the type-1 protein phosphatase also showed 21% sequence identity with a region of mammalian alkaline phosphatases.

  • Green DD, Yang SI, Mumby MC
  • Molecular cloning and sequence analysis of the catalytic subunit of bovine type 2A protein phosphatase.
  • Proc Natl Acad Sci U S A. 1987; 84: 4880-4
  • Display abstract

  • We have isolated a cDNA clone corresponding to the Mr 38,000 catalytic subunit of bovine type 2A protein phosphatase. The cDNA was isolated from a bovine adrenal gland cDNA library through the use of oligonucleotide probes whose sequences were based on partial amino acid sequence obtained from cyanogen bromide fragments of the purified cardiac enzyme. The entire 1724-base-pair cDNA has been sequenced and found to contain an open reading frame coding for a protein of 325 amino acids having a calculated molecular weight of 37,320. The deduced amino acid sequence contains the experimentally determined sequences of five different cyanogen bromide peptides. Transfection of COS-m6 cells with the cloned cDNA resulted in transient expression of a protein that could be detected by immunoblot analysis with a monoclonal antibody directed against the purified cardiac protein phosphatase. The expressed protein had the same apparent molecular weight as the purified enzyme when analyzed by NaDodSO4/polyacrylamide gel electrophoresis, suggesting that this clone contains the entire coding region of the phosphatase mRNA. The cloned cDNA hybridizes to a mRNA of 2.0 kilobases in bovine heart and adrenal gland. Under conditions of reduced stringency, the cDNA also hybridizes to a mRNA species of 1.2 kilobases in cardiac tissue.

• Metabolism (metabolic pathways involving proteins which contain this domain)

• Click the image to view the interactive version of the map in iPath

  % proteins involved KEGG pathway ID Description 10.74 map04720 Long-term potentiation 10.56 map04310 Wnt signaling pathway 8.45 map04010 MAPK signaling pathway 5.81 map04510 Focal adhesion 5.81 map04910 Insulin signaling pathway 5.81 map04810 Regulation of actin cytoskeleton 5.63 map04530 Tight junction 5.63 map04350 TGF-beta signaling pathway 5.63 map04730 Long-term depression 4.93 map04370 VEGF signaling pathway 4.93 map04662 B cell receptor signaling pathway 4.93 map04210 Apoptosis 4.93 map04660 T cell receptor signaling pathway 4.93 map04020 Calcium signaling pathway 4.93 map04360 Axon guidance 4.93 map04650 Natural killer cell mediated cytotoxicity 0.35 map02010 ABC transporters - General 0.18 map00760 Nicotinate and nicotinamide metabolism 0.18 map00530 Aminosugars metabolism 0.18 map00740 Riboflavin metabolism 0.18 map00730 Thiamine metabolism 0.18 map00051 Fructose and mannose metabolism 0.18 map00230 Purine metabolism This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with PP2Ac domain which could be assigned to a KEGG orthologous group, and not all proteins containing PP2Ac domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of PP2Ac domains in PDB

  PDB code	Main view	Title
  1aui		HUMAN CALCINEURIN HETERODIMER
  1fjm		PROTEIN SERINE/THREONINE PHOSPHATASE-1 (ALPHA ISOFORM, TYPE I) COMPLEXED WITH MICROCYSTIN-LR TOXIN
  1g5b		BACTERIOPHAGE LAMBDA SER/THR PROTEIN PHOSPHATASE
  1it6		CRYSTAL STRUCTURE OF THE COMPLEX BETWEEN CALYCULIN A AND THE CATALYTIC SUBUNIT OF PROTEIN PHOSPHATASE 1
  1jk7		CRYSTAL STRUCTURE OF THE TUMOR-PROMOTER OKADAIC ACID BOUND TO PROTEIN PHOSPHATASE-1
  1m63		Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes
  1mf8		Crystal Structure of human calcineurin complexed with cyclosporin A and human cyclophilin
  1s70		Complex between protein ser/thr phosphatase-1 (delta) and the myosin phosphatase targeting subunit 1 (MYPT1)
  1s95		Structure of serine/threonine protein phosphatase 5
  1tco		TERNARY COMPLEX OF A CALCINEURIN A FRAGMENT, CALCINEURIN B, FKBP12 AND THE IMMUNOSUPPRESSANT DRUG FK506 (TACROLIMUS)
  1u32		Crystal structure of a Protein Phosphatase-1: Calcineurin Hybrid Bound to Okadaic Acid
  1v73		Crystal Structure of Cold-Active Protein-Tyrosine Phosphatase of a Psychrophile Shewanella SP.
  1wao		PP5 structure
  2bcd		X-ray crystal structure of Protein Phosphatase-1 with the marine toxin motuporin bound
  2bdx		X-ray Crystal Structure of dihydromicrocystin-LA bound to Protein Phosphatase-1
  2iae		Crystal structure of a protein phosphatase 2A (PP2A) holoenzyme.
  2ie3		Structure of the Protein Phosphatase 2A Core Enzyme Bound to Tumor-inducing Toxins
  2ie4		Structure of the Protein Phosphatase 2A Core Enzyme Bound to okadaic acid
  2jog		Structure of the calcineurin-NFAT complex
  2npp		Structure of the Protein Phosphatase 2A Holoenzyme
  2nyl		Crystal structure of Protein Phosphatase 2A (PP2A) holoenzyme with the catalytic subunit carboxyl terminus truncated
  2nym		Crystal Structure of Protein Phosphatase 2A (PP2A) with C-terminus truncated catalytic subunit
  2o8a		rat PP1cgamma complexed with mouse inhibitor-2
  2o8g		Rat pp1c gamma complexed with mouse inhibitor-2
  2p6b		Crystal Structure of Human Calcineurin in Complex with PVIVIT Peptide
  2z72		New Structure Of Cold-Active Protein Tyrosine Phosphatase At 1.1 Angstrom
  2zbm		Crystal Structure of I115M Mutant Cold-Active Protein Tyrosine Phosphatase
  3c5w		Complex between PP2A-specific methylesterase PME-1 and PP2A core enzyme
  3dw8		Structure of a Protein Phosphatase 2A Holoenzyme with B55 subunit
  3e7a		Crystal Structure of Protein Phosphatase-1 Bound to the natural toxin Nodularin-R
  3e7b		Crystal Structure of Protein Phosphatase-1 Bound to the natural toxin inhibitor Tautomycin
  3egg		Crystal structure of a complex between Protein Phosphatase 1 alpha (PP1) and the PP1 binding and PDZ domains of Spinophilin
  3egh		Crystal structure of a complex between Protein Phosphatase 1 alpha (PP1), the PP1 binding and PDZ domains of Spinophilin and the small natural molecular toxin Nodularin-R
  3fga		Structural Basis of PP2A and Sgo interaction
  3h60		Catalytic domain of human Serine/Threonine Phosphatase 5 (PP5c)with two Mn2+ atoms
  3h61		Catalytic domain of human Serine/Threonine Phosphatase 5 (PP5c) with two Mn2+ atoms originally soaked with norcantharidin (which is present in the structure in the hydrolyzed form)
  3h62		Catalytic domain of human Serine/Threonine Phosphatase 5 (PP5c) with two Mn2+ atoms complexed with cantharidic acid
  3h63		Catalytic domain of human Serine/Threonine Phosphatase 5 (PP5c) with two Mn2+ atoms originally soaked with cantharidin (which is present in the structure in the hydrolyzed form)
  3h64		Catalytic domain of human Serine/Threonine Phosphatase 5 (PP5c) with two Mn2+ atoms complexed with endothall
  3h66		Catalytic domain of human Serine/Threonine Phosphatase 5 (PP5c) with two Zn2+ atoms
  3h67		Catalytic domain of human Serine/Threonine Phosphatase 5 (PP5c)with two Zn2+ atoms complexed with cantharidic acid
  3h68		Catalytic domain of human Serine/Threonine Phosphatase 5 (PP5c)with two Zn2+ atoms originally soaked with cantharidin (which is present in the structure in the hydrolyzed form)
  3h69		Catalytic domain of human Serine/Threonine Phosphatase 5 (PP5c) with two Zn2+ atoms complexed with endothall
  3hvq		Crystal structure of a complex between Protein Phosphatase 1 alpha (PP1) and the PP1 binding and PDZ domains of Neurabin
  3icf		Structure of Protein serine/threonine phosphatase from Saccharomyces cerevisiae with similarity to human phosphatase PP5
  3k7v		Protein phosphatase 2A core complex bound to dinophysistoxin-1
  3k7w		Protein phosphatase 2A core complex bound to dinophysistoxin-2
  3ll8		Crystal Structure of Calcineurin in Complex with AKAP79 Peptide
  3n5u		Crystal structure of an Rb C-terminal peptide bound to the catalytic subunit of PP1
  3p71		Crystal structure of the complex of LCMT-1 and PP2A
  3v4y		Crystal Structure of the first Nuclear PP1 holoenzyme
  4f0z		Crystal Structure of Calcineurin in Complex with the Calcineurin-Inhibiting Domain of the African Swine Fever Virus Protein A238L
  4g9j		Protein Ser/Thr phosphatase-1 in complex with cell-permeable peptide
  4i5l		Structural mechanism of trimeric PP2A holoenzyme involving PR70: insight for Cdc6 dephosphorylation
  4i5n		Structural mechanism of trimeric PP2A holoenzyme involving PR70: insight for Cdc6 dephosphorylation
  4il1		Crystal Structure of the Rat Calcineurin
  4iyp		structure of the nPP2Ac-alpha4 complex
  4ja7		Rat PP5 co-crystallized with P5SA-2
  4ja9		Rat PP5 apo
  4lac		Crystal Structure of Protein Phosphatase 2A (PP2A) and PP2A phosphatase activator (PTPA) complex with ATPgammaS
  4mov		1.45 A Resolution Crystal Structure of Protein Phosphatase 1
  4moy		Structure of a second nuclear PP1 Holoenzyme, crystal form 1
  4mp0		Structure of a second nuclear PP1 Holoenzyme, crystal form 2
  4or9		4OR9
  4ora		4ORA
  4orb		4ORB
  4orc		4ORC
  4ut2		4UT2
  4ut3		4UT3
  4v0u		4V0U
  4v0v		4V0V
  4v0w		4V0W
  4v0x		4V0X
  4xpn		4XPN
  4zvz		4ZVZ
  4zx2		4ZX2
  5b8i		5B8I
  5c1v		5C1V
  5hpe		5HPE
  5inb		5INB
  5ioh		5IOH
  5j28		5J28
  5jpe		5JPE
  5jpf		5JPF

• Links (links to other resources describing this domain)

• INTERPRO	IPR006186
  PFAM	STphosphatase

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