Detail Information for IndEnz0018001228
IED ID IndEnz0018001228
Enzyme Type ID peroxidase001228
Protein Name Protein phosphatase 3 catalytic subunit alpha
EC 3.1.3.16
CAM-PRP catalytic subunit
Calcineurin A alpha
Calmodulin-dependent calcineurin A subunit alpha isoform
CNA alpha
Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform
Gene Name PPP3CA CALNA CNA
Organism Homo sapiens (Human)
Taxonomic Lineage cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human)
Enzyme Sequence MSEPKAIDPKLSTTDRVVKAVPFPPSHRLTAKEVFDNDGKPRVDILKAHLMKEGRLEESVALRIITEGASILRQEKNLLDIDAPVTVCGDIHGQFFDLMKLFEVGGSPANTRYLFLGDYVDRGYFSIECVLYLWALKILYPKTLFLLRGNHECRHLTEYFTFKQECKIKYSERVYDACMDAFDCLPLAALMNQQFLCVHGGLSPEINTLDDIRKLDRFKEPPAYGPMCDILWSDPLEDFGNEKTQEHFTHNTVRGCSYFYSYPAVCEFLQHNNLLSILRAHEAQDAGYRMYRKSQTTGFPSLITIFSAPNYLDVYNNKAAVLKYENNVMNIRQFNCSPHPYWLPNFMDVFTWSLPFVGEKVTEMLVNVLNICSDDELGSEEDGFDGATAAARKEVIRNKIRAIGKMARVFSVLREESESVLTLKGLTPTGMLPSGVLSGGKQTLQSATVEAIEADEAIKGFSPQHKITSFEEAKGLDRINERMPPRRDAMPSDANLNSINKALTSETNGTDSNGSNSSNIQ
Enzyme Length 521
Uniprot Accession Number Q08209
Absorption
Active Site ACT_SITE 151; /note=Proton donor; /evidence=ECO:0000305|PubMed:8524402
Activity Regulation ACTIVITY REGULATION: Activated by Ca(2+)-bound calmodulin following an increase in intracellular Ca(2+). At low Ca(2+) concentrations, the catalytic subunit (also known as calcineurin A) is inactive and is bound to the regulatory subunit (also known as calcineurin B) in which only two high-affinity binding sites are occupied by Ca(2+). In response to elevated calcium levels, the occupancy of the low-affinity sites on calcineurin B by Ca(2+) causes a conformational change of the C-terminal regulatory domain of calcineurin A, resulting in the exposure of the calmodulin-binding domain and in the partial activation of calcineurin A. The subsequent binding of Ca(2+)-bound calmodulin leads to the displacement of the autoinhibitory domain from the active site and possibly of the autoinhibitory segment from the substrate binding site which fully activates calcineurin A. Inhibited by immunosuppressant drug FK506 (tacrolimus) in complex with FKBP12 and also by immunosuppressant drug cyclosporin A (CsA) in complex with PPIA/cyclophilin A; the inhibition is Ca(2+)-dependent (PubMed:26248042). {ECO:0000250|UniProtKB:P16298, ECO:0000269|PubMed:26248042}.
Binding Site
Calcium Binding
catalytic Activity CATALYTIC ACTIVITY: Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] + phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474, ChEBI:CHEBI:83421; EC=3.1.3.16; Evidence={ECO:0000269|PubMed:15671020, ECO:0000269|PubMed:18838687, ECO:0000269|PubMed:19154138, ECO:0000269|PubMed:23468591, ECO:0000305|PubMed:26248042}; CATALYTIC ACTIVITY: Reaction=H2O + O-phospho-L-threonyl-[protein] = L-threonyl-[protein] + phosphate; Xref=Rhea:RHEA:47004, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15377, ChEBI:CHEBI:30013, ChEBI:CHEBI:43474, ChEBI:CHEBI:61977; EC=3.1.3.16; Evidence={ECO:0000269|PubMed:15671020, ECO:0000269|PubMed:18838687, ECO:0000269|PubMed:19154138, ECO:0000269|PubMed:23468591, ECO:0000305|PubMed:26248042};
DNA Binding
EC Number 3.1.3.16
Enzyme Function FUNCTION: Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals (PubMed:15671020, PubMed:18838687, PubMed:19154138, PubMed:23468591, PubMed:30254215). Many of the substrates contain a PxIxIT motif and/or a LxVP motif (PubMed:17498738, PubMed:17502104, PubMed:22343722, PubMed:23468591, PubMed:27974827). In response to increased Ca(2+) levels, dephosphorylates and activates phosphatase SSH1 which results in cofilin dephosphorylation (PubMed:15671020). In response to increased Ca(2+) levels following mitochondrial depolarization, dephosphorylates DNM1L inducing DNM1L translocation to the mitochondrion (PubMed:18838687). Positively regulates the CACNA1B/CAV2.2-mediated Ca(2+) release probability at hippocampal neuronal soma and synaptic terminals (By similarity). Dephosphorylates heat shock protein HSPB1 (By similarity). Dephosphorylates and activates transcription factor NFATC1 (PubMed:19154138). In response to increased Ca(2+) levels, regulates NFAT-mediated transcription probably by dephosphorylating NFAT and promoting its nuclear translocation (PubMed:26248042). Dephosphorylates and inactivates transcription factor ELK1 (PubMed:19154138). Dephosphorylates DARPP32 (PubMed:19154138). May dephosphorylate CRTC2 at 'Ser-171' resulting in CRTC2 dissociation from 14-3-3 proteins (PubMed:30611118). Dephosphorylates transcription factor TFEB at 'Ser-211' following Coxsackievirus B3 infection, promoting nuclear translocation (PubMed:33691586). Required for postnatal development of the nephrogenic zone and superficial glomeruli in the kidneys, cell cycle homeostasis in the nephrogenic zone, and ultimately normal kidney function (By similarity). Plays a role in intracellular AQP2 processing and localization to the apical membrane in the kidney, may thereby be required for efficient kidney filtration (By similarity). Required for secretion of salivary enzymes amylase, peroxidase, lysozyme and sialic acid via formation of secretory vesicles in the submandibular glands (By similarity). Required for calcineurin activity and homosynaptic depotentiation in the hippocampus (By similarity). Required for normal differentiation and survival of keratinocytes and therefore required for epidermis superstructure formation (By similarity). Positively regulates osteoblastic bone formation, via promotion of osteoblast differentiation (By similarity). Positively regulates osteoclast differentiation, potentially via NFATC1 signaling (By similarity). May play a role in skeletal muscle fiber type specification, potentially via NFATC1 signaling (By similarity). Negatively regulates MAP3K14/NIK signaling via inhibition of nuclear translocation of the transcription factors RELA and RELB (By similarity). Required for antigen-specific T-cell proliferation response (By similarity). {ECO:0000250|UniProtKB:P48452, ECO:0000250|UniProtKB:P63328, ECO:0000250|UniProtKB:P63329, ECO:0000269|PubMed:15671020, ECO:0000269|PubMed:17498738, ECO:0000269|PubMed:17502104, ECO:0000269|PubMed:18838687, ECO:0000269|PubMed:19154138, ECO:0000269|PubMed:22343722, ECO:0000269|PubMed:23468591, ECO:0000269|PubMed:26248042, ECO:0000269|PubMed:27974827, ECO:0000269|PubMed:30254215, ECO:0000269|PubMed:30611118, ECO:0000269|PubMed:33691586}.
Temperature Dependency
PH Dependency
Pathway
nucleotide Binding
Features Active site (1); Alternative sequence (4); Beta strand (18); Chain (1); Compositional bias (1); Helix (17); Initiator methionine (1); Metal binding (7); Modified residue (4); Motif (1); Mutagenesis (4); Natural variant (10); Region (7); Site (1); Turn (6)
Keywords 3D-structure;Acetylation;Alternative splicing;Calmodulin-binding;Cell junction;Cell membrane;Cell projection;Craniosynostosis;Cytoplasm;Disease variant;Dwarfism;Epilepsy;Hydrolase;Iron;Membrane;Mental retardation;Metal-binding;Nitration;Phosphoprotein;Protein phosphatase;Reference proteome;Synapse;Zinc
Interact With R4GN89; P62993; P63098; P54578; Q8VHW5; P24588; O95644; Q13469; P63098; P46939; O36972; Q9NYB9-2; P24588; P49418; Q9H993; Q96GX8; Q96KS9; P27987; P63098; Q9UPX8-4; P00441; Q8IZW8; Q6ZMU5; Q13432; Q96EJ4
Induction
Subcellular Location SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19154138, ECO:0000269|PubMed:22343722}. Cell membrane {ECO:0000269|PubMed:22343722, ECO:0000269|PubMed:28881575}; Peripheral membrane protein {ECO:0000269|PubMed:22343722}. Cell membrane, sarcolemma {ECO:0000250|UniProtKB:P63329}. Cytoplasm, myofibril, sarcomere, Z line {ECO:0000250|UniProtKB:P63329}. Cell projection, dendritic spine {ECO:0000269|PubMed:22343722}. Note=Colocalizes with ACTN1 and MYOZ2 at the Z line in heart and skeletal muscle (By similarity). Recruited to the cell membrane by scaffold protein AKAP5 following L-type Ca(2+)-channel activation (PubMed:22343722). {ECO:0000250|UniProtKB:P63329, ECO:0000269|PubMed:22343722}.
Modified Residue MOD_RES 2; /note=N-acetylserine; /evidence=ECO:0007744|PubMed:22814378; MOD_RES 224; /note=3'-nitrotyrosine; /evidence=ECO:0000250|UniProtKB:P63328; MOD_RES 469; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:P63329; MOD_RES 492; /note=Phosphoserine; /evidence=ECO:0007744|PubMed:23186163
Post Translational Modification
Signal Peptide
Structure 3D X-ray crystallography (15); NMR spectroscopy (2)
Cross Reference PDB 1AUI; 1M63; 1MF8; 2JOG; 2JZI; 2P6B; 2R28; 2W73; 3LL8; 4F0Z; 4Q5U; 5C1V; 5SVE; 6NUC; 6NUF; 6NUU; 6UUQ;
Mapped Pubmed ID 10860980; 11015619; 11030334; 11231878; 12015605; 12135494; 12577067; 12586544; 12975316; 14704270; 15671033; 16150694; 16189514; 16880514; 16920709; 17320203; 17474147; 17478429; 18296442; 18628988; 18660489; 18815128; 19034380; 19285944; 193860; 19422382; 19458075; 19492085; 19851316; 19879877; 19896943; 19913121; 20107831; 20195357; 20379146; 20379614; 20413672; 20422345; 20501444; 20514436; 20628086; 20700529; 20711500; 21047202; 21070662; 21233773; 21674474; 21785830; 21900206; 21903422; 22100452; 22164265; 22270398; 22285318; 22360420; 22506312; 22665060; 22688515; 22691791; 22739212; 23317196; 23744075; 23824189; 23888774; 24191726; 24298017; 24418105; 24672054; 24954618; 25286016; 25416956; 25609649; 25637383; 25720963; 26812016; 27009276; 27307045; 27911714; 28842480; 28967377; 30380548; 30536857; 30699351; 30776328; 31375679; 31399054; 31415762; 31619735; 32422433; 32859215; 32936779; 33963760; 34711683; 34795676; 6330098; 7479966; 7545680; 7657645; 7708705; 7889407; 8397339; 8576111; 8631904; 8684469; 8799126; 9106655; 9312192; 9660947; 9727000;
Motif MOTIF 307..311; /note=SAPNY motif; /evidence=ECO:0000305|PubMed:26248042
Gene Encoded By
Mass 58,688
Kinetics BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=2.04 uM for NFATC1 {ECO:0000269|PubMed:19154138}; KM=2.22 uM for DARPP32 {ECO:0000269|PubMed:19154138};
Metal Binding METAL 90; /note="Iron"; /evidence="ECO:0000269|PubMed:12218175, ECO:0000269|PubMed:17498738, ECO:0000269|PubMed:22343722, ECO:0000269|PubMed:26248042, ECO:0000269|PubMed:27974827, ECO:0000269|PubMed:8524402, ECO:0007744|PDB:1AUI, ECO:0007744|PDB:1M63, ECO:0007744|PDB:2P6B, ECO:0007744|PDB:3LL8, ECO:0007744|PDB:5C1V, ECO:0007744|PDB:5SVE"; METAL 92; /note="Iron; via tele nitrogen"; /evidence="ECO:0000269|PubMed:12218175, ECO:0000269|PubMed:17498738, ECO:0000269|PubMed:22343722, ECO:0000269|PubMed:26248042, ECO:0000269|PubMed:27974827, ECO:0000269|PubMed:8524402, ECO:0007744|PDB:1AUI, ECO:0007744|PDB:1M63, ECO:0007744|PDB:2P6B, ECO:0007744|PDB:3LL8, ECO:0007744|PDB:5C1V, ECO:0007744|PDB:5SVE"; METAL 118; /note="Iron"; /evidence="ECO:0000269|PubMed:12218175, ECO:0000269|PubMed:17498738, ECO:0000269|PubMed:22343722, ECO:0000269|PubMed:26248042, ECO:0000269|PubMed:27974827, ECO:0000269|PubMed:8524402, ECO:0007744|PDB:1AUI, ECO:0007744|PDB:1M63, ECO:0007744|PDB:2P6B, ECO:0007744|PDB:3LL8, ECO:0007744|PDB:5C1V, ECO:0007744|PDB:5SVE"; METAL 118; /note="Zinc"; /evidence="ECO:0000269|PubMed:12218175, ECO:0000269|PubMed:17498738, ECO:0000269|PubMed:22343722, ECO:0000269|PubMed:26248042, ECO:0000269|PubMed:27974827, ECO:0000269|PubMed:8524402, ECO:0007744|PDB:1AUI, ECO:0007744|PDB:1M63, ECO:0007744|PDB:2P6B, ECO:0007744|PDB:3LL8, ECO:0007744|PDB:5C1V, ECO:0007744|PDB:5SVE"; METAL 150; /note="Zinc"; /evidence="ECO:0000269|PubMed:12218175, ECO:0000269|PubMed:17498738, ECO:0000269|PubMed:22343722, ECO:0000269|PubMed:26248042, ECO:0000269|PubMed:27974827, ECO:0000269|PubMed:8524402, ECO:0007744|PDB:1AUI, ECO:0007744|PDB:1M63, ECO:0007744|PDB:2P6B, ECO:0007744|PDB:3LL8, ECO:0007744|PDB:5C1V, ECO:0007744|PDB:5SVE"; METAL 199; /note="Zinc; via tele nitrogen"; /evidence="ECO:0000269|PubMed:12218175, ECO:0000269|PubMed:17498738, ECO:0000269|PubMed:22343722, ECO:0000269|PubMed:26248042, ECO:0000269|PubMed:27974827, ECO:0000269|PubMed:8524402, ECO:0007744|PDB:1AUI, ECO:0007744|PDB:1M63, ECO:0007744|PDB:2P6B, ECO:0007744|PDB:3LL8, ECO:0007744|PDB:5C1V, ECO:0007744|PDB:5SVE"; METAL 281; /note="Zinc; via pros nitrogen"; /evidence="ECO:0000269|PubMed:12218175, ECO:0000269|PubMed:17498738, ECO:0000269|PubMed:22343722, ECO:0000269|PubMed:26248042, ECO:0000269|PubMed:27974827, ECO:0000269|PubMed:8524402, ECO:0007744|PDB:1AUI, ECO:0007744|PDB:1M63, ECO:0007744|PDB:2P6B, ECO:0007744|PDB:3LL8, ECO:0007744|PDB:5C1V, ECO:0007744|PDB:5SVE"
Rhea ID RHEA:20629; RHEA:47004
Cross Reference Brenda 3.1.3.16;