Full text data of PLA2G4A
PLA2G4A
(CPLA2, PLA2G4)
[Confidence: low (only semi-automatic identification from reviews)]
Cytosolic phospholipase A2; cPLA2 (Phospholipase A2 group IVA; Phospholipase A2; 3.1.1.4; Phosphatidylcholine 2-acylhydrolase; Lysophospholipase; 3.1.1.5)
Cytosolic phospholipase A2; cPLA2 (Phospholipase A2 group IVA; Phospholipase A2; 3.1.1.4; Phosphatidylcholine 2-acylhydrolase; Lysophospholipase; 3.1.1.5)
UniProt
P47712
ID PA24A_HUMAN Reviewed; 749 AA.
AC P47712; B1AKG4; Q29R80;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-JAN-2011, sequence version 2.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Cytosolic phospholipase A2;
DE Short=cPLA2;
DE AltName: Full=Phospholipase A2 group IVA;
DE Includes:
DE RecName: Full=Phospholipase A2;
DE EC=3.1.1.4;
DE AltName: Full=Phosphatidylcholine 2-acylhydrolase;
DE Includes:
DE RecName: Full=Lysophospholipase;
DE EC=3.1.1.5;
GN Name=PLA2G4A; Synonyms=CPLA2, PLA2G4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, AND VARIANT
RP LYS-651.
RX PubMed=1904318; DOI=10.1016/0092-8674(91)90556-E;
RA Clark J.D., Lin L.-L., Kriz R.W., Ramesha C.S., Sultzman L.A.,
RA Lin A.Y., Milona N., Knopf J.L.;
RT "A novel arachidonic acid-selective cytosolic PLA2 contains a Ca(2+)-
RT dependent translocation domain with homology to PKC and GAP.";
RL Cell 65:1043-1051(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT LYS-651.
RX PubMed=1869522;
RA Sharp J., White D., Chiou G., Goodson T., Gamboa G., McClure D.,
RA Burgett S., Hoskins J., Skatrud P., Sportsman J., Becker G., Kang L.,
RA Roberts E., Kramer R.;
RT "Molecular cloning and expression of human Ca(2+)-sensitive cytosolic
RT phospholipase A2.";
RL J. Biol. Chem. 266:14850-14853(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ILE-224 AND LYS-651.
RG NIEHS SNPs program;
RL Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT LYS-651.
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP MUTAGENESIS OF SER-505, AND PHOSPHORYLATION AT SER-505.
RX PubMed=8381049; DOI=10.1016/0092-8674(93)90666-E;
RA Lin L.-L., Wartmann M., Lin A.Y., Knopf J.L., Seth A., Davis R.J.;
RT "cPLA2 is phosphorylated and activated by MAP kinase.";
RL Cell 72:269-278(1993).
RN [7]
RP ACTIVE SITE, MUTAGENESIS OF CYS-139; CYS-141; CYS-151; SER-195;
RP SER-215; CYS-220; SER-228; CYS-324; CYS-331; SER-577; CYS-620; CYS-634
RP AND CYS-726, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=8083230;
RA Sharp J.D., Pickard R.T., Chiou X.G., Manetta J.V., Kovacevic S.,
RA Miller J.R., Varshavsky A.D., Roberts E.F., Strifler B.A., Brems D.N.,
RA Kramer R.M.;
RT "Serine 228 is essential for catalytic activities of 85-kDa cytosolic
RT phospholipase A2.";
RL J. Biol. Chem. 269:23250-23254(1994).
RN [8]
RP CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, ACTIVE SITE, AND MUTAGENESIS
RP OF SER-228.
RX PubMed=8619991; DOI=10.1021/bi952541k;
RA Huang Z., Payette P., Abdullah K., Cromlish W.A., Kennedy B.P.;
RT "Functional identification of the active-site nucleophile of the human
RT 85-kDa cytosolic phospholipase A2.";
RL Biochemistry 35:3712-3721(1996).
RN [9]
RP ACTIVE SITE, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ARG-200; SER-228
RP AND ASP-549.
RX PubMed=8702602; DOI=10.1074/jbc.271.32.19225;
RA Pickard R.T., Chiou X.G., Strifler B.A., DeFelippis M.R., Hyslop P.A.,
RA Tebbe A.L., Yee Y.K., Reynolds L.J., Dennis E.A., Kramer R.M.,
RA Sharp J.D.;
RT "Identification of essential residues for the catalytic function of
RT 85-kDa cytosolic phospholipase A2. Probing the role of histidine,
RT aspartic acid, cysteine, and arginine.";
RL J. Biol. Chem. 271:19225-19231(1996).
RN [10]
RP PHOSPHORYLATION AT SER-505 AND SER-727.
RX PubMed=9468497; DOI=10.1074/jbc.273.8.4449;
RA Boersch-Haubold A.G., Bartoli F., Asselin J., Dudler T., Kramer R.M.,
RA Apitz-Castro R., Watson S.P., Gelb M.H.;
RT "Identification of the phosphorylation sites of cytosolic
RT phospholipase A2 in agonist-stimulated human platelets and HeLa
RT cells.";
RL J. Biol. Chem. 273:4449-4458(1998).
RN [11]
RP INTERACTION WITH KAT5.
RX PubMed=11416127; DOI=10.1128/MCB.21.14.4470-4481.2001;
RA Sheridan A.M., Force T., Yoon H.J., O'Leary E., Choukroun G.,
RA Taheri M.R., Bonventre J.V.;
RT "PLIP, a novel splice variant of Tip60, interacts with group IV
RT cytosolic phospholipase A(2), induces apoptosis, and potentiates
RT prostaglandin production.";
RL Mol. Cell. Biol. 21:4470-4481(2001).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-729, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-268; SER-437; SER-727
RP AND SER-729, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-268; SER-437 AND
RP SER-729, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-437, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 16-141 IN COMPLEX WITH
RP CALCIUM IONS, AND DOMAIN.
RX PubMed=9430701; DOI=10.1074/jbc.273.3.1596;
RA Perisic O., Fong S., Lynch D.E., Bycroft M., Williams R.L.;
RT "Crystal structure of a calcium-phospholipid binding domain from
RT cytosolic phospholipase A2.";
RL J. Biol. Chem. 273:1596-1604(1998).
RN [20]
RP STRUCTURE BY NMR OF 1-138 IN COMPLEX WITH CALCIUM IONS, DOMAIN, AND
RP SUBCELLULAR LOCATION.
RX PubMed=9665851; DOI=10.1006/jmbi.1998.1874;
RA Xu G.-Y., McDonagh T., Yu H.-A., Nalefski E.A., Clark J.D.,
RA Cumming D.A.;
RT "Solution structure and membrane interactions of the C2 domain of
RT cytosolic phospholipase A2.";
RL J. Mol. Biol. 280:485-500(1998).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) IN COMPLEX WITH CALCIUM IONS,
RP AND ACTIVE SITE.
RX PubMed=10319815; DOI=10.1016/S0092-8674(00)80744-8;
RA Dessen A., Tang J., Schmidt H., Stahl M., Clark J.D., Seehra J.,
RA Somers W.S.;
RT "Crystal structure of human cytosolic phospholipase A2 reveals a novel
RT topology and catalytic mechanism.";
RL Cell 97:349-360(1999).
RN [22]
RP VARIANT [LARGE SCALE ANALYSIS] GLN-442.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Selectively hydrolyzes arachidonyl phospholipids in the
CC sn-2 position releasing arachidonic acid. Together with its
CC lysophospholipid activity, it is implicated in the initiation of
CC the inflammatory response.
CC -!- CATALYTIC ACTIVITY: Phosphatidylcholine + H(2)O = 1-
CC acylglycerophosphocholine + a carboxylate.
CC -!- CATALYTIC ACTIVITY: 2-lysophosphatidylcholine + H(2)O =
CC glycerophosphocholine + a carboxylate.
CC -!- ENZYME REGULATION: Stimulated by agonists such as ATP, EGF,
CC thrombin and bradykinin as well as by cytosolic Ca(2+).
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC Vmax=2.7 umol/min/mg enzyme for the phospholipase A2 reaction;
CC Vmax=4.6 umol/min/mg enzyme for the lysophosphatase reaction;
CC -!- SUBUNIT: Interacts with KAT5.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasmic vesicle.
CC Note=Translocates to membrane vesicles in a calcium-dependent
CC fashion.
CC -!- TISSUE SPECIFICITY: Expressed in various tissues such as
CC macrophages, platelets, neutrophils, fibroblasts and lung
CC endothelium.
CC -!- DOMAIN: The N-terminal C2 domain associates with lipid membranes
CC upon calcium binding. It modulates enzyme activity by presenting
CC the active site to its substrate in response to elevations of
CC cytosolic Ca(2+).
CC -!- PTM: Activated by phosphorylation at both Ser-505 and Ser-727.
CC -!- SIMILARITY: Contains 1 C2 domain.
CC -!- SIMILARITY: Contains 1 PLA2c domain.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/pla2g4a/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PLA2G4AID41733ch1q31.html";
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DR EMBL; M72393; AAB00789.1; -; mRNA.
DR EMBL; M68874; AAA60105.1; -; mRNA.
DR EMBL; AY552098; AAS45712.1; -; Genomic_DNA.
DR EMBL; AL022147; CAB42689.2; -; Genomic_DNA.
DR EMBL; AL049797; CAI22252.1; -; Genomic_DNA.
DR EMBL; AL022147; CAI22252.1; JOINED; Genomic_DNA.
DR EMBL; BC114340; AAI14341.1; -; mRNA.
DR PIR; A39329; A39329.
DR RefSeq; NP_077734.1; NM_024420.2.
DR UniGene; Hs.497200; -.
DR PDB; 1BCI; NMR; -; A=1-138.
DR PDB; 1CJY; X-ray; 2.50 A; A/B=1-749.
DR PDB; 1RLW; X-ray; 2.40 A; A=17-138.
DR PDBsum; 1BCI; -.
DR PDBsum; 1CJY; -.
DR PDBsum; 1RLW; -.
DR ProteinModelPortal; P47712; -.
DR SMR; P47712; 13-721.
DR IntAct; P47712; 1.
DR MINT; MINT-118843; -.
DR STRING; 9606.ENSP00000356436; -.
DR BindingDB; P47712; -.
DR ChEMBL; CHEMBL3816; -.
DR DrugBank; DB00180; Flunisolide.
DR DrugBank; DB00591; Fluocinolone Acetonide.
DR DrugBank; DB01047; Fluocinonide.
DR DrugBank; DB00324; Fluorometholone.
DR DrugBank; DB00846; Flurandrenolide.
DR DrugBank; DB00588; Fluticasone Propionate.
DR DrugBank; DB00253; Medrysone.
DR DrugBank; DB01103; Quinacrine.
DR PhosphoSite; P47712; -.
DR DMDM; 1352707; -.
DR PaxDb; P47712; -.
DR PRIDE; P47712; -.
DR Ensembl; ENST00000367466; ENSP00000356436; ENSG00000116711.
DR GeneID; 5321; -.
DR KEGG; hsa:5321; -.
DR UCSC; uc001gsc.3; human.
DR CTD; 5321; -.
DR GeneCards; GC01P186798; -.
DR HGNC; HGNC:9035; PLA2G4A.
DR HPA; CAB010050; -.
DR MIM; 600522; gene.
DR neXtProt; NX_P47712; -.
DR PharmGKB; PA271; -.
DR eggNOG; NOG257248; -.
DR HOGENOM; HOG000115420; -.
DR HOVERGEN; HBG053479; -.
DR InParanoid; P47712; -.
DR KO; K16342; -.
DR OMA; ETLIHNR; -.
DR OrthoDB; EOG73V6JM; -.
DR PhylomeDB; P47712; -.
DR BRENDA; 3.1.1.4; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_604; Hemostasis.
DR EvolutionaryTrace; P47712; -.
DR GeneWiki; PLA2G4A; -.
DR GenomeRNAi; 5321; -.
DR NextBio; 20586; -.
DR PMAP-CutDB; P47712; -.
DR PRO; PR:P47712; -.
DR ArrayExpress; P47712; -.
DR Bgee; P47712; -.
DR CleanEx; HS_PLA2G4A; -.
DR Genevestigator; P47712; -.
DR GO; GO:0016023; C:cytoplasmic membrane-bounded vesicle; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; NAS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome.
DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR GO; GO:0047498; F:calcium-dependent phospholipase A2 activity; EXP:Reactome.
DR GO; GO:0005544; F:calcium-dependent phospholipid binding; IDA:UniProtKB.
DR GO; GO:0004622; F:lysophospholipase activity; IEA:UniProtKB-EC.
DR GO; GO:0019369; P:arachidonic acid metabolic process; TAS:Reactome.
DR GO; GO:0050482; P:arachidonic acid secretion; IEA:Ensembl.
DR GO; GO:0035965; P:cardiolipin acyl-chain remodeling; TAS:Reactome.
DR GO; GO:0071236; P:cellular response to antibiotic; IEA:Ensembl.
DR GO; GO:0046456; P:icosanoid biosynthetic process; IEA:Ensembl.
DR GO; GO:0006654; P:phosphatidic acid biosynthetic process; TAS:Reactome.
DR GO; GO:0036151; P:phosphatidylcholine acyl-chain remodeling; TAS:Reactome.
DR GO; GO:0036152; P:phosphatidylethanolamine acyl-chain remodeling; TAS:Reactome.
DR GO; GO:0036148; P:phosphatidylglycerol acyl-chain remodeling; TAS:Reactome.
DR GO; GO:0036149; P:phosphatidylinositol acyl-chain remodeling; TAS:Reactome.
DR GO; GO:0036150; P:phosphatidylserine acyl-chain remodeling; TAS:Reactome.
DR GO; GO:0009395; P:phospholipid catabolic process; IEA:InterPro.
DR GO; GO:0006663; P:platelet activating factor biosynthetic process; NAS:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0042127; P:regulation of cell proliferation; IEA:Ensembl.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR002642; LysoPLipase_cat_dom.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF01735; PLA2_B; 1.
DR SMART; SM00239; C2; 1.
DR SMART; SM00022; PLAc; 1.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR PROSITE; PS50004; C2; 1.
DR PROSITE; PS51210; PLA2C; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium; Complete proteome; Cytoplasm;
KW Cytoplasmic vesicle; Direct protein sequencing; Hydrolase;
KW Lipid degradation; Lipid metabolism; Metal-binding; Phosphoprotein;
KW Polymorphism; Reference proteome.
FT CHAIN 1 749 Cytosolic phospholipase A2.
FT /FTId=PRO_0000187262.
FT DOMAIN 5 106 C2.
FT DOMAIN 140 740 PLA2c.
FT REGION 1 178 Phospholipid binding (Probable).
FT ACT_SITE 228 228 Nucleophile.
FT ACT_SITE 549 549 Proton acceptor.
FT METAL 40 40 Calcium 1.
FT METAL 40 40 Calcium 2.
FT METAL 41 41 Calcium 1; via carbonyl oxygen.
FT METAL 43 43 Calcium 1.
FT METAL 43 43 Calcium 2.
FT METAL 65 65 Calcium 1.
FT METAL 93 93 Calcium 2.
FT METAL 94 94 Calcium 2; via carbonyl oxygen.
FT METAL 95 95 Calcium 2.
FT MOD_RES 268 268 Phosphothreonine.
FT MOD_RES 437 437 Phosphoserine.
FT MOD_RES 505 505 Phosphoserine; by MAPK.
FT MOD_RES 727 727 Phosphoserine.
FT MOD_RES 729 729 Phosphoserine.
FT VARIANT 103 103 G -> R (in dbSNP:rs28395828).
FT /FTId=VAR_029276.
FT VARIANT 224 224 V -> I (in dbSNP:rs12720588).
FT /FTId=VAR_018760.
FT VARIANT 442 442 H -> Q (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035826.
FT VARIANT 637 637 I -> V (in dbSNP:rs28395831).
FT /FTId=VAR_062128.
FT VARIANT 651 651 R -> K (in dbSNP:rs2307198).
FT /FTId=VAR_018424.
FT MUTAGEN 139 139 C->A: No effect on phospholipase
FT activity; when associated with A-141 and
FT A-151.
FT MUTAGEN 141 141 C->A: No effect on phospholipase
FT activity; when associated with A-139 and
FT A-151.
FT MUTAGEN 151 151 C->A: No effect on phospholipase
FT activity; when associated with A-139 and
FT A-141.
FT MUTAGEN 195 195 S->A: 5-fold reduced phospholipase and
FT lysophosphatase activities. 100-fold
FT reduced phospholipase and lysophosphatase
FT activities; when associated with A-577.
FT MUTAGEN 200 200 R->A,H: Abolishes phospholipase activity.
FT MUTAGEN 200 200 R->K: Reduces phospholipase activity 200-
FT fold.
FT MUTAGEN 215 215 S->A: No effect on phospholipase or
FT lysophosphatase activity.
FT MUTAGEN 220 220 C->A: No effect on phospholipase
FT activity.
FT MUTAGEN 228 228 S->A,C,T: Abolishes both phospholipase
FT and lysophosphatase activities.
FT MUTAGEN 324 324 C->A: No effect on phospholipase
FT activity; when associated with A-331.
FT MUTAGEN 331 331 C->A: No effect on phospholipase
FT activity; when associated with A-324.
FT MUTAGEN 505 505 S->A: Decreases agonist-stimulated
FT release of arachidonic acid.
FT MUTAGEN 549 549 D->A: Abolishes phospholipiase activity.
FT MUTAGEN 549 549 D->E: Reduces phospholipiase activity
FT 2000-fold.
FT MUTAGEN 549 549 D->N: Reduces phospholipiase activity
FT 300-fold.
FT MUTAGEN 577 577 S->A: 7-fold reduced phospholipase and
FT lysophosphatase activities. 100-fold
FT reduced phospholipase and lysophosphatase
FT activities; when associated with A-195.
FT MUTAGEN 620 620 C->A: No effect on phospholipase
FT activity; when associated with A-634.
FT MUTAGEN 634 634 C->A: No effect on phospholipase
FT activity; when associated with A-620.
FT MUTAGEN 726 726 C->A: No effect on phospholipase
FT activity.
FT STRAND 18 29
FT HELIX 34 39
FT STRAND 44 49
FT STRAND 51 54
FT STRAND 57 60
FT STRAND 70 79
FT STRAND 86 93
FT STRAND 96 98
FT STRAND 100 108
FT HELIX 109 111
FT STRAND 117 124
FT TURN 125 127
FT STRAND 128 137
FT STRAND 143 146
FT HELIX 152 177
FT HELIX 179 181
FT STRAND 190 194
FT HELIX 198 214
FT HELIX 218 220
FT STRAND 221 226
FT HELIX 228 239
FT TURN 241 245
FT HELIX 248 260
FT HELIX 263 266
FT HELIX 269 284
FT HELIX 291 304
FT HELIX 305 307
FT HELIX 313 318
FT TURN 319 321
FT STRAND 326 333
FT HELIX 341 343
FT STRAND 344 349
FT STRAND 354 356
FT TURN 357 360
FT STRAND 361 363
FT HELIX 365 367
FT STRAND 370 373
FT STRAND 376 379
FT HELIX 386 393
FT HELIX 396 399
FT HELIX 401 404
FT HELIX 417 423
FT HELIX 426 429
FT HELIX 463 476
FT STRAND 488 490
FT TURN 492 495
FT STRAND 543 548
FT HELIX 550 552
FT HELIX 558 561
FT HELIX 564 566
FT STRAND 570 575
FT HELIX 588 599
FT HELIX 611 615
FT STRAND 619 623
FT STRAND 636 641
FT HELIX 646 648
FT STRAND 650 652
FT HELIX 660 666
FT STRAND 670 672
FT HELIX 687 702
FT HELIX 705 718
SQ SEQUENCE 749 AA; 85239 MW; EE71CA0EBE617856 CRC64;
MSFIDPYQHI IVEHQYSHKF TVVVLRATKV TKGAFGDMLD TPDPYVELFI STTPDSRKRT
RHFNNDINPV WNETFEFILD PNQENVLEIT LMDANYVMDE TLGTATFTVS SMKVGEKKEV
PFIFNQVTEM VLEMSLEVCS CPDLRFSMAL CDQEKTFRQQ RKEHIRESMK KLLGPKNSEG
LHSARDVPVV AILGSGGGFR AMVGFSGVMK ALYESGILDC ATYVAGLSGS TWYMSTLYSH
PDFPEKGPEE INEELMKNVS HNPLLLLTPQ KVKRYVESLW KKKSSGQPVT FTDIFGMLIG
ETLIHNRMNT TLSSLKEKVN TAQCPLPLFT CLHVKPDVSE LMFADWVEFS PYEIGMAKYG
TFMAPDLFGS KFFMGTVVKK YEENPLHFLM GVWGSAFSIL FNRVLGVSGS QSRGSTMEEE
LENITTKHIV SNDSSDSDDE SHEPKGTENE DAGSDYQSDN QASWIHRMIM ALVSDSALFN
TREGRAGKVH NFMLGLNLNT SYPLSPLSDF ATQDSFDDDE LDAAVADPDE FERIYEPLDV
KSKKIHVVDS GLTFNLPYPL ILRPQRGVDL IISFDFSARP SDSSPPFKEL LLAEKWAKMN
KLPFPKIDPY VFDREGLKEC YVFKPKNPDM EKDCPTIIHF VLANINFRKY RAPGVPRETE
EEKEIADFDI FDDPESPFST FNFQYPNQAF KRLHDLMHFN TLNNIDVIKE AMVESIEYRR
QNPSRCSVSL SNVEARRFFN KEFLSKPKA
//
ID PA24A_HUMAN Reviewed; 749 AA.
AC P47712; B1AKG4; Q29R80;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 11-JAN-2011, sequence version 2.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Cytosolic phospholipase A2;
DE Short=cPLA2;
DE AltName: Full=Phospholipase A2 group IVA;
DE Includes:
DE RecName: Full=Phospholipase A2;
DE EC=3.1.1.4;
DE AltName: Full=Phosphatidylcholine 2-acylhydrolase;
DE Includes:
DE RecName: Full=Lysophospholipase;
DE EC=3.1.1.5;
GN Name=PLA2G4A; Synonyms=CPLA2, PLA2G4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, AND VARIANT
RP LYS-651.
RX PubMed=1904318; DOI=10.1016/0092-8674(91)90556-E;
RA Clark J.D., Lin L.-L., Kriz R.W., Ramesha C.S., Sultzman L.A.,
RA Lin A.Y., Milona N., Knopf J.L.;
RT "A novel arachidonic acid-selective cytosolic PLA2 contains a Ca(2+)-
RT dependent translocation domain with homology to PKC and GAP.";
RL Cell 65:1043-1051(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT LYS-651.
RX PubMed=1869522;
RA Sharp J., White D., Chiou G., Goodson T., Gamboa G., McClure D.,
RA Burgett S., Hoskins J., Skatrud P., Sportsman J., Becker G., Kang L.,
RA Roberts E., Kramer R.;
RT "Molecular cloning and expression of human Ca(2+)-sensitive cytosolic
RT phospholipase A2.";
RL J. Biol. Chem. 266:14850-14853(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ILE-224 AND LYS-651.
RG NIEHS SNPs program;
RL Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT LYS-651.
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP MUTAGENESIS OF SER-505, AND PHOSPHORYLATION AT SER-505.
RX PubMed=8381049; DOI=10.1016/0092-8674(93)90666-E;
RA Lin L.-L., Wartmann M., Lin A.Y., Knopf J.L., Seth A., Davis R.J.;
RT "cPLA2 is phosphorylated and activated by MAP kinase.";
RL Cell 72:269-278(1993).
RN [7]
RP ACTIVE SITE, MUTAGENESIS OF CYS-139; CYS-141; CYS-151; SER-195;
RP SER-215; CYS-220; SER-228; CYS-324; CYS-331; SER-577; CYS-620; CYS-634
RP AND CYS-726, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=8083230;
RA Sharp J.D., Pickard R.T., Chiou X.G., Manetta J.V., Kovacevic S.,
RA Miller J.R., Varshavsky A.D., Roberts E.F., Strifler B.A., Brems D.N.,
RA Kramer R.M.;
RT "Serine 228 is essential for catalytic activities of 85-kDa cytosolic
RT phospholipase A2.";
RL J. Biol. Chem. 269:23250-23254(1994).
RN [8]
RP CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, ACTIVE SITE, AND MUTAGENESIS
RP OF SER-228.
RX PubMed=8619991; DOI=10.1021/bi952541k;
RA Huang Z., Payette P., Abdullah K., Cromlish W.A., Kennedy B.P.;
RT "Functional identification of the active-site nucleophile of the human
RT 85-kDa cytosolic phospholipase A2.";
RL Biochemistry 35:3712-3721(1996).
RN [9]
RP ACTIVE SITE, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ARG-200; SER-228
RP AND ASP-549.
RX PubMed=8702602; DOI=10.1074/jbc.271.32.19225;
RA Pickard R.T., Chiou X.G., Strifler B.A., DeFelippis M.R., Hyslop P.A.,
RA Tebbe A.L., Yee Y.K., Reynolds L.J., Dennis E.A., Kramer R.M.,
RA Sharp J.D.;
RT "Identification of essential residues for the catalytic function of
RT 85-kDa cytosolic phospholipase A2. Probing the role of histidine,
RT aspartic acid, cysteine, and arginine.";
RL J. Biol. Chem. 271:19225-19231(1996).
RN [10]
RP PHOSPHORYLATION AT SER-505 AND SER-727.
RX PubMed=9468497; DOI=10.1074/jbc.273.8.4449;
RA Boersch-Haubold A.G., Bartoli F., Asselin J., Dudler T., Kramer R.M.,
RA Apitz-Castro R., Watson S.P., Gelb M.H.;
RT "Identification of the phosphorylation sites of cytosolic
RT phospholipase A2 in agonist-stimulated human platelets and HeLa
RT cells.";
RL J. Biol. Chem. 273:4449-4458(1998).
RN [11]
RP INTERACTION WITH KAT5.
RX PubMed=11416127; DOI=10.1128/MCB.21.14.4470-4481.2001;
RA Sheridan A.M., Force T., Yoon H.J., O'Leary E., Choukroun G.,
RA Taheri M.R., Bonventre J.V.;
RT "PLIP, a novel splice variant of Tip60, interacts with group IV
RT cytosolic phospholipase A(2), induces apoptosis, and potentiates
RT prostaglandin production.";
RL Mol. Cell. Biol. 21:4470-4481(2001).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-729, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-268; SER-437; SER-727
RP AND SER-729, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-268; SER-437 AND
RP SER-729, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-437, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 16-141 IN COMPLEX WITH
RP CALCIUM IONS, AND DOMAIN.
RX PubMed=9430701; DOI=10.1074/jbc.273.3.1596;
RA Perisic O., Fong S., Lynch D.E., Bycroft M., Williams R.L.;
RT "Crystal structure of a calcium-phospholipid binding domain from
RT cytosolic phospholipase A2.";
RL J. Biol. Chem. 273:1596-1604(1998).
RN [20]
RP STRUCTURE BY NMR OF 1-138 IN COMPLEX WITH CALCIUM IONS, DOMAIN, AND
RP SUBCELLULAR LOCATION.
RX PubMed=9665851; DOI=10.1006/jmbi.1998.1874;
RA Xu G.-Y., McDonagh T., Yu H.-A., Nalefski E.A., Clark J.D.,
RA Cumming D.A.;
RT "Solution structure and membrane interactions of the C2 domain of
RT cytosolic phospholipase A2.";
RL J. Mol. Biol. 280:485-500(1998).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) IN COMPLEX WITH CALCIUM IONS,
RP AND ACTIVE SITE.
RX PubMed=10319815; DOI=10.1016/S0092-8674(00)80744-8;
RA Dessen A., Tang J., Schmidt H., Stahl M., Clark J.D., Seehra J.,
RA Somers W.S.;
RT "Crystal structure of human cytosolic phospholipase A2 reveals a novel
RT topology and catalytic mechanism.";
RL Cell 97:349-360(1999).
RN [22]
RP VARIANT [LARGE SCALE ANALYSIS] GLN-442.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Selectively hydrolyzes arachidonyl phospholipids in the
CC sn-2 position releasing arachidonic acid. Together with its
CC lysophospholipid activity, it is implicated in the initiation of
CC the inflammatory response.
CC -!- CATALYTIC ACTIVITY: Phosphatidylcholine + H(2)O = 1-
CC acylglycerophosphocholine + a carboxylate.
CC -!- CATALYTIC ACTIVITY: 2-lysophosphatidylcholine + H(2)O =
CC glycerophosphocholine + a carboxylate.
CC -!- ENZYME REGULATION: Stimulated by agonists such as ATP, EGF,
CC thrombin and bradykinin as well as by cytosolic Ca(2+).
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC Vmax=2.7 umol/min/mg enzyme for the phospholipase A2 reaction;
CC Vmax=4.6 umol/min/mg enzyme for the lysophosphatase reaction;
CC -!- SUBUNIT: Interacts with KAT5.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasmic vesicle.
CC Note=Translocates to membrane vesicles in a calcium-dependent
CC fashion.
CC -!- TISSUE SPECIFICITY: Expressed in various tissues such as
CC macrophages, platelets, neutrophils, fibroblasts and lung
CC endothelium.
CC -!- DOMAIN: The N-terminal C2 domain associates with lipid membranes
CC upon calcium binding. It modulates enzyme activity by presenting
CC the active site to its substrate in response to elevations of
CC cytosolic Ca(2+).
CC -!- PTM: Activated by phosphorylation at both Ser-505 and Ser-727.
CC -!- SIMILARITY: Contains 1 C2 domain.
CC -!- SIMILARITY: Contains 1 PLA2c domain.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/pla2g4a/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PLA2G4AID41733ch1q31.html";
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DR EMBL; M72393; AAB00789.1; -; mRNA.
DR EMBL; M68874; AAA60105.1; -; mRNA.
DR EMBL; AY552098; AAS45712.1; -; Genomic_DNA.
DR EMBL; AL022147; CAB42689.2; -; Genomic_DNA.
DR EMBL; AL049797; CAI22252.1; -; Genomic_DNA.
DR EMBL; AL022147; CAI22252.1; JOINED; Genomic_DNA.
DR EMBL; BC114340; AAI14341.1; -; mRNA.
DR PIR; A39329; A39329.
DR RefSeq; NP_077734.1; NM_024420.2.
DR UniGene; Hs.497200; -.
DR PDB; 1BCI; NMR; -; A=1-138.
DR PDB; 1CJY; X-ray; 2.50 A; A/B=1-749.
DR PDB; 1RLW; X-ray; 2.40 A; A=17-138.
DR PDBsum; 1BCI; -.
DR PDBsum; 1CJY; -.
DR PDBsum; 1RLW; -.
DR ProteinModelPortal; P47712; -.
DR SMR; P47712; 13-721.
DR IntAct; P47712; 1.
DR MINT; MINT-118843; -.
DR STRING; 9606.ENSP00000356436; -.
DR BindingDB; P47712; -.
DR ChEMBL; CHEMBL3816; -.
DR DrugBank; DB00180; Flunisolide.
DR DrugBank; DB00591; Fluocinolone Acetonide.
DR DrugBank; DB01047; Fluocinonide.
DR DrugBank; DB00324; Fluorometholone.
DR DrugBank; DB00846; Flurandrenolide.
DR DrugBank; DB00588; Fluticasone Propionate.
DR DrugBank; DB00253; Medrysone.
DR DrugBank; DB01103; Quinacrine.
DR PhosphoSite; P47712; -.
DR DMDM; 1352707; -.
DR PaxDb; P47712; -.
DR PRIDE; P47712; -.
DR Ensembl; ENST00000367466; ENSP00000356436; ENSG00000116711.
DR GeneID; 5321; -.
DR KEGG; hsa:5321; -.
DR UCSC; uc001gsc.3; human.
DR CTD; 5321; -.
DR GeneCards; GC01P186798; -.
DR HGNC; HGNC:9035; PLA2G4A.
DR HPA; CAB010050; -.
DR MIM; 600522; gene.
DR neXtProt; NX_P47712; -.
DR PharmGKB; PA271; -.
DR eggNOG; NOG257248; -.
DR HOGENOM; HOG000115420; -.
DR HOVERGEN; HBG053479; -.
DR InParanoid; P47712; -.
DR KO; K16342; -.
DR OMA; ETLIHNR; -.
DR OrthoDB; EOG73V6JM; -.
DR PhylomeDB; P47712; -.
DR BRENDA; 3.1.1.4; 2681.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_604; Hemostasis.
DR EvolutionaryTrace; P47712; -.
DR GeneWiki; PLA2G4A; -.
DR GenomeRNAi; 5321; -.
DR NextBio; 20586; -.
DR PMAP-CutDB; P47712; -.
DR PRO; PR:P47712; -.
DR ArrayExpress; P47712; -.
DR Bgee; P47712; -.
DR CleanEx; HS_PLA2G4A; -.
DR Genevestigator; P47712; -.
DR GO; GO:0016023; C:cytoplasmic membrane-bounded vesicle; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; NAS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0005743; C:mitochondrial inner membrane; TAS:Reactome.
DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR GO; GO:0047498; F:calcium-dependent phospholipase A2 activity; EXP:Reactome.
DR GO; GO:0005544; F:calcium-dependent phospholipid binding; IDA:UniProtKB.
DR GO; GO:0004622; F:lysophospholipase activity; IEA:UniProtKB-EC.
DR GO; GO:0019369; P:arachidonic acid metabolic process; TAS:Reactome.
DR GO; GO:0050482; P:arachidonic acid secretion; IEA:Ensembl.
DR GO; GO:0035965; P:cardiolipin acyl-chain remodeling; TAS:Reactome.
DR GO; GO:0071236; P:cellular response to antibiotic; IEA:Ensembl.
DR GO; GO:0046456; P:icosanoid biosynthetic process; IEA:Ensembl.
DR GO; GO:0006654; P:phosphatidic acid biosynthetic process; TAS:Reactome.
DR GO; GO:0036151; P:phosphatidylcholine acyl-chain remodeling; TAS:Reactome.
DR GO; GO:0036152; P:phosphatidylethanolamine acyl-chain remodeling; TAS:Reactome.
DR GO; GO:0036148; P:phosphatidylglycerol acyl-chain remodeling; TAS:Reactome.
DR GO; GO:0036149; P:phosphatidylinositol acyl-chain remodeling; TAS:Reactome.
DR GO; GO:0036150; P:phosphatidylserine acyl-chain remodeling; TAS:Reactome.
DR GO; GO:0009395; P:phospholipid catabolic process; IEA:InterPro.
DR GO; GO:0006663; P:platelet activating factor biosynthetic process; NAS:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0042127; P:regulation of cell proliferation; IEA:Ensembl.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR002642; LysoPLipase_cat_dom.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF01735; PLA2_B; 1.
DR SMART; SM00239; C2; 1.
DR SMART; SM00022; PLAc; 1.
DR SUPFAM; SSF49562; SSF49562; 1.
DR SUPFAM; SSF52151; SSF52151; 1.
DR PROSITE; PS50004; C2; 1.
DR PROSITE; PS51210; PLA2C; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Calcium; Complete proteome; Cytoplasm;
KW Cytoplasmic vesicle; Direct protein sequencing; Hydrolase;
KW Lipid degradation; Lipid metabolism; Metal-binding; Phosphoprotein;
KW Polymorphism; Reference proteome.
FT CHAIN 1 749 Cytosolic phospholipase A2.
FT /FTId=PRO_0000187262.
FT DOMAIN 5 106 C2.
FT DOMAIN 140 740 PLA2c.
FT REGION 1 178 Phospholipid binding (Probable).
FT ACT_SITE 228 228 Nucleophile.
FT ACT_SITE 549 549 Proton acceptor.
FT METAL 40 40 Calcium 1.
FT METAL 40 40 Calcium 2.
FT METAL 41 41 Calcium 1; via carbonyl oxygen.
FT METAL 43 43 Calcium 1.
FT METAL 43 43 Calcium 2.
FT METAL 65 65 Calcium 1.
FT METAL 93 93 Calcium 2.
FT METAL 94 94 Calcium 2; via carbonyl oxygen.
FT METAL 95 95 Calcium 2.
FT MOD_RES 268 268 Phosphothreonine.
FT MOD_RES 437 437 Phosphoserine.
FT MOD_RES 505 505 Phosphoserine; by MAPK.
FT MOD_RES 727 727 Phosphoserine.
FT MOD_RES 729 729 Phosphoserine.
FT VARIANT 103 103 G -> R (in dbSNP:rs28395828).
FT /FTId=VAR_029276.
FT VARIANT 224 224 V -> I (in dbSNP:rs12720588).
FT /FTId=VAR_018760.
FT VARIANT 442 442 H -> Q (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035826.
FT VARIANT 637 637 I -> V (in dbSNP:rs28395831).
FT /FTId=VAR_062128.
FT VARIANT 651 651 R -> K (in dbSNP:rs2307198).
FT /FTId=VAR_018424.
FT MUTAGEN 139 139 C->A: No effect on phospholipase
FT activity; when associated with A-141 and
FT A-151.
FT MUTAGEN 141 141 C->A: No effect on phospholipase
FT activity; when associated with A-139 and
FT A-151.
FT MUTAGEN 151 151 C->A: No effect on phospholipase
FT activity; when associated with A-139 and
FT A-141.
FT MUTAGEN 195 195 S->A: 5-fold reduced phospholipase and
FT lysophosphatase activities. 100-fold
FT reduced phospholipase and lysophosphatase
FT activities; when associated with A-577.
FT MUTAGEN 200 200 R->A,H: Abolishes phospholipase activity.
FT MUTAGEN 200 200 R->K: Reduces phospholipase activity 200-
FT fold.
FT MUTAGEN 215 215 S->A: No effect on phospholipase or
FT lysophosphatase activity.
FT MUTAGEN 220 220 C->A: No effect on phospholipase
FT activity.
FT MUTAGEN 228 228 S->A,C,T: Abolishes both phospholipase
FT and lysophosphatase activities.
FT MUTAGEN 324 324 C->A: No effect on phospholipase
FT activity; when associated with A-331.
FT MUTAGEN 331 331 C->A: No effect on phospholipase
FT activity; when associated with A-324.
FT MUTAGEN 505 505 S->A: Decreases agonist-stimulated
FT release of arachidonic acid.
FT MUTAGEN 549 549 D->A: Abolishes phospholipiase activity.
FT MUTAGEN 549 549 D->E: Reduces phospholipiase activity
FT 2000-fold.
FT MUTAGEN 549 549 D->N: Reduces phospholipiase activity
FT 300-fold.
FT MUTAGEN 577 577 S->A: 7-fold reduced phospholipase and
FT lysophosphatase activities. 100-fold
FT reduced phospholipase and lysophosphatase
FT activities; when associated with A-195.
FT MUTAGEN 620 620 C->A: No effect on phospholipase
FT activity; when associated with A-634.
FT MUTAGEN 634 634 C->A: No effect on phospholipase
FT activity; when associated with A-620.
FT MUTAGEN 726 726 C->A: No effect on phospholipase
FT activity.
FT STRAND 18 29
FT HELIX 34 39
FT STRAND 44 49
FT STRAND 51 54
FT STRAND 57 60
FT STRAND 70 79
FT STRAND 86 93
FT STRAND 96 98
FT STRAND 100 108
FT HELIX 109 111
FT STRAND 117 124
FT TURN 125 127
FT STRAND 128 137
FT STRAND 143 146
FT HELIX 152 177
FT HELIX 179 181
FT STRAND 190 194
FT HELIX 198 214
FT HELIX 218 220
FT STRAND 221 226
FT HELIX 228 239
FT TURN 241 245
FT HELIX 248 260
FT HELIX 263 266
FT HELIX 269 284
FT HELIX 291 304
FT HELIX 305 307
FT HELIX 313 318
FT TURN 319 321
FT STRAND 326 333
FT HELIX 341 343
FT STRAND 344 349
FT STRAND 354 356
FT TURN 357 360
FT STRAND 361 363
FT HELIX 365 367
FT STRAND 370 373
FT STRAND 376 379
FT HELIX 386 393
FT HELIX 396 399
FT HELIX 401 404
FT HELIX 417 423
FT HELIX 426 429
FT HELIX 463 476
FT STRAND 488 490
FT TURN 492 495
FT STRAND 543 548
FT HELIX 550 552
FT HELIX 558 561
FT HELIX 564 566
FT STRAND 570 575
FT HELIX 588 599
FT HELIX 611 615
FT STRAND 619 623
FT STRAND 636 641
FT HELIX 646 648
FT STRAND 650 652
FT HELIX 660 666
FT STRAND 670 672
FT HELIX 687 702
FT HELIX 705 718
SQ SEQUENCE 749 AA; 85239 MW; EE71CA0EBE617856 CRC64;
MSFIDPYQHI IVEHQYSHKF TVVVLRATKV TKGAFGDMLD TPDPYVELFI STTPDSRKRT
RHFNNDINPV WNETFEFILD PNQENVLEIT LMDANYVMDE TLGTATFTVS SMKVGEKKEV
PFIFNQVTEM VLEMSLEVCS CPDLRFSMAL CDQEKTFRQQ RKEHIRESMK KLLGPKNSEG
LHSARDVPVV AILGSGGGFR AMVGFSGVMK ALYESGILDC ATYVAGLSGS TWYMSTLYSH
PDFPEKGPEE INEELMKNVS HNPLLLLTPQ KVKRYVESLW KKKSSGQPVT FTDIFGMLIG
ETLIHNRMNT TLSSLKEKVN TAQCPLPLFT CLHVKPDVSE LMFADWVEFS PYEIGMAKYG
TFMAPDLFGS KFFMGTVVKK YEENPLHFLM GVWGSAFSIL FNRVLGVSGS QSRGSTMEEE
LENITTKHIV SNDSSDSDDE SHEPKGTENE DAGSDYQSDN QASWIHRMIM ALVSDSALFN
TREGRAGKVH NFMLGLNLNT SYPLSPLSDF ATQDSFDDDE LDAAVADPDE FERIYEPLDV
KSKKIHVVDS GLTFNLPYPL ILRPQRGVDL IISFDFSARP SDSSPPFKEL LLAEKWAKMN
KLPFPKIDPY VFDREGLKEC YVFKPKNPDM EKDCPTIIHF VLANINFRKY RAPGVPRETE
EEKEIADFDI FDDPESPFST FNFQYPNQAF KRLHDLMHFN TLNNIDVIKE AMVESIEYRR
QNPSRCSVSL SNVEARRFFN KEFLSKPKA
//
MIM
600522
*RECORD*
*FIELD* NO
600522
*FIELD* TI
+600522 PHOSPHOLIPASE A2, GROUP IVA; PLA2G4A
;;PHOSPHOLIPASE A2, CYTOSOLIC, CALCIUM-DEPENDENT, ALPHA;;
read moreCPLA2-ALPHA
PHOSPHOLIPASE A2, GROUP IVA, DEFICIENCY OF, INCLUDED
*FIELD* TX
DESCRIPTION
Cytosolic phospholipase A2 (PLA2; EC 3.1.1.4) catalyzes the release of
arachidonic acid from membrane phospholipids. Arachidonic acid in turn
serves as precursor for a wide spectrum of biologic effectors,
collectively known as eicosanoids, that are involved in hemodynamic
regulation, inflammatory responses, and other cellular processes
(summary by Tay et al., 1995). (Eicosanoids are lipid mediators of
inflammation; they include a variety of compounds (prostaglandins,
thromboxanes, leukotrienes, hydroxy- and epoxy-fatty acids, lipoxins,
and isoprostanes) that are derived from the ubiquitous 20-carbon atom
arachidonate (20 in Greek is 'eicosa') and a few similar polyunsaturated
fatty acids (summary by De Caterina and Zampolli, 2004).)
Dennis (1994) reviewed various types of PLA2. The best characterized is
the group II PLA2 originally isolated from human synovial fluid (i.e.,
PLA2G2A; 172411). Groups I (human pancreatic, PLA2G1B (172410); also
found in cobras and kraits), II (synovial; also found in rattlesnakes
and vipers), and III (forms of which were described in bee and lizard)
are secreted; group IV is cytosolic.
CLONING
Cytosolic phospholipase A2 described here (see GenBank GENBANK AF065216)
is distinct from the synovial phospholipase A2 (PLA2G2A; 172411); it has
a large molecular weight; is DTT-insensitive; is activated at a
nanomolar to micromolar calcium concentration range, which prevails in
the cytosol; and is arachidonic acid-specific at the sn-2 position
(Skorecki, 1995). PLA2B, the synovial phospholipase A2 described by
Seilhamer et al. (1989), is a small molecular weight enzyme that is
DTT-sensitive. PLA2B is secreted from cells, active in the micromolar to
millimolar calcium concentration range that prevails in the
extracellular medium, and active in inflammatory exudates.
Sharp et al. (1991) amplified PLA2G4A by PCR with human U937 monoblast
cells, using degenerate primers designed from the purified sequenced
protein. They cloned PLA2G4A cDNA from a U937 library screened with the
PCR product. The deduced 749-amino acid protein has a predicted
molecular mass of 85 kD and contains several potential PKC and tyrosine
kinase phosphorylation sites. Northern blot analysis detected an
approximately 3-kb transcript in U937 cells. Western blot analysis of
U937 cells revealed that PLA2G4 migrates with an apparent molecular mass
of 100 kD.
MAPPING
Tay et al. (1995) mapped the PLA2G4A gene to rat chromosome 13 by
PCR-based intercross genotyping and to human 1q25 by fluorescence in
situ hybridization. The gene encoding the enzyme
prostaglandin-endoperoxide synthase-2, also known as cyclooxygenase-2
(PTGS2; 600262), had previously been mapped to the same chromosomal
region, raising the possibility of coordinate regulation. PTGS2 is
downstream of cytosolic phospholipase A2 in the biochemical pathway for
eicosanoid production.
BIOCHEMICAL FEATURES
Dessen et al. (1999) reported the x-ray crystal structure of human
PLA2G4A at 2.5-angstrom resolution. The structure provided insight into
the origin of arachidonate selectivity and interfacial activation,
clarified the roles of ser228, asp549, and arg200, and revealed the
interplay between the C2 and catalytic domains.
GENE FUNCTION
By site-directed mutagenesis and biochemical analysis of the recombinant
protein, Sharp et al. (1994) determined that ser228 participates in the
catalytic mechanism of cPLA2 and that both the phospholipase A2 and the
lysophospholipase activities are catalyzed by the same active site
residue(s).
PLA2G4A, the cytosolic phospholipase A2, appears to subserve
transmembrane signaling responses to extracellular ligands (Skorecki,
1995).
Sheridan et al. (2001) found that cPLA2 interacts with both splice
variants of HTATIP (601409), a protein that was originally isolated as
an HIV-1 TAT-interactive protein. In transfection experiments, they
found that cPLA2 and HTATIP coimmunoprecipitate and colocalize. Using
serum withdrawal to induce growth arrest and apoptosis in mouse renal
mesangial cells, Sheridan et al. (2001) found cytosolic to nuclear
translocation of endogenous complexes correlated with onset of
apoptosis. CPLA2 and HITATIP synergistically induced arachidonic acid
production following serum withdrawal.
MOLECULAR GENETICS
In a 45-year-old man with suspected inherited prostanoid biosynthesis
deficiency due to recurrent episodes of multiple complicated ulcers of
the small intestine despite no use of cyclooxygenase inhibitors, Adler
et al. (2008) found markedly reduced levels of thromboxane B2 and
12-hydroxyeicosatetraenoic acid (12-HETE) produced by platelets and
leukotriene B4 released from calcium ionophore-activated blood,
consistent with an almost complete absence of the release of arachidonic
acid during platelet activation. Platelet aggregation and degranulation
induced by adenosine diphosphate or collagen were diminished but
normalized with the addition of arachidonic acid. The authors identified
compound heterozygosity for 2 missense mutations in the PLA2G4A gene,
S111P (600522.0001) and R485H (600522.0002), in the patient; his
asymptomatic mother and sister, who were found to have intermediate
levels of platelet-derived thromboxane B2 and 12-HETE that were below or
at the lower end of the normal range, were each heterozygous for 1 of
the mutations, respectively. A known SNP in the PLA2G4A gene, K651R, was
also detected on the same allele as the R485H variant.
ANIMAL MODEL
Haq et al. (2003) generated mice deficient in PLA2G4A by targeted
disruption. Heart size was larger in knockout mice compared to wildtype
littermates, and both heart and skeletal myocyte cross-sectional area
were significantly greater in knockout mice. Haq et al. (2003) found
that cytosolic PLA2, the protein product of the PLA2G4A gene, is a
negative regulator of growth, specifically of striated muscle. They
showed that normal growth of skeletal muscle, as well as normal and
pathologic stress-induced hypertrophic growth of the heart, were
exaggerated in Pla2g4a -/- mice. The mechanism underlying this phenotype
is that cytosolic PLA2 negatively regulates insulin-like growth factor-1
(IGF1; 147440) signaling. Absence of cytosolic PLA2 leads to sustained
activation of the IGF1 pathway, which results from the failure of
3-phosphoinositide-dependent protein kinase-1 (PDK1; 605213) to recruit
and phosphorylate protein kinase C-zeta (176982), the negative regulator
of IGF1 signaling. Arachidonic acid restores activation of PKC-zeta,
correcting the exaggerated IGF1 signaling. Haq et al. (2003) concluded
that cytosolic PLA2 and arachidonic acid regulate striated muscle growth
by modulating multiple growth-regulatory pathways.
Ichinose et al. (2002) found that Pla2g4a-null mice were less able than
wildtype mice to maintain systemic oxygenation during left main stem
bronchus occlusion, and they did not increase pulmonary vascular
resistance during occlusion, as did wildtype mice. Inhibition of
cyclooxygenase or nitric oxide synthase, as well as breathing 10% oxygen
for 3 weeks, restored hypoxic pulmonary vasoconstriction in mutant mice.
Ichinose et al. (2002) concluded that Pla2g4a contributes to the murine
pulmonary vasoconstrictor response to hypoxia and that augmenting
pulmonary vascular tone restores vasoconstriction in the absence of
Pla2g4a activity.
Hegen et al. (2003) generated cPla2-alpha -/- mice on a DBA/1LacJ
background susceptible to collagen-induced arthritis (CIA), a mouse
model of rheumatoid arthritis (180300). The mutant mice were much less
likely to develop CIA than wildtype mice, although there was no
difference in their anti-collagen antibody levels. Hegen et al. (2003)
concluded that cPLA2-alpha plays a critical role in CIA pathogenesis.
After contusive spinal cord injury in rats, Liu et al. (2006) found
increased overall Pla2 activity and markedly increased cytosolic Pla2
expression (6- to 7-fold) mainly within neurons and oligodendrocytes of
the spinal cord. In vitro, endogenous Pla2 induced spinal cord neuronal
death, which was reversed by the Pla2 inhibitor mepacrine.
Microinjection of Pla2 into spinal cord in vivo resulted in confined
demyelination and later diffuse tissue necrosis, as well as increased
inflammation, oxidation, and tissue damage with corresponding
electrophysiologic and behavioral impairment. Liu et al. (2006)
suggested that Pla2 may be a converging molecule that mediates
pathogenesis of multiple injury pathways in spinal cord injury and that
blocking its action may reduce tissue damage.
*FIELD* AV
.0001
PHOSPHOLIPASE A2, GROUP IV A, DEFICIENCY OF
PLA2G4A, SER111PRO
In a 45-year-old man with ulcers of the small intestine, platelet
dysfunction, and globally decreased eicosanoid production, Adler et al.
(2008) identified compound heterozygosity for a 331T-C transition and a
1454G-A transition in the PLA2G4A gene, resulting in a ser111-to-pro
(S111P) and an arg485-to-his (R485H; 600522.0002) substitution,
respectively. The patient's asymptomatic mother and sister, who had
intermediate reductions in eicosanoid biosynthesis, were heterozygous
for the S111P and R485H mutations, respectively.
.0002
PHOSPHOLIPASE A2, GROUP IV A, DEFICIENCY OF
PLA2G4A, ARG485HIS
See 600522.0001 and Adler et al. (2008).
*FIELD* RF
1. Adler, D. H.; Cogan, J. D.; Phillips, J. A., III; Schnetz-Boutaud,
N.; Milne, G. L.; Iverson, T.; Stein, J. A.; Brenner, D. A.; Morrow,
J. D.; Boutaud, O.; Oates, J. A.: Inherited human cPLA(2-alpha) deficiency
is associated with impaired eicosanoid biosynthesis, small intestinal
ulceration, and platelet dysfunction. J. Clin. Invest. 118: 2121-2131,
2008. Note: Erratum: J. Clin. Invest. 119: 2844 only, 2009.
2. De Caterina, R.; Zampolli, A.: From asthma to atherosclerosis--5-lipoxygenase,
leukotrienes, and inflammation. New Eng. J. Med. 350: 4-7, 2004.
3. Dennis, E. A.: Diversity of group types, regulation, and function
of phospholipase A2. J. Biol. Chem. 269: 13057-13060, 1994.
4. Dessen, A.; Tang, J.; Schmidt, H.; Stahl, M.; Clark, J. D.; Seehra,
J.; Somers, W. S.: Crystal structure of human cytosolic phospholipase
A(2) reveals a novel topology and catalytic mechanism. Cell 97:
349-360, 1999.
5. Haq, S.; Kilter, H.; Michael, A.; Tao, J.; O'Leary, E.; Sun, X.
M.; Walters, B.; Bhattacharya, K.; Chen, X.; Cui, L.; Andreucci, M.;
Rosenzweig, A.; Guerrero, J. L.; Patten, R.; Liao, R.; Molkentin,
J.; Picard, M.; Bonventre, J. V.; Force, T.: Deletion of cytosolic
phospholipase A2 promotes striated muscle growth. Nature Med. 9:
944-951, 2003. Note: Erratum: Nature Med. 9: 1221 only, 2003.
6. Hegen, M.; Sun, L.; Uozumi, N.; Kume, K.; Goad, M. E.; Nickerson-Nutter,
C. L.; Shimizu, T.; Clark, J. D.: Cytosolic phospholipase A2-alpha-deficient
mice are resistant to collagen-induced arthritis. J. Exp. Med. 197:
1297-1302, 2003.
7. Ichinose, F.; Ullrich, R.; Sapirstein, A.; Jones, R. C.; Bonventre,
J. V.; Serhan, C. N.; Bloch, K. D.; Zapol, W. M.: Cytosolic phospholipase
A2 in hypoxic pulmonary vasoconstriction. J. Clin. Invest. 109:
1493-1500, 2002.
8. Liu, N.-K.; Zhang, Y. P.; Titsworth, W. L.; Jiang, X.; Han, S.;
Lu, P.-H.; Shields, C. B.; Xu, X.-M.: A novel role of phospholipase
A2 in mediating spinal cord secondary injury. Ann. Neurol. 59: 606-619,
2006.
9. Seilhamer, J. J.; Plant, S.; Pruzanski, W.; Schilling, J.; Stefanski,
E.; Vadas, P.; Johnson, L. K.: Multiple forms of phospholipase A(2)
in arthritic synovial fluid. J. Biochem. 106: 38-42, 1989.
10. Sharp, J. D.; Pickard, R. T.; Chiou, X. G.; Manetta, J. V.; Kovacevic,
S.; Miller, J. R.; Varshavsky, A. D.; Roberts, E. F.; Strifler, B.
A.; Brems, D. N.; Kramer, R. M.: Serine 228 is essential for catalytic
activities of 85-kDa cytosolic phospholipase A2. J. Biol. Chem. 269:
23250-23254, 1994.
11. Sharp, J. D.; White, D. L.; Chiou, X. G.; Goodson, T.; Gamboa,
G. C.; McClure, D.; Burgett, S.; Hoskins, J.; Skatrud, P. L.; Sportsman,
J. R.; Becker, G. W.; Kang, L. H.; Roberts, E. F.; Kramer, R. M.:
Molecular cloning and expression of human Ca(2+)-sensitive cytosolic
phospholipase A2. J. Biol. Chem. 266: 14850-14853, 1991.
12. Sheridan, A. M.; Force, T.; Yoon, H.-J.; O'Leary, E.; Choukroun,
G.; Taheri, M. R.; Bonventre, J. V.: PLIP, a novel splice variant
of Tip60, interacts with group IV cytosolic phospholipase A2, induces
apoptosis, and potentiates prostaglandin production. Molec. Cell.
Biol. 21: 4470-4481, 2001.
13. Skorecki, K. L.: Personal Communication. Toronto, Canada 4/19/1995.
14. Tay, A.; Simon, J. S.; Squire, J.; Hamel, K.; Jacob, H. J.; Skorecki,
K.: Cytosolic phospholipase A2 gene in human and rat: chromosomal
localization and polymorphic markers. Genomics 26: 138-141, 1995.
*FIELD* CN
Marla J. F. O'Neill - updated: 12/23/2008
Cassandra L. Kniffin - updated: 8/6/2007
Paul J. Converse - updated: 3/14/2006
Patricia A. Hartz - updated: 10/14/2005
Victor A. McKusick - updated: 1/20/2004
Ada Hamosh - updated: 6/17/2003
Patricia A. Hartz - updated: 7/2/2002
Patricia A. Hartz - updated: 4/26/2002
Stylianos E. Antonarakis - updated: 5/21/1999
*FIELD* CD
Victor A. McKusick: 5/10/1995
*FIELD* ED
terry: 12/20/2012
terry: 10/3/2012
carol: 11/18/2011
carol: 12/24/2008
terry: 12/23/2008
wwang: 8/23/2007
ckniffin: 8/6/2007
mgross: 3/14/2006
mgross: 10/14/2005
cwells: 1/22/2004
terry: 1/20/2004
alopez: 7/28/2003
alopez: 6/17/2003
terry: 6/17/2003
carol: 7/2/2002
carol: 4/29/2002
terry: 4/26/2002
mgross: 5/24/1999
mgross: 5/21/1999
alopez: 3/3/1999
carol: 11/23/1998
mark: 2/5/1997
jenny: 2/4/1997
mark: 8/21/1995
mark: 5/10/1995
*RECORD*
*FIELD* NO
600522
*FIELD* TI
+600522 PHOSPHOLIPASE A2, GROUP IVA; PLA2G4A
;;PHOSPHOLIPASE A2, CYTOSOLIC, CALCIUM-DEPENDENT, ALPHA;;
read moreCPLA2-ALPHA
PHOSPHOLIPASE A2, GROUP IVA, DEFICIENCY OF, INCLUDED
*FIELD* TX
DESCRIPTION
Cytosolic phospholipase A2 (PLA2; EC 3.1.1.4) catalyzes the release of
arachidonic acid from membrane phospholipids. Arachidonic acid in turn
serves as precursor for a wide spectrum of biologic effectors,
collectively known as eicosanoids, that are involved in hemodynamic
regulation, inflammatory responses, and other cellular processes
(summary by Tay et al., 1995). (Eicosanoids are lipid mediators of
inflammation; they include a variety of compounds (prostaglandins,
thromboxanes, leukotrienes, hydroxy- and epoxy-fatty acids, lipoxins,
and isoprostanes) that are derived from the ubiquitous 20-carbon atom
arachidonate (20 in Greek is 'eicosa') and a few similar polyunsaturated
fatty acids (summary by De Caterina and Zampolli, 2004).)
Dennis (1994) reviewed various types of PLA2. The best characterized is
the group II PLA2 originally isolated from human synovial fluid (i.e.,
PLA2G2A; 172411). Groups I (human pancreatic, PLA2G1B (172410); also
found in cobras and kraits), II (synovial; also found in rattlesnakes
and vipers), and III (forms of which were described in bee and lizard)
are secreted; group IV is cytosolic.
CLONING
Cytosolic phospholipase A2 described here (see GenBank GENBANK AF065216)
is distinct from the synovial phospholipase A2 (PLA2G2A; 172411); it has
a large molecular weight; is DTT-insensitive; is activated at a
nanomolar to micromolar calcium concentration range, which prevails in
the cytosol; and is arachidonic acid-specific at the sn-2 position
(Skorecki, 1995). PLA2B, the synovial phospholipase A2 described by
Seilhamer et al. (1989), is a small molecular weight enzyme that is
DTT-sensitive. PLA2B is secreted from cells, active in the micromolar to
millimolar calcium concentration range that prevails in the
extracellular medium, and active in inflammatory exudates.
Sharp et al. (1991) amplified PLA2G4A by PCR with human U937 monoblast
cells, using degenerate primers designed from the purified sequenced
protein. They cloned PLA2G4A cDNA from a U937 library screened with the
PCR product. The deduced 749-amino acid protein has a predicted
molecular mass of 85 kD and contains several potential PKC and tyrosine
kinase phosphorylation sites. Northern blot analysis detected an
approximately 3-kb transcript in U937 cells. Western blot analysis of
U937 cells revealed that PLA2G4 migrates with an apparent molecular mass
of 100 kD.
MAPPING
Tay et al. (1995) mapped the PLA2G4A gene to rat chromosome 13 by
PCR-based intercross genotyping and to human 1q25 by fluorescence in
situ hybridization. The gene encoding the enzyme
prostaglandin-endoperoxide synthase-2, also known as cyclooxygenase-2
(PTGS2; 600262), had previously been mapped to the same chromosomal
region, raising the possibility of coordinate regulation. PTGS2 is
downstream of cytosolic phospholipase A2 in the biochemical pathway for
eicosanoid production.
BIOCHEMICAL FEATURES
Dessen et al. (1999) reported the x-ray crystal structure of human
PLA2G4A at 2.5-angstrom resolution. The structure provided insight into
the origin of arachidonate selectivity and interfacial activation,
clarified the roles of ser228, asp549, and arg200, and revealed the
interplay between the C2 and catalytic domains.
GENE FUNCTION
By site-directed mutagenesis and biochemical analysis of the recombinant
protein, Sharp et al. (1994) determined that ser228 participates in the
catalytic mechanism of cPLA2 and that both the phospholipase A2 and the
lysophospholipase activities are catalyzed by the same active site
residue(s).
PLA2G4A, the cytosolic phospholipase A2, appears to subserve
transmembrane signaling responses to extracellular ligands (Skorecki,
1995).
Sheridan et al. (2001) found that cPLA2 interacts with both splice
variants of HTATIP (601409), a protein that was originally isolated as
an HIV-1 TAT-interactive protein. In transfection experiments, they
found that cPLA2 and HTATIP coimmunoprecipitate and colocalize. Using
serum withdrawal to induce growth arrest and apoptosis in mouse renal
mesangial cells, Sheridan et al. (2001) found cytosolic to nuclear
translocation of endogenous complexes correlated with onset of
apoptosis. CPLA2 and HITATIP synergistically induced arachidonic acid
production following serum withdrawal.
MOLECULAR GENETICS
In a 45-year-old man with suspected inherited prostanoid biosynthesis
deficiency due to recurrent episodes of multiple complicated ulcers of
the small intestine despite no use of cyclooxygenase inhibitors, Adler
et al. (2008) found markedly reduced levels of thromboxane B2 and
12-hydroxyeicosatetraenoic acid (12-HETE) produced by platelets and
leukotriene B4 released from calcium ionophore-activated blood,
consistent with an almost complete absence of the release of arachidonic
acid during platelet activation. Platelet aggregation and degranulation
induced by adenosine diphosphate or collagen were diminished but
normalized with the addition of arachidonic acid. The authors identified
compound heterozygosity for 2 missense mutations in the PLA2G4A gene,
S111P (600522.0001) and R485H (600522.0002), in the patient; his
asymptomatic mother and sister, who were found to have intermediate
levels of platelet-derived thromboxane B2 and 12-HETE that were below or
at the lower end of the normal range, were each heterozygous for 1 of
the mutations, respectively. A known SNP in the PLA2G4A gene, K651R, was
also detected on the same allele as the R485H variant.
ANIMAL MODEL
Haq et al. (2003) generated mice deficient in PLA2G4A by targeted
disruption. Heart size was larger in knockout mice compared to wildtype
littermates, and both heart and skeletal myocyte cross-sectional area
were significantly greater in knockout mice. Haq et al. (2003) found
that cytosolic PLA2, the protein product of the PLA2G4A gene, is a
negative regulator of growth, specifically of striated muscle. They
showed that normal growth of skeletal muscle, as well as normal and
pathologic stress-induced hypertrophic growth of the heart, were
exaggerated in Pla2g4a -/- mice. The mechanism underlying this phenotype
is that cytosolic PLA2 negatively regulates insulin-like growth factor-1
(IGF1; 147440) signaling. Absence of cytosolic PLA2 leads to sustained
activation of the IGF1 pathway, which results from the failure of
3-phosphoinositide-dependent protein kinase-1 (PDK1; 605213) to recruit
and phosphorylate protein kinase C-zeta (176982), the negative regulator
of IGF1 signaling. Arachidonic acid restores activation of PKC-zeta,
correcting the exaggerated IGF1 signaling. Haq et al. (2003) concluded
that cytosolic PLA2 and arachidonic acid regulate striated muscle growth
by modulating multiple growth-regulatory pathways.
Ichinose et al. (2002) found that Pla2g4a-null mice were less able than
wildtype mice to maintain systemic oxygenation during left main stem
bronchus occlusion, and they did not increase pulmonary vascular
resistance during occlusion, as did wildtype mice. Inhibition of
cyclooxygenase or nitric oxide synthase, as well as breathing 10% oxygen
for 3 weeks, restored hypoxic pulmonary vasoconstriction in mutant mice.
Ichinose et al. (2002) concluded that Pla2g4a contributes to the murine
pulmonary vasoconstrictor response to hypoxia and that augmenting
pulmonary vascular tone restores vasoconstriction in the absence of
Pla2g4a activity.
Hegen et al. (2003) generated cPla2-alpha -/- mice on a DBA/1LacJ
background susceptible to collagen-induced arthritis (CIA), a mouse
model of rheumatoid arthritis (180300). The mutant mice were much less
likely to develop CIA than wildtype mice, although there was no
difference in their anti-collagen antibody levels. Hegen et al. (2003)
concluded that cPLA2-alpha plays a critical role in CIA pathogenesis.
After contusive spinal cord injury in rats, Liu et al. (2006) found
increased overall Pla2 activity and markedly increased cytosolic Pla2
expression (6- to 7-fold) mainly within neurons and oligodendrocytes of
the spinal cord. In vitro, endogenous Pla2 induced spinal cord neuronal
death, which was reversed by the Pla2 inhibitor mepacrine.
Microinjection of Pla2 into spinal cord in vivo resulted in confined
demyelination and later diffuse tissue necrosis, as well as increased
inflammation, oxidation, and tissue damage with corresponding
electrophysiologic and behavioral impairment. Liu et al. (2006)
suggested that Pla2 may be a converging molecule that mediates
pathogenesis of multiple injury pathways in spinal cord injury and that
blocking its action may reduce tissue damage.
*FIELD* AV
.0001
PHOSPHOLIPASE A2, GROUP IV A, DEFICIENCY OF
PLA2G4A, SER111PRO
In a 45-year-old man with ulcers of the small intestine, platelet
dysfunction, and globally decreased eicosanoid production, Adler et al.
(2008) identified compound heterozygosity for a 331T-C transition and a
1454G-A transition in the PLA2G4A gene, resulting in a ser111-to-pro
(S111P) and an arg485-to-his (R485H; 600522.0002) substitution,
respectively. The patient's asymptomatic mother and sister, who had
intermediate reductions in eicosanoid biosynthesis, were heterozygous
for the S111P and R485H mutations, respectively.
.0002
PHOSPHOLIPASE A2, GROUP IV A, DEFICIENCY OF
PLA2G4A, ARG485HIS
See 600522.0001 and Adler et al. (2008).
*FIELD* RF
1. Adler, D. H.; Cogan, J. D.; Phillips, J. A., III; Schnetz-Boutaud,
N.; Milne, G. L.; Iverson, T.; Stein, J. A.; Brenner, D. A.; Morrow,
J. D.; Boutaud, O.; Oates, J. A.: Inherited human cPLA(2-alpha) deficiency
is associated with impaired eicosanoid biosynthesis, small intestinal
ulceration, and platelet dysfunction. J. Clin. Invest. 118: 2121-2131,
2008. Note: Erratum: J. Clin. Invest. 119: 2844 only, 2009.
2. De Caterina, R.; Zampolli, A.: From asthma to atherosclerosis--5-lipoxygenase,
leukotrienes, and inflammation. New Eng. J. Med. 350: 4-7, 2004.
3. Dennis, E. A.: Diversity of group types, regulation, and function
of phospholipase A2. J. Biol. Chem. 269: 13057-13060, 1994.
4. Dessen, A.; Tang, J.; Schmidt, H.; Stahl, M.; Clark, J. D.; Seehra,
J.; Somers, W. S.: Crystal structure of human cytosolic phospholipase
A(2) reveals a novel topology and catalytic mechanism. Cell 97:
349-360, 1999.
5. Haq, S.; Kilter, H.; Michael, A.; Tao, J.; O'Leary, E.; Sun, X.
M.; Walters, B.; Bhattacharya, K.; Chen, X.; Cui, L.; Andreucci, M.;
Rosenzweig, A.; Guerrero, J. L.; Patten, R.; Liao, R.; Molkentin,
J.; Picard, M.; Bonventre, J. V.; Force, T.: Deletion of cytosolic
phospholipase A2 promotes striated muscle growth. Nature Med. 9:
944-951, 2003. Note: Erratum: Nature Med. 9: 1221 only, 2003.
6. Hegen, M.; Sun, L.; Uozumi, N.; Kume, K.; Goad, M. E.; Nickerson-Nutter,
C. L.; Shimizu, T.; Clark, J. D.: Cytosolic phospholipase A2-alpha-deficient
mice are resistant to collagen-induced arthritis. J. Exp. Med. 197:
1297-1302, 2003.
7. Ichinose, F.; Ullrich, R.; Sapirstein, A.; Jones, R. C.; Bonventre,
J. V.; Serhan, C. N.; Bloch, K. D.; Zapol, W. M.: Cytosolic phospholipase
A2 in hypoxic pulmonary vasoconstriction. J. Clin. Invest. 109:
1493-1500, 2002.
8. Liu, N.-K.; Zhang, Y. P.; Titsworth, W. L.; Jiang, X.; Han, S.;
Lu, P.-H.; Shields, C. B.; Xu, X.-M.: A novel role of phospholipase
A2 in mediating spinal cord secondary injury. Ann. Neurol. 59: 606-619,
2006.
9. Seilhamer, J. J.; Plant, S.; Pruzanski, W.; Schilling, J.; Stefanski,
E.; Vadas, P.; Johnson, L. K.: Multiple forms of phospholipase A(2)
in arthritic synovial fluid. J. Biochem. 106: 38-42, 1989.
10. Sharp, J. D.; Pickard, R. T.; Chiou, X. G.; Manetta, J. V.; Kovacevic,
S.; Miller, J. R.; Varshavsky, A. D.; Roberts, E. F.; Strifler, B.
A.; Brems, D. N.; Kramer, R. M.: Serine 228 is essential for catalytic
activities of 85-kDa cytosolic phospholipase A2. J. Biol. Chem. 269:
23250-23254, 1994.
11. Sharp, J. D.; White, D. L.; Chiou, X. G.; Goodson, T.; Gamboa,
G. C.; McClure, D.; Burgett, S.; Hoskins, J.; Skatrud, P. L.; Sportsman,
J. R.; Becker, G. W.; Kang, L. H.; Roberts, E. F.; Kramer, R. M.:
Molecular cloning and expression of human Ca(2+)-sensitive cytosolic
phospholipase A2. J. Biol. Chem. 266: 14850-14853, 1991.
12. Sheridan, A. M.; Force, T.; Yoon, H.-J.; O'Leary, E.; Choukroun,
G.; Taheri, M. R.; Bonventre, J. V.: PLIP, a novel splice variant
of Tip60, interacts with group IV cytosolic phospholipase A2, induces
apoptosis, and potentiates prostaglandin production. Molec. Cell.
Biol. 21: 4470-4481, 2001.
13. Skorecki, K. L.: Personal Communication. Toronto, Canada 4/19/1995.
14. Tay, A.; Simon, J. S.; Squire, J.; Hamel, K.; Jacob, H. J.; Skorecki,
K.: Cytosolic phospholipase A2 gene in human and rat: chromosomal
localization and polymorphic markers. Genomics 26: 138-141, 1995.
*FIELD* CN
Marla J. F. O'Neill - updated: 12/23/2008
Cassandra L. Kniffin - updated: 8/6/2007
Paul J. Converse - updated: 3/14/2006
Patricia A. Hartz - updated: 10/14/2005
Victor A. McKusick - updated: 1/20/2004
Ada Hamosh - updated: 6/17/2003
Patricia A. Hartz - updated: 7/2/2002
Patricia A. Hartz - updated: 4/26/2002
Stylianos E. Antonarakis - updated: 5/21/1999
*FIELD* CD
Victor A. McKusick: 5/10/1995
*FIELD* ED
terry: 12/20/2012
terry: 10/3/2012
carol: 11/18/2011
carol: 12/24/2008
terry: 12/23/2008
wwang: 8/23/2007
ckniffin: 8/6/2007
mgross: 3/14/2006
mgross: 10/14/2005
cwells: 1/22/2004
terry: 1/20/2004
alopez: 7/28/2003
alopez: 6/17/2003
terry: 6/17/2003
carol: 7/2/2002
carol: 4/29/2002
terry: 4/26/2002
mgross: 5/24/1999
mgross: 5/21/1999
alopez: 3/3/1999
carol: 11/23/1998
mark: 2/5/1997
jenny: 2/4/1997
mark: 8/21/1995
mark: 5/10/1995