PLA2G4A (phospholipase A2, group IVA (cytosolic, calcium-dependent))

	PLA2G4A gene. PLA2G4A is comprised of 18 exons. The ATG start codon is located within exon 2 and the TAG stop codon is found in exon 18. The sizes of exons 1-18 are 135 bp, 101 bp, 81 bp, 148 bp, 113 bp, 37 bp, 141 bp, 136 bp, 222 bp, 114 bp, 137 bp, 92 bp, 71 bp, 242 bp, 184 bp, 195 bp, 157 bp, and 604 bp, respectively.
Description	According to Entrez-Gene, human PLA2G4A maps to locus NC_000001.10. This gene contains 18 exons that encompass approximately 160 kb of genomic DNA. In mice, Pla2g4a maps to NC_000067.5 and contains 18 exons that span 131 kb of DNA within the mouse genome.
Transcription	Human PLA2G4A mRNA (NG_024420) consists of 2940 bp, and murine Pla2g4a mRNA (NM_008869) contains 2846 bp.
Pseudogene	No pseudogene has been identified for PLA2G4A.

	cPLA2-alpha structure. The binding of calcium (Ca2+) ions to the C2 domain promotes the translocation of cPLA2alpha from the cytosol to the perinuclear/membrane region of the cell. Following this change in subcellular localization, cPLA2alpha is phosphorylated on key serine residues by MAPKs (ERK1/ERK2 and p38), Ca2+/calmodulin-dependent protein kinase II (CaMKII), or MAPK-interacting kinase (Mnk1). Ser228 is located in the first catalytic domain and is critical for the enzymatic activity of cPLA2alpha.
Description	cPLA2alpha is an 85 kDa protein consisting of 749 amino acids. cPLA2alpha belongs to the alpha-beta hydrolase family which is identified by a characteristic nucleophile elbow with a consensus sequence of Sm-X-Nu-Sm (Sm = small residue, X = any residue and Nu = nucleophile). The protein contains an N-terminal C2 domain (Ca2+-dependent, phospholipid binding) and two catalytic domains (alpha/beta hydrolase). The N-terminal region of the first catalytic domain contains the lipase consensus sequence, GXSGS. At the active site, cPLA2alpha contains a serine nucleophile (Ser228) through which the catalytic mechanism is initiated. The active site is partially covered by a solvent-accessible flexible lid which spans from Arg413 to Gln457. cPLA2alpha displays interfacial activation as it exists in both "closed lid" and "open lid" forms. Upon membrane binding, gross conformational changes in the enzyme result in the movement of the cPLA2alpha lid thus exposing a greater hydrophobic surface and the active site. This allows the fatty acyl chain of a substrate phospholipid molecule to enter the active site.
Expression	cPLA2alpha is ubiquitously expressed throughout normal tissues, but is often overexpressed in human cancers.
Localisation	Prior to activation, cPLA2alpha is localized to the cytoplasm. Upon an influx of intracellular calcium (Ca2+), however, Ca2+ ions bind to the C2 domain and promote the translocation of cPLA2alpha to either the nuclear envelope, Golgi apparatus, endoplasmic reticulum, or plasma membrane. The membrane-associated localization is then stabilized through the binding of the protein to anionic phospholipids or by phosphorylation of Ser505, Ser515, or Ser727. As a result of these molecular events, the enzymatic activity of cPLA2alpha is increased.
Function	Following activation by Ca2+ concentration and/or phosphorylation, cPLA2alpha hydrolyzes phospholipids at the sn-2-acyl ester bond to yield both free fatty acid as well as lysophospholipid second messengers. Phosphatidylcholine (PC) is the most abundant phospholipid in mammalian cell membranes and is the primary target of cPLA2alpha. The cPLA2alpha-mediated cleavage of PC results in the release of arachidonic acid (AA) and lysophosphatidylcholine (LPC). AA is further metabolized to prostaglandins and leukotrienes by the cyclooxygenase and 5-lipoxygenase pathways, respectively. Thus, cPLA2alpha and AA are key contributors to the inflammatory process. Lipid second messengers such as LPC and lysophosphatidic acid (LPA) are involved in downstream signal transduction that affects cell survival, proliferation, motility, and invasiveness.
Homology	Homologs of human PLA2G4A have been identified in the following organisms : Pan troglodytes, Canis lupus familiaris, Bos taurus, Mus musculus, Rattus norvegicus, Gallus gallus, Danio rerio. In addition, at least four paralogs of cPLA2 have been identified in mammals. They include cPLA2alpha, cPLA2beta, cPLA2gamma, and cPLA2delta. All paralogs contain the N-terminal C2 domain except cPLA2gamma. Human cPLA2gamma also harbors a myristoylation site at the N-terminus and is farnesylated at the C-terminus. The main residues that are essential to cPLA2 catalytic activity (Arg200, Ser228, Asp549, Arg566) are conserved among all four paralogs of the enzyme.

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