1. BIOCHEMICAL PROPERTIES OF THE PHOSPHOLI- PASE A2 RECEPTOR Phospholipase A2 (PLA2) comprises a diverse family of lipolytic enzymes which hydrolyzes the sn-2 fatty acid ester bond of glycerophospholipids to produce free fatty acids

Phospholipase A2 (PLA2) comprises a diverse family of lipolytic enzymes which hydrolyzes the sn-2 fatty acid ester bond of glycerophospholipids to produce free fatty acids and lysophspholipids. Low molecular-weight (13—18-kDa) secretory PLA2s (sPLA2s) have several common characteristics including the presence of six to eight disulfide bridges and are classified into 10 different groups. To date, most of the biological activities of sPLA2s have been attributed to their enzymatic capacity to hydrolyze membrane phospholipids. However, the discovery of the PLA2 receptor (PLA2R) has expanded our concept of the sPLA2 family. 3) In addition to the digestive function, sPLA2 can exert various biological responses through the binding to the cell surface PLA2R. PLA2R has been identified as the binding protein for group IB sPLA2 (sPLA2-IB), 4) which had long been thought, given its abundance in digestive organs, to play a role in the digestion of glycerophospholipids in nutrients. PLA2R is a type I transmembrane glycoprotein with a molecular mass of 180 kDa and is composed of a large extracellular portion consisting of an N-terminal cysteine-rich region, a fibronectin-like type II domain, and a tandem repeat of eight carbohydrate-recognition domains (CRDs), as well as a short intracellular C-terminal region. Its overall molecular organization is related to a unique member of the C-type animal lectin family (subgroup VI), which includes the macrophage mannose receptor and DEC-205 in dendritic cells. Most of the extracellular portion of PLA2R is composed of eight CRD-like domains, which are responsible for sPLA2 binding. In particular, the three CRD-like domains from CRD3 to CRD5 are sufficient for conferring sPLA2-IB binding activity. However, the critical residues required for the sugar/Ca binding found in the mannose receptor are not conserved in the CRD-like domains of the PLA2R. The PLA2R does not possess Ca 2 -dependent lectin activity. The intracellular region of human PLA2R contains a consensus sequence motif (Asn-Pro-Xxx-Tyr motif) of coated pit-mediated endocytosis originally identified in the low-density lipoprotein (LDL) receptor. The PLA2R is expressed in alveolar type II epithelial cells and a subset of splenic lymphocytes, but not in the peritoneal macrophages where the mannose receptor is abundantly expressed. There is strict species specificity in the relationship between sPLA2 ligands and the PLA2R. 5) In mice, sPLA2-IB acts as a ligand of the PLA2R. Although group IIA sPLA2 (sPLA2-IIA) can also bind to mouse PLA2R with lower affinity than sPLA2-IB, some inbred mouse strains have a natural frameshift mutation in the sPLA2-IIA gene. A novel type of group X sPLA2 (sPLA2-X), which possesses 16 cysteine residues located at positions characteristic of both sPLA2-IB and sPLA2-IIA, can also act as a high-affinity ligand for mouse PLA2R. The expressions of sPLA2-IB and -X are detected in alveolar type II epithelial cells and splenic cells in mice, where they can work as a functional PLA2R ligand in vivo. Intriguingly, both sPLA2 ligands are produced as inactive proenzymes and the activation with proteolytic enzymes such as trypsin and proprotein convertases is essential for optimum binding to the receptor. In contrast to rodents, the natural ligands for the human PLA2R remain obscure at present. The binding affinity of human sPLA2-IB was calculated to be about 400 nM, which is rather weak compared with those calculated in rodents. In contrast, sPLA2-IIA does not bind to the human PLA2R and there is no information regarding the potency of sPLA2-X as a ligand for the human PLA2R. Potential roles of the recently identified sPLA2s as endogenous ligands of the human PLA2R should be evaluated in future studies.