BRAIN ACETYLHYDROLASE THAT INACTIVATES PLATELET-ACTIVATING-FACTOR IS A G-PROTEIN-LIKE TRIMER

THE platelet-activating factor PAF (1-O-alkyl-2-acetyl-sn-glycero-3-ph osphocholine) is a potent lipid first messenger active in general cell activation, fertilization, inflammatory and allergic reactions, asthm a, HIV pathogenesis, carcinogenesis, and apoptosis(1-5). There is subs tantial evidence that PAF is involved in intracellular signalling, but the pathways are poorly understood. Inactivation of PAF is carried ou t by specific intra- and extracellular acetylhydrolases(6) (PAF-AHs), a subfamily of phospholipases A2 that remove the sn-2 acetyl group, Ma mmalian brain contains at least three intracellular isoforms, of which PAF-AH(Ib) is the best characterized(7-9). This isoform contains a he terodimer of two homologous catalytic subunits alpha(1) and alpha(2), each of relative molecular mass 26K, and a non-catalytic 45K beta-subu nit, a homologue of the beta-subunit of trimeric G proteins. We now re port the crystal structure of the bovine alpha(1) subunit of PAF-AH(Ib ) at 1.7 Angstrom resolution in complex with a reaction product, aceta te, The tertiary fold of this protein is closely reminiscent of that f ound in p21(ras) and other GTPases. The active site is made up of a tr ypsin-like triad of Ser 47, His 195 and Asp 192, Thus, the intact PAF- AH(Ib) molecule is an unusual G-protein-like (alpha(1)/alpha(2))beta t rimer.