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-phosphocholine) is a potent lipid first messenger active in general cell activation, fertilization, inflammatory and allergic reactions, asthma, HIV pathogenesis, carcinogenesis, and apoptosis. There is substantial evidence that PAF is involved in intracellular signalling, but the pathways are poorly understood. Inactivation of PAF is carried out by specific intra- and extracellular acetylhydrolases (PAF-AHs), a subfamily of phospholipases A2 that remove the sn-2 acetyl group. Mammalian brain contains at least three intracellular isoforms, of which PAF-AH(Ib) is the best characterized. This isoform contains a heterodimer of two homologous catalytic subunits alpha1 and alpha2, each of relative molecular mass 26K, and a non-catalytic 45K beta-subunit, a homologue of the beta-subunit of trimeric G proteins. We now report the crystal structure of the bovine alpha1 subunit of PAF-AH(Ib) at 1.7 A resolution in complex with a reaction product, acetate. The tertiary fold of this protein is closely reminiscent of that found in p21(ras) and other GTPases. The active site is made up of a trypsin-like triad of Ser 47, His 195 and Asp 192. Thus, the intact PAF-AH(Ib) molecule is an unusual G-protein-like (alpha1/alpha2)beta trimer.
Ho
Y S
YS
Department of Molecular Physiology and Biological Physics, University of Virginia Health Sciences Center, Charlottesville 22906-0011, USA.
Swenson
L
L
Derewenda
U
U
Serre
L
L
Wei
Y
Y
Dauter
Z
Z
Hattori
M
M
Adachi
T
T
Aoki
J
J
Arai
H
H
Inoue
K
K
Derewenda
Z S
ZS
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002417:Cattle; D018360:Crystallography, X-Ray; D019204:GTP-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010741:Phospholipases A / Q000737:chemistry* / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism*; D011487:Protein Conformation; D013379:Substrate Specificity
D010972:Platelet Activating Factor; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D019204:GTP-Binding Proteins