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Brain acetylhydrolase that inactivates platelet-activating factor is a G-protein-like trimer

Nature volume 385, pages 89–93 (1997)Cite this article

Abstract

THE platelet-activating factor PAF (l-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 apoptosis1–5. 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 acetylhydrolases6 (PAF-AHs), a subfamily of phospho-lipases A2 that remove the sn-2 acetyl group. Mammalian brain contains at least three intracellular isoforms, of which PAF-AH(Ib) is the best characterized7–9. This isoform contains a heterodimer of two homologous catalytic subunits α1 and α2,, each of relative molecular mass 26K, and a non-catalytic 45K β-subunit, a homologue of the β-subunit of trimeric G proteins. We now report the crystal structure of the bovine α1 subunit of PAF-AH(Ib) at 1.7 Å resolution in complex with a reaction product, acetate. The tertiary fold of this protein is closely reminiscent of that found in p21ras 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 (α1/α2)β trimer.

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Author notes

  1. Laurence Serre

    Present address: Institute de Biologie Structurale (IBS), Avenue des Martyrs, 38042, Grenoble Cedex, France

  2. Lora Swenson and Laurence Serre: Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

  3. Zbyszek Dauter: EMBLOutstation, 22603 Hamburg, Germany

  4. Mitsuharu Hattori, Tomoya Adachi, Junken Aoki, Hiroyuki Arai and Keizo Inoue: Department of Health Chemistry, Faculty of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113, Japan

Authors and Affiliations

  1. Department of Molecular Physiology and Biological Physics, University of Virginia Health Sciences Center, PO Box 10011, 1300 Jefferson Park Avenue, Charlottesville, Virginia, 22906-0011, USA

    Yew S. Ho, Lora Swenson, Urszula Derewenda, Laurence Serre, Yunyi Wei, Zbyszek Dauter, Mitsuharu Hattori, Tomoya Adachi, Junken Aoki, Hiroyuki Arai, Keizo Inoue & Zygmunt S. Derewenda

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Ho, Y., Swenson, L., Derewenda, U. et al. Brain acetylhydrolase that inactivates platelet-activating factor is a G-protein-like trimer. Nature 385, 89–93 (1997). https://doi.org/10.1038/385089a0

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