title: Autotaxin: structure-function and signaling.
abstract: Autotaxin (ATX), or ecto-nucleotide pyrophosphatase/phosphodiesterase-2, is a secreted lysophospholipase D (lysoPLD) that hydrolyzes extracellular lysophospholipids into the lipid mediator lysophosphatidic acid (LPA), a ligand for specific G protein-coupled receptors. ATX-LPA signaling is essential for development and has been implicated in a great diversity of (patho)physiological processes, ranging from lymphocyte homing to tumor progression. Structural and functional studies have revealed what makes ATX a unique lysoPLD, and how secreted ATX binds to its target cells. The ATX catalytic domain shows a characteristic bimetallic active site followed by a shallow binding groove that can accommodate nucleotides as well as the glycerol moiety of lysophospholipids, and by a deep lipid-binding pocket. In addition, the catalytic domain has an open tunnel of unknown function adjacent to the active site. Here, we discuss our current understanding of ATX structure-function relationships and signaling mechanisms, and how ATX isoforms use distinct mechanisms to target LPA production to the plasma membrane, notably binding to integrins and heparan sulfate proteoglycans. We also briefly discuss the development of drug-like inhibitors of ATX.
authors.affiliation: Divisions of Biochemistry, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands.
authors.forename: Anastassis
authors.initials: A
authors.lastname: Perrakis
authors.affiliation: Cell Biology, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands.
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Moolenaar
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D008246:Lysophospholipids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000072417:Protein Domains; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D000099189:Lysophospholipase D
chemical_list: D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid
keywords: G protein-coupled receptors; ecto-nucleotide pyrophosphatase/phosphodiesterase; inhibitors; lysophosphatidic acid