title: Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling.
abstract: Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA). ATX-LPA signalling is involved in multiple biological and pathophysiological processes, including vasculogenesis, fibrosis, cholestatic pruritus and tumour progression. ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function. We present crystal structures of rat ATX bound to 7α-hydroxycholesterol and the bile salt tauroursodeoxycholate (TUDCA), showing how the tunnel selectively binds steroids. A structure of ATX simultaneously harbouring TUDCA in the tunnel and LPA in the pocket, together with kinetic analysis, reveals that bile salts act as partial non-competitive inhibitors of ATX, thereby attenuating LPA receptor activation. This unexpected interplay between ATX-LPA signalling and select steroids, notably natural bile salts, provides a molecular basis for the emerging association of ATX with disorders associated with increased circulating levels of bile salts. Furthermore, our findings suggest potential clinical implications in the use of steroid drugs.
authors.affiliation: Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Willem-Jan
authors.initials: WJ
authors.lastname: Keune
authors.affiliation: Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Jens
authors.initials: J
authors.lastname: Hausmann
authors.affiliation: Department of Hepatology and Gastroenterology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ruth
authors.initials: R
authors.lastname: Bolier
authors.affiliation: Department of Hepatology and Gastroenterology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Tolenaars
authors.affiliation: Department of Hepatology and Gastroenterology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kremer
authors.affiliation: Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Heidebrecht
authors.affiliation: Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Robbie P
authors.initials: RP
authors.lastname: Joosten
authors.affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, Kentucky 40511, USA.|Department of Veterans Affairs, Medical Center Lexington, Kentucky 40511, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Sunkara
authors.affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, Kentucky 40511, USA.|Department of Veterans Affairs, Medical Center Lexington, Kentucky 40511, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, Kentucky 40511, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Matas-Rico
authors.affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, Kentucky 40511, USA.
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Moolenaar
authors.affiliation: Department of Hepatology and Gastroenterology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Oude Elferink
authors.affiliation: Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Anastassis
authors.initials: A
authors.lastname: Perrakis
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008246:Lysophospholipids / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D015398:Signal Transduction; D013256:Steroids / Q000737:chemistry / Q000378:metabolism*; D013655:Taurochenodeoxycholic Acid / Q000737:chemistry / Q000378:metabolism; D000099189:Lysophospholipase D
chemical_list: D001647:Bile Acids and Salts; D006888:Hydroxycholesterols; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D049368:Receptors, Lysophosphatidic Acid; D013256:Steroids; D013655:Taurochenodeoxycholic Acid; D000099189:Lysophospholipase D; C011724:cholest-5-en-3 beta,7 alpha-diol; C031655:ursodoxicoltaurine; C032881:lysophosphatidic acid