Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling

Willem-Jan Keune, Jens Hausmann, Ruth Bolier, Dagmar Tolenaars, Andreas Kremer, Tatjana Heidebrecht, Robbie P. Joosten, Manjula Sunkara, Andrew J. Morris, Elisa Matas-Rico, Wouter H. Moolenaar, Ronald P. Oude Elferink () and Anastassis Perrakis ()
Additional contact information
Willem-Jan Keune: Netherlands Cancer Institute
Jens Hausmann: Netherlands Cancer Institute
Ruth Bolier: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam
Dagmar Tolenaars: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam
Andreas Kremer: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam
Tatjana Heidebrecht: Netherlands Cancer Institute
Robbie P. Joosten: Netherlands Cancer Institute
Manjula Sunkara: Gill Heart Institute, University of Kentucky
Andrew J. Morris: Gill Heart Institute, University of Kentucky
Elisa Matas-Rico: Netherlands Cancer Institute
Wouter H. Moolenaar: Netherlands Cancer Institute
Ronald P. Oude Elferink: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam
Anastassis Perrakis: Netherlands Cancer Institute

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11248

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