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.
Document Type
Article
Publication Date
4-14-2016
Digital Object Identifier (DOI)
https://doi.org/10.1038/ncomms11248
Related Content
The crystal structures have been deposited in the Protein Data Bank with accession codes: 5DLT, 5DLV, 5DLW.
Repository Citation
Keune, Willem-Jan; Hausmann, Jens; Bolier, Ruth; Tolenaars, Dagmar; Kremer, Andreas; Heidebrecht, Tatjana; Joosten, Robbie P.; Sunkara, Manjula; Morris, Andrew J.; Matas-Rico, Elisa; Moolenaar, Wouter H.; Oude Elferink, Ronald P.; and Perrakis, Anastassis, "Steroid Binding to Autotaxin Links Bile Salts and Lysophosphatidic Acid Signalling" (2016). Gill Heart & Vascular Institute Faculty Publications. 10.
https://uknowledge.uky.edu/heart_facpub/10
Supplementary Information: Supplementary Figures 1-6
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Biochemistry, Biophysics, and Structural Biology Commons, Cardiology Commons, Pharmacy and Pharmaceutical Sciences Commons
Notes/Citation Information
Published in Nature Communications, v. 7, article no. 11248, p. 1-10.
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