RT Journal Article
T1 Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling
A1 Keune, Willen-Jan
A1 Hausmann, Jens
A1 Bolier, Ruth
A1 Tolenaars, Dagmar
A1 Kremer, Andreas
A1 Heidebrecht, Tatjana
A1 Joosten, Robbie P
A1 Sunkara, Manjula
A1 Morris, Andrew J
A1 Matas-Rico, Elisa
A1 Moolenaar, Wouter H
A1 Oude Elferink, Ronald P
A1 Perrakis, Anastassis
K1 Esteroides
AB 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.
PB Springer Nature
YR 2016
FD 2016-04
LK https://hdl.handle.net/10630/34423
UL https://hdl.handle.net/10630/34423
LA eng
NO Keune, WJ., Hausmann, J., Bolier, R. et al. Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling. Nat Commun 7, 11248 (2016). https://doi.org/10.1038/ncomms11248
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 20 ene 2026