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Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling.

Keune WJ, Hausmann J, Bolier R, Tolenaars D, Kremer A, Heidebrecht T, Joosten RP, Sunkara M, Morris AJ, Matas-Rico E, Moolenaar WH, Oude Elferink RP, Perrakis A - Nat Commun (2016)

Bottom Line: Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA).ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function.Furthermore, our findings suggest potential clinical implications in the use of steroid drugs.

View Article: PubMed Central - PubMed

Affiliation: Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus

The tunnel of ATX.(a) A cartoon representation of the domain structure of ATX combined with a transparent surface highlighting the position of tunnel; the SMB domains are coloured in pink and magenta, the PDE domain in green, the NUC domain in blue, the lasso loop wrapping around the NUC domain in orange and the short loop connecting the SMB domains to the PDE domain in cyan; the zinc ions are shown as spheres; a yellow background highlights the tunnel site, (b) the same cartoon model, with bound LPA18:1 (PDB:3NKP) and a yellow circle designating the tunnel site. All structural images were generated using PyMOL (http:// www.pymol.org) or CCP4mg48.
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f1: The tunnel of ATX.(a) A cartoon representation of the domain structure of ATX combined with a transparent surface highlighting the position of tunnel; the SMB domains are coloured in pink and magenta, the PDE domain in green, the NUC domain in blue, the lasso loop wrapping around the NUC domain in orange and the short loop connecting the SMB domains to the PDE domain in cyan; the zinc ions are shown as spheres; a yellow background highlights the tunnel site, (b) the same cartoon model, with bound LPA18:1 (PDB:3NKP) and a yellow circle designating the tunnel site. All structural images were generated using PyMOL (http:// www.pymol.org) or CCP4mg48.

Mentions: Crystal structures of ATX89 (ENPP2) revealed a catalytic domain with a bimetallic active site adjacent to a catalytic threonine. Substrate binding takes place in a shallow hydrophilic groove that accommodates nucleotides as well as the glycerol moiety of lysophospholipids, and in a deep hydrophobic pocket binding the lysophospholipid acyl chain. In addition, the catalytic domain together with the first of two somatomedin-β (SMB) domains, form a tunnel adjacent to the active site (Fig. 1a,b).


Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling.

Keune WJ, Hausmann J, Bolier R, Tolenaars D, Kremer A, Heidebrecht T, Joosten RP, Sunkara M, Morris AJ, Matas-Rico E, Moolenaar WH, Oude Elferink RP, Perrakis A - Nat Commun (2016)

The tunnel of ATX.(a) A cartoon representation of the domain structure of ATX combined with a transparent surface highlighting the position of tunnel; the SMB domains are coloured in pink and magenta, the PDE domain in green, the NUC domain in blue, the lasso loop wrapping around the NUC domain in orange and the short loop connecting the SMB domains to the PDE domain in cyan; the zinc ions are shown as spheres; a yellow background highlights the tunnel site, (b) the same cartoon model, with bound LPA18:1 (PDB:3NKP) and a yellow circle designating the tunnel site. All structural images were generated using PyMOL (http:// www.pymol.org) or CCP4mg48.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834639&req=5

f1: The tunnel of ATX.(a) A cartoon representation of the domain structure of ATX combined with a transparent surface highlighting the position of tunnel; the SMB domains are coloured in pink and magenta, the PDE domain in green, the NUC domain in blue, the lasso loop wrapping around the NUC domain in orange and the short loop connecting the SMB domains to the PDE domain in cyan; the zinc ions are shown as spheres; a yellow background highlights the tunnel site, (b) the same cartoon model, with bound LPA18:1 (PDB:3NKP) and a yellow circle designating the tunnel site. All structural images were generated using PyMOL (http:// www.pymol.org) or CCP4mg48.
Mentions: Crystal structures of ATX89 (ENPP2) revealed a catalytic domain with a bimetallic active site adjacent to a catalytic threonine. Substrate binding takes place in a shallow hydrophilic groove that accommodates nucleotides as well as the glycerol moiety of lysophospholipids, and in a deep hydrophobic pocket binding the lysophospholipid acyl chain. In addition, the catalytic domain together with the first of two somatomedin-β (SMB) domains, form a tunnel adjacent to the active site (Fig. 1a,b).

Bottom Line: Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA).ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function.Furthermore, our findings suggest potential clinical implications in the use of steroid drugs.

View Article: PubMed Central - PubMed

Affiliation: Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

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.

No MeSH data available.


Related in: MedlinePlus