α5β1 Integrins are Receptors for Bile Acids with a (Nor-)Ursodeoxycholane Scaffold

Integrins are ubiquitously expressed cell adhesion receptors and the most prevalent bidirectional signaling molecules on the cell surface. They are involved in osmosensing in the liver [1,2,3] and facilitate the communication between the extracellular matrix and cytoplasmic proteins. Upon activation, integrins undergo large-scale conformational changes from a compact, bent state to an open, extended state [4]. A recent study combined immunofluorescence staining (IFS) experiments and molecular dynamics (MD) simulations to identify tauroursodeoxycholic acid (TUDC) as potent agonist of α5β1 integrins in hepatocytes [5]. Activation of α5β1 leads to choleresis by FAK/c-Src/MAPK dependent signaling events [6,7,8]. TUDC-induced integrin activation and subsequent signaling is sensitive to inhibition by the trihydroxylated taurocholic acid (TC), which tightly binds to α5β1 in MD simulations. However, effects of other bile acids on α5β1 integrin activation have not been investigated at the molecular level.

In this study, we report on combined IFS experiments and MD simulations that indicate that α5β1 integrins are not exclusively activated by TUDC. 24-nor-ursodeoxycholic acid (norUDCA), a side chain-shortened homologue of UDCA, induces conformational changes in the βA domain of α5β1 that are similar to the one evoked by TUDC, but overall less pronounced. Conformational changes in simulations of integrin ectodomains bound with the taurine conjugate of norUDCA (TnorUDCA) and glycoursodeoxycholic acid (GUDC) were significantly less pronounced. Unconjugated UDCA, similar to the inhibitory TC, only showed insignificant alterations in the structure of the integrin ectodomain and was considered fully inactive. A ranking based on the extent of structural changes observed during the MD simulations correlates with results from IFS experiments on the efficacy of the bile acids.

These results indicate that norUDCA activates α5β1 integrins and that MD simulations are able to predict different degrees of bile-acid induced integrin activation. Minor structural changes in the bile acids strongly influence their efficacy. This holds true for a comparison of TUDC (activating) vs. TC (inhibitory) and norUDCA (activating) vs. UDCA (nonactivating).

We are grateful to the ''Zentrum für Informations und Medientechnologie'' (ZIM) at the Heinrich Heine University for computational support. This work was supported by the Deutsche Forschungsgemeinschaft through the Collaborative Research Center SFB 974 (''Communication and Systems Relevance during Liver Damage and Regeneration'', Düsseldorf).

References:

[1] Häussinger D et al.: Gastroenterology 2003, 124(5): 1476 – 1487

[2] vom Dahl S et al.: J Biol Chem 2003, 278(29): 27088 – 27095

[3] Schließ et al.: J Biol Chem 2004, 279(20): 21294 – 301

[4] Xiong JP et al.: Science 2001, 294(5541): 339 – 345

[5] Gohlke H et al.: Hepatology 2013, 57(3): 1117 – 1129

[6] Schließ F et al.: Gastroenterology 1997, 113(4): 1306 – 1314

[7] Beuers U et al.: Hepatology 2001, 33(5): 1206 – 1216

[8] Häussinger D et al.: Gastroenterology 2003, 124(5): 1476 – 1487

Corresponding author: Bonus, Michele

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