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Abstract
Functional selectivity is the ligand-specific activation of certain signal transduction pathways at a receptor and has been described for G protein-coupled receptors. However, it has not yet been described for ligands interacting with integrins without αI domain. Here, we show by molecular dynamics simulations that four side chain-modified derivatives of tauroursodeoxycholic acid (TUDC), an agonist of α5β1 integrin, differentially shift the conformational equilibrium of α5β1 integrin towards the active state, in line with the extent of β1 integrin activation from immunostaining. Unlike TUDC, 24-nor-ursodeoxycholic acid (norUDCA)-induced β1 integrin activation triggered only transient activation of extracellular signal-regulated kinases and p38 mitogen-activated protein kinase and, consequently, only transient insertion of the bile acid transporter Bsep into the canalicular membrane, and did not involve activation of epidermal growth factor receptor. These results provide evidence that TUDC and norUDCA exert a functional selectivity at α5β1 integrin and may provide a rationale for differential therapeutic use of UDCA and norUDCA.
Highlights
Functional selectivity is the ligand-specific activation of certain signal transduction pathways at a receptor and has been described for G protein-coupled receptors
We tested to what extent side chain-modified derivatives of tauroursodeoxycholic acid (TUDC) (24-nor-ursodeoxycholic acid, its taurine conjugate (TnorUDCA), glycoursodeoxycholic acid (GUDC), and unconjugated UDCA; Supplementary Fig. 1) can directly activate α5β1 integrins and whether the signaling events downstream of integrin activation differ from those triggered by TUDC
TUDC leads to a kink angle of helix α1 of 147.3 ± 0.1°, a tilt angle of helix α7 of 138.2 ± 0.1°, and a distance between the βA-domain and the β-propeller of 36.68 ± 0.01 Å, whereas TC leads to angles of 142.0 ± 0.1° and 126.6 ± 0.1°, respectively, and a distance of 35.77 ± 0.01 Å (Figs. 1c,h and 2c, Supplementary Table 2). norursodeoxycholic acid (norUDCA) induces α1 kink and α7 tilt angles similar in magnitude as in the case of TUDC (149.2 ± 0.1° and 138.2 ± 0.1°, respectively), whereas the distance between β-propeller and βA-domain is ~0.6 Å smaller (Figs. 1d and 2a,c, Supplementary Table 2)
Summary
Functional selectivity is the ligand-specific activation of certain signal transduction pathways at a receptor and has been described for G protein-coupled receptors. Unlike TUDC, 24-norursodeoxycholic acid (norUDCA)-induced β1 integrin activation triggered only transient activation of extracellular signal-regulated kinases and p38 mitogen-activated protein kinase and, only transient insertion of the bile acid transporter Bsep into the canalicular membrane, and did not involve activation of epidermal growth factor receptor These results provide evidence that TUDC and norUDCA exert a functional selectivity at α5β1 integrin and may provide a rationale for differential therapeutic use of UDCA and norUDCA. A ligand likely achieves this type of differential activation by stabilizing only a specific subset of receptor conformations, in particular those that favor interactions with only a specific subset of downstream signaling molecules[1] This phenomenon has so far been described in detail only for G protein-coupled receptors (GPCRs)[2], but the observation that αMβ2 integrins respond differently to fibrinogen- and CD40L-binding has led to the suggestion that this model could be extended to integrins with an αI domain[3,4]. Our results demonstrate that norUDCA directly activates α5β1 integrins in hepatocytes and provide evidence that TUDC and norUDCA exert a functional selectivity for certain signal transduction pathways in α5β1 integrin
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