PUBLICATION
Evolution of the bile salt nuclear receptor FXR in vertebrates
- Authors
- Reschly, E.J., Ai, N., Ekins, S., Welsh, W.J., Hagey, L.R., Hofmann, A.F., and Krasowski, M.D.
- ID
- ZDB-PUB-080327-19
- Date
- 2008
- Source
- Journal of Lipid Research 49(7): 1577-1587 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Bile Acids and Salts/chemistry
- Bile Acids and Salts/metabolism*
- Cattle
- Cell Line
- Crystallography, X-Ray
- Evolution, Molecular*
- Ligands
- Models, Molecular
- Molecular Structure
- RNA-Binding Proteins/chemistry
- RNA-Binding Proteins/metabolism*
- Spectrometry, Mass, Electrospray Ionization
- Vertebrates/genetics
- Vertebrates/metabolism*
- PubMed
- 18362391 Full text @ J. Lipid Res.
Citation
Reschly, E.J., Ai, N., Ekins, S., Welsh, W.J., Hagey, L.R., Hofmann, A.F., and Krasowski, M.D. (2008) Evolution of the bile salt nuclear receptor FXR in vertebrates. Journal of Lipid Research. 49(7):1577-1587.
Abstract
Bile salts, the major end-metabolites of cholesterol, vary significantly in structure across vertebrate species, suggesting that nuclear receptors binding these molecules may show adaptive evolutionary changes. We compared across species the bile salt specificity of the major transcriptional regulator of bile salt synthesis, the farnesoid X receptor (FXR). We found that FXRs have changed specificity for primary bile salts across species by altering the shape and size of the ligand-binding pocket. In particular, the ligand-binding pockets of sea lamprey (Petromyzon marinus) and zebrafish (Danio rerio) FXRs, as predicted by homology models, are flat and ideal for binding planar, evolutionarily early bile alcohols. In contrast, human FXR has a curved binding pocket best suited for the bent steroid ring configuration typical of evolutionarily more recent bile acids. We also found that the putative and ideal for binding planar, evolutionarily early bile alcohols. In contrast, human FXR has a curved binding pocket best suited for the bent stFXR from the sea squirt Ciona intestinalis, a chordate invertebrate, was completely insensitive to activation by bile salts but was activated by sulfated pregnane steroids, suggesting that the endogenous ligands of this receptor may be steroidal in nature. Our observations present an integrated picture of co-evolution of bile salt structure and that of the binding pocket of their target nuclear receptor FXR.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping