Abstract
BackgroundRetinoids are a class of compounds that are chemically related to vitamin A, which is an essential nutrient that plays a key role in vision, cell growth and differentiation. In vivo, retinoids must bind with specific proteins to perform their necessary functions. Plasma retinol-binding protein (RBP) and epididymal retinoic acid binding protein (ERABP) carry retinoids in bodily fluids, while cellular retinol-binding proteins (CRBPs) and cellular retinoic acid-binding proteins (CRABPs) carry retinoids within cells. Interestingly, although all of these transport proteins possess similar structures, the modes of binding for the different retinoid ligands with their carrier proteins are different.Methodology/Principal FindingsIn this work, we analyzed the various retinoid transport mechanisms using structure and sequence comparisons, binding site analyses and molecular dynamics simulations. Our results show that in the same family of proteins and subcellular location, the orientation of a retinoid molecule within a binding protein is same, whereas when different families of proteins are considered, the orientation of the bound retinoid is completely different. In addition, none of the amino acid residues involved in ligand binding is conserved between the transport proteins. However, for each specific binding protein, the amino acids involved in the ligand binding are conserved. The results of this study allow us to propose a possible transport model for retinoids.Conclusions/SignificanceOur results reveal the differences in the binding modes between the different retinoid-binding proteins.
Highlights
Vitamin A is an essential nutrient that plays a key role in vision, cell growth and differentiation, and embryonic development
retinol-binding protein (RBP), epididymal retinoic acid binding protein (ERABP), cellular retinol-binding proteins (CRBPs) and cellular retinoic acid-binding proteins (CRABPs) bind similar ligands (RBP and CRBPs both bind retinol; ERABP and CRABPs both bind retinoic acid), the protein-ligand binding patterns are very different among them (Fig. 1)
When comparing different families of proteins and subcellular locations, the binding orientations of retinoids are completely different. In both of the extracellular retinoid-binding proteins (RBP and ERABP), the b-ionone ring of the ligand is positioned in the center of the barrel with the isoprene tail extending along the barrel axis pointing toward the solvent
Summary
Vitamin A is an essential nutrient that plays a key role in vision, cell growth and differentiation, and embryonic development. Retinal (retinaldehyde), the aldehyde derived from retinol, is essential for vision, while retinoic acid is essential for skin health and bone growth These chemical compounds are collectively known as retinoids and possess the same structural motif (i.e., all-trans double bonds) found in retinol. All retinoids possess a b-ionone ring and a polyunsaturated side chain containing an alcohol, an aldehyde, a carboxylic acid group or an ester group [1] Because of their chemical instability and fairly low solubility in aqueous media, retinoids must be bound by specific proteins in bodily fluids and within cells. Retinoids are a class of compounds that are chemically related to vitamin A, which is an essential nutrient that plays a key role in vision, cell growth and differentiation. All of these transport proteins possess similar structures, the modes of binding for the different retinoid ligands with their carrier proteins are different
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