Vitamin A, in its various forms, is an essential component of mammalian health. In addition to its well-documented role in vision, Vitamin A contributes to several other important biological functions including nuclear transcription, skin cell differentiation, growth, and immunity. As animals are not capable of synthesis, vitamin A and its metabolites (collectively know as the retinoids) must be obtained through the diet (Goodman 1984). Two major forms of vitamin A are found in food: retinol and carotenoids. All of these fat-soluble vitamins contain two distinct structural features that contribute to all of their activity. The first is a β-ionone ring to which the second critical motif, an isoprenoid chain, is attached.
Retinol, the major circulating form of vitamin A, is not biologically active. Rather, it serves as the metabolic precursor for the active retinoids (Chapman 2012). Oxidation at C-15 converts retinol to the visual pigment retinal, while subsequent oxidation of the aldehyde produces retinoic acid, which is involved in gene transcription (Figure 1). It is important for the body to maintain plasma retinol homeostasis to serve as a precursor reservoir for these active retinoids.
Mobilization of Vitamin A from the liver and its circulation to peripheral tissues is a highly regulated process. Delivery without appreciable loss of retinol requires it be bound tightly to plasma retinol-binding protein (RBP). RBP, first described by Goodman and colleagues in 1968, is synthesized in the endoplasmic reticulum of hepatocytes and contains a single binding site for only all-trans-retinol (Goodman 1980). Upon secretion into the plasma, Retinol-RBP circulates as a complex with a larger protein, transthyretin (TTR). As a tetramer, one TTR is capable of binding two molecules of retinol-binding protein and such binding prevents the loss of the low molecular weight RBP through glomerular filtration at the kidneys (Newcomer and Ong 2000). In the transport of vitamin A, retinol-binding protein provides a comprehensive study of protein-protein and protein-ligand interactions. This review outlines the structural features of plasma retinol-binding protein and relates them to the intermolecular interactions and functional role of this protein.
Structural Features of Retinol-Binding Protein
Retinol-binding protein is a member of the lipocalins, a family of extracellular proteins involved in the transport of small, hydrophobic molecules. RBP consists of 182 amino acid residues. The primary amino acid sequence and distribution of 3 disulfide bridges has been elucidated via cyanogen bromide (CNBr) fragmentation (Figure 2 and Figure 3). Primary structure ultimately determines the protein’s three-dimensional arrangement and RBP was the first lipocalin molecule for which X-ray structure was described. As such, serves as a “prototypic” reference for newly reported lipocalin structures (Newcomer et.al. 1984).