Figure 1.
Comparison of retinoid binding in their transport proteins.
In the same protein family and subcellular location, retinol and retinoic acid have the same binding orientation (A, B), while in different protein families and subcellular locations, the binding orientations of the ligands are completely different (C, D). (a) In both of the extracellular proteins (RBP, ERABP), the β-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. (b) The orientation of the ligand is, therefore, opposite to that in the corresponding intracellular retinoid-binding proteins (CRBPs and CRABPs). The red, blue, green and pink lines indicate RBP (PDB code: 1brp), ERABP (PDB code: 1epb), CRBP (PDB code: 1crb), and CRABP (PDB code: 1cbs) protein structures, respectively. The colors representing retinol and retinoic acid correspond to different transport protein colors.
Figure 2.
The retinol-binding cavity in RBP and CRBP.
Ligand binding sites show as cartoon and transparent surface respectively. The binding site surface is illustrated by meshed colors according to the electrostatic potential. We show the binding cavity in different directions to facilitate the observation of the polar interaction between the retinol and the transport proteins. (A) The yellow dashed line is the polar interaction between the retinol –OH and GLN98 in RBP. (B) The yellow dashed line is the polar interaction between the retinol –OH and GLN108 in CRBP. Water molecules (red balls) adjacent to the retinol –OH form polar interactions between water molecules and other water molecules or side chain amino acids (left picture).
Figure 3.
The retinoic acid-binding cavity in ERABP and CRABP.
The retinoic acid binding sites are displayed and colored as in Figure 2. (A) In ERABP, three positively charged amino acids (Arg80, Lys85 and Lys115) along with the retinoic acid carboxylate form a network of three ion pairs at the entrance end of the amphipathic binding site. Additional polar side chains and water molecules that participate in the network are included. (B) The carboxylate of the ligand interacts with a trio of residues (Arg132, Tyr134 and Arg111) in CRABP.
Figure 4.
The retinoid possible transport model.
In plasma, retinol binds with RBP in a higher-affinity form. Some of the retinol is oxidized to retinoic acid in the epididymis, which is required for sperm maturation. Most of the plasma retinol is transported to the interior of target cells across and across the cell membrane by a specific receptor. The retinol is picked up from the membrane by an intracellular structural homolog, called cellular retinol-binding protein (CRBP), in a lower-affinity form. Once inside the cells, the low affinity form may be readily used by the cell. In different subcellular locations, the retinol binding orientation is reversed. When the body is in need of vitamin A, the retinol dissociates from the CRBP, which is converted into retinoic acid and bound by CRABP. CRABP then transports retinoic acid to the nucleus across the nuclear receptor, thereby activating gene transcription.