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Retinol Binding Protein and Its Interaction with Transthyretin

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Transport of vitamin A to the target cells is mediated by the lipocalin retinol-binding protein. In plasma, RBP is found in a complex with its carrier protein Transthyretin (TTR). The structures of RBP free and in complex with TTR provide the details of the protein–protein interaction.

Introduction

Vitamin A is unique among the vitamins in having two separable functions. The parent compound, retinol (also known as vitamin A alcohol) is itself inactive but serves as the precursor for the production of various active forms that include the aldehyde retinal and retinoic acid. The light-induced cis-trans isomerization of the former is the initial signal required for vision, while the latter regulates gene expression by serving as a ligand for specific nuclear receptors of the steroid hormone super-family.1 Thus the vitamin is essential not only for vision, but also has a hormonal action as retinoic acid in processes such as morphogenesis and proper differentiation and maintenance of various tissues,2 particularly epithelium. All of the physiologically active forms of the vitamin are hydrophobic molecules that readily partition into lipid-rich sites and consequently the specific transport of the vitamin is mediated by both intra and extra cellular binding proteins. Only small amounts of the vitamin are required (several mg of retinol per day are adequate to support good health for humans) and these specific transport proteins allow for efficient mobilization of the vitamin by minimizing the loss to nonspecific interactions with membranes. The extra cellular transport protein for retinol (retinol binding protein, RBP) is a member of the lipocalin super-family. RBP circulates in the plasma bound to its carrier protein transthyretin (TTR) and this protein-protein complex is thought to interact with specific cell receptors to deliver retinol to the target cells. Because of its role in the specific transport of an essential vitamin, this lipocalin has been the focus of a great deal of research. This review represents a very brief summary of the structure and function of the RBP:TTR complex.

The body maintains a homeostatic level of retinol in plasma to serve as a constant source of precursor for active retinoids. This retinol is able to circulate throughout without appreciable loss because it is tightly bound to the 21000 Da plasma retinol binding protein (RBP), first described by Goodman and colleagues in 1968.3 RBP is synthesized primarily in the liver, where it requires the binding of retinol to trigger its secretion.4 Other sites of synthesis are known5 and include the kidney, peritubular and Sertoli cells of the testis,6,7 the retinal pigment epithelium,8,9 and the choroid plexus of the brain.10 Synthesis in the kidney is for the purpose of returning salvaged retinol to the circulation while the other sites are for the purpose of moving retinol across those cells that form the blood-organ barriers of the testis, retina, and brain.

Whether vitamin A is to be ultimately utilized as retinoic acid, 11-cis-retinal or another retinoid, RBP delivers only all-trans-retinol, and only retinol can trigger secretion of RBP.4 In the plasma, RBP binds to the larger protein, transthyretin (TTR, previously referred to as thyroxine binding prealbumin). The binding of RBP to TTR was suggested to prevent extensive loss of the low molecular weight RBP through glomerular filtration.3 This hypothesis was supported by the much later experiments of Blaner and colleagues with TTR “knockout” mice that demonstrate that RBP is rapidly clearly from the plasma in TTR deficient mice.11 In vitro one tetramer of TTR can bind two molecules of retinol binding protein. However, the concentration of RBP in the plasma is limiting and as a consequence the complex isolated from serum is composed of TTR and RBP in a one to one stoichiometry with a resultant molecular mass of about 80000 Da.

The RBP Structure Provided the First View of the Lipocalin Structure

RBP was the first lipocalin for which an X-ray structure was described12 and thus serves as a sort of ‘prototype’ or reference for the description of subsequently reported lipocalin structures. The identification of the then novel fold and the fact that so much is known about the biological function of RBP make it a paradigm for the study of lipocalins. Structures have been determined for the human,12-14 bovine,15 porcine16 and chicken17 proteins. The basic structural framework of RBP is an eight-stranded up-and-down β-barrel onto which a carboxy-terminal α-helix is packed. Because of the characteristic twist of β-sheets and the orthogonal stacking of the two layers of β-sheet, a cylindrical structure is formed. The amino terminus of the protein, which includes one of the three regions of highly conserved amino acids found in lipocalins, seals one end of the cylinder, while the opposite end is the entrance to the binding cavity. It is this calyx or cup-like structure that inspired the name ‘lipocalin’ for this superfamily of proteins of which RBP is a member. All three regions of highly conserved amino acid sequence, which are spaced throughout in the linear sequence and constitute the ‘motif ’ characteristic of this superfamily,18,19 converge in the three-dimensional structure at the base of the calyx. The loops that connect the β-strands of the barrel are generally short, except for the loop between the first two strands which is longer and folds over the open end of the barrel.

The Retinol Binding Site

All-trans-retinol binds with the isoprene tail fully extended in the β-barrel with the trimethyl cyclohexylene ring innermost in a hand-in-glove-like fit in a hydrophobic cavity. Aromatic amino acids dominate at the ring end of the ligand. The ligand hydroxyl is at the protein surface and is solvent accessible. The high degree of complementarity in the shape of the binding site for the ligand is consistent with the fact that RBP is less tolerant of changes to the ring end of the ligand structure (for review see ref. 20) where structural differences would be difficult to accommodate without the rearrangement of amino acids in the protein core. In contrast, RBP binds retinal and retinoic acid with affinities comparable to that for retinol. The aldehyde and carboxylate can be accommodated in the binding site with only minor changes at the entrance of the β-barrel where the polar/charged groups can remain solvent exposed. Crystal structures of bovine RBP with all-trans-retinoic acid, N-ethyl retinamide, and 4-hydroxyphenyl retinamide21,22 all illustrate the relative ease with which a ligand modified at the alcohol end can fit in the binding cavity.

A comparison of the apo and holo structures of bovine RBP revealed a ligand-induced conformational change which is confined to the entrance loop that includes amino acid residues 33-36. The most striking difference (illustrated in fig. 1) is in the orientation of amino acids Leu-35 and Phe-36. Phe-36 moves into the space occupied by the isoprene tail in the holo protein.15

Figure 1. The structure of bovine retinol binding protein.

Figure 1

The structure of bovine retinol binding protein. A cartoon rendering of RBP (pdb code 1HBP) in which α-helices are shown as cylinders and β-strands as arrows. The conformational change that accompanies ligand binding is confined to amino (more...)

The Retinol Binding Protein Transthyretin Complex

As mentioned above, retinol-RBP in plasma is found in a complex with transthyretin. The affinity of RBP for TTR is roughly micromolar20 and the two proteins readily copurify. The proteins co-elute on gel filtration columns if not dialyzed into low ionic strength buffer prior to the application of sample.

The structure of TTR has also been determined , as well as the structures of the protein:protein complexes of chicken RBP and human TTR23 and human RBP:TTR.24 Transthyretin is a homotetramer which is best described as a dimer of dimers. Monomers associate into dimers via the formation of an eight-stranded antiparallel β-sheet to which each monomer contributes four β-strands. The dimers are associated such that the two β-sheets are back-to-back at the center of the tetramer, creating a large solvent channel passing between the two sheets.25 In the channel is the binding pocket for two molecules of thyroxine.

The open end of the RBP barrel docks up against TTR at a twofold axis of symmetry perpendicular to the large solvent channel that provides access to the thyroxine binding sites. That small portion of the retinol which remains solvent accessible when bound to uncomplexed RBP is fully concealed with the formation of the ternary complex. This serves to protect the reactive end of the molecule and also substantially slows release of retinol from its RBP binding site (unpublished observation, Ong and Kakkad). In the human:human TTR:RBP complex, the accessible surface area of 42 amino acids is reduced by complex formation, and RBP and TTR contribute 21 amino acids each to the interface. As is typical for protein:protein interaction sites, hydrophobic amino acids are at the center of the site and charged amino acids at the periphery of the site. Leu and Ile are the predominant amino acids in the interface. Half of the amino acid side chains are hydrophobic or aromatic (16 and five, respectively). The hydrophobic nature of the interface is consistent with the observation that complex dissociates only at low ionic strength. The docking interface is compatible for TTR and RBP-retinol, but less so for the non-physiological complex that RBP can form in vitro with retinoic acid, or even for RBP when free of retinol. As mentioned above, ligand binding to RBP induces a conformational change which results in the movement of the loop which includes amino acids 35 and 36.15 These amino acids are found at the protein:protein interface and in the apo protein are not positioned for favorable interaction with TTR, hence the observed diminished affinity of apo-RBP for TTR.

As described above, the face that TTR presents in the formation of the complex is at the twofold axis which relates the dimers of TTR in the tetramer. Consequently, the binding site for RBP is symmetric (despite the fact that RBP itself is not) and of a total of 21 amino acid residues of TTR that are buried in the complex, 12 are duplicates, i.e., six amino acids occur twice in the binding site. A variety of naturally occurring mutations in transthyretin have been described, and the mutation of Ile(84) to Asn or Ser abrogates RBP:TTR complex formation. 26 Individuals with this variant of TTR have substantially lowered plasma concentrations of RBP due to kidney filtration,27 an observation which confirms the importance of complex formation in vitamin A homeostasis. Ile-84 is one of the amino acids that is contributed by two monomers to the RBP recognition site. The duplication of Ile-84 in the RBP binding site and its location at the heart of the hydrophobic interface is consistent with the severity of the consequences of the mutation of this surface amino acid. RBP affinity for I84S-TTR is negligible. 26 While the structures of piscine TTR and RBP are highly conserved with respect to their human counterparts, RBP and TTR do not form a complex in sea bream.28 One key sequence difference is that the Ile(84) is a serine in the fish TTR. The complementarity of the TTR:RBP interface and the central location of ile-84 are illustrated in Figure 2.

Figure 2. The interaction of transthyretin and retinol-binding protein.

Figure 2

The interaction of transthyretin and retinol-binding protein. A) A space-filled rendering of the transthyretin (white and blue and purple) and RBP (pink) interface in which shape complementarity is apparent. B) A ribbon drawing of the interaction. In (more...)

In addition to the interface created by the docking of the barrel entrance of RBP at a TTR dimer twofold axis, an interaction of TTR with the carboxy terminus of RBP was revealed in the crystal structure of the human RBP:TTR complex. In the previously determined X-ray structures of human RBP alone the carboxy terminus was not visible and therefore disordered. 12-14 This interaction was not observed for the structure of the heterologous complex of chicken RBP and human TTR23 as the carboxy-terminal eight amino acids are found only in mammalian RBPs. However, the interaction appears to be biologically relevant as it has been observed that naturally occurring truncated forms of RBP are more readily cleared from the plasma than full length RBP.29,30 As indicated, complex formation prevents extensive loss of RBP through glomerular filtration and the loss of the two carboxy-terminal leucines (182-183) that are found nestled in a groove formed by the docking of RBP on to TTR may lead to a reduced affinity of RBP for TTR.

In Figure 3 space-filled renderings of the RBP and the RBP:TTR complex are presented in which regions of RBP have been highlighted to illustrate those stretches of the protein that various groups have demonstrated to be involved in TTR binding. As mentioned above, Zanotti et al15 defined the conformational differences in the apo and holo protein that can account for the observation that apo-RBP has a reduced affinity for TTR. This region of the protein (shown in purple) is an integral part of the protein:protein recognition interface. Site directed mutagenesis experiments by Sivaprasadarao and Findlay31 indicated that the loop which includes residues 92-98 (cyan in the drawing) is required for TTR binding. In contrast, point mutations at positions 63 and 64 (red) had no effect on TTR affinity. This is somewhat surprising in light of the fact these two residues, which in the native protein are leucines, are found at the interface, but entirely consistent with the results of Melhus et al32 who observed that monoclonal antibodies to a synthetic peptide of RBP amino acids 60-70 (red and darker red), can immunoprecipitate TTR:RBP. In addition, Noy et al33 observe that retinol dissociates from RBP prior to RBP:TTR complex dissociation. Such a sequence of events can be envisioned if the loop which includes amino acids 60-70 could peel away from the interface to allow ligand exit. Perhaps intermediate structures, which allow for interaction of RBP with a putative cell surface receptor, as well as TTR, exist. The carboxy terminus of RBP, which appears to modulate RBP:TTR affinity is shown in magenta. It is positioned in contact with the 60-70 loop, which is clearly part of the recognition surface.

Figure 3. Amino acids that have been shown to affect RBP:TTR complex formation experimentally.

Figure 3

Amino acids that have been shown to affect RBP:TTR complex formation experimentally. Regions of RBP that have been shown experimentally to be important for TTR binding are shown in purple, cyan, red, brown and magenta in free RBP (A) and the (B) RBP:TTR (more...)

Because TTR is a dimer of dimers, there are two equivalent binding sites for RBP. Furthermore, the twofold symmetry of the recognition interface itself results in two possible relative positionings of the two RBPs onto TTR. Both quaternary structures have been observed crystallographically. In the complex of chicken RBP with human TTR, the RBP molecules make the bulk of the contacts with the same dimer of TTR (where a dimer of TTR is the unit of monomers associated via the formation of the eight-stranded β-sheet) and in the human:human complex the RBPs make the bulk of the interactions with monomers of TTR from the two different dimers (fig. 4). It is not possible to say whether the difference in quaternary structure reflects a true structural difference between the mixed species and human complexes, or whether they are simply the quaternary structure selected by the different crystallization conditions.

Figure 4. The quaternary structures of the RBP:TTR complexes.

Figure 4

The quaternary structures of the RBP:TTR complexes. The human RBP:human TTR complex (top) and chicken RBP: human TTR complex (bottom). RBP is in green, and TTR is colored in shades of blue and purple.

While the excellent surface complementarity of the interaction between RBP and TTR is illustrated in Figure 2A, from Figure 2B one can appreciate the fact that the TTR interaction sites on RBP are confined to loops at one end of the barrel. In an effort to confirm that TTR affinity is conferred by these loops, Sundaram et al34 prepared a chimera of RBP and the rat epididymal retinoic acid binding protein (ERABP), also a lipocalin for which a structure has been determined.35 The chimera was composed of an ERABP in which the two TTR-binding loops of RBP were substituted for their counterparts in ERABP. This hybrid protein has affinity for TTR.36

Naturally Occurring Mutant Forms of RBP

Vitamin A status is routinely evaluated by analysis of serum RBP levels. Only in extreme cases of malnourishment do the serum levels of RBP drop, but these can be readily restored to normal levels with ingestion of the vitamin. However, two instances of vitamin A deficiency which were not ameliorated by vitamin A intake have been reported.37-39 Only one of these cases, in which no serum RBP could be detected, has been fully characterized, and in this case two point mutations in two separate alleles were identified.39 One mutation results in the substitution of asparagine for isoleucine at position 41. This amino acid side chain forms part of the retinol binding site and is positioned roughly 5 Å from the ionone ring. The incorporation of a polar amino acid for a hydrophobic amino acid would surely result in a binding pocket which is less complementary in chemistry to its ligand and consequently a protein with diminished affinity for retinol. The second substitution is an aspartate for a glycine at position 75. It would appear that the protein fold would be much less forgiving of this latter change. This glycine is also found in the binding pocket and the substitution of the much larger aspartate which carries a negative charge at this position would undoubtedly have grave structural consequences.

The physiological consequence of the above mutations is that the sisters in whom it was identified suffer from night blindness. Although biological processes in addition to vision require vitamin A, these needs can apparently be met by less specific transport systems. Quadro et al40 have generated RBP-/- mice and find that although these mice have markedly impaired retinal function during the first few months of life, they are otherwise healthy and capable of reproducing. If provided with a diet sufficient in vitamin A the mice have normal vision by five months of age. RBP thus appears to be required for efficient retinol mobilization in times of insufficient dietary intake. The alternative pathway is likely via hydrolysis of retinyl esters in the chylomicrons released to the circulation from the small intestine.41 These esters are available from hydrolysis by lipoprotein lipase, releasing retinol for cellular uptake.42 Interestingly, the retina takes up the retinol released in this way very poorly, compared to other tissues. Conversely, the retina takes up retinol from RBP avidly, much faster than most tissues except kidney.11 This is consistent with a specific mechanism for uptake. As noted next, this is an important subject that is still unresolved.

Interaction with a Putative RBP Receptor

Retinol in the extracellular compartment must be taken up by the cell, but encapsulated in the RBP:TTR complex it is restricted from freely partitioning into the cell membrane. Undoubtedly some entry into the membrane fraction can occur by a non-specific process, and some investigators contend that such a process may account for all retinol uptake by cells. However, it is not clear that such an unregulated transport system can achieve the level of specificity dictated by the differing requirements of cell types for retinol. Experimental data support the existence of a cell surface receptor for RBP, and other data suggest that this interaction site may overlap with the TTR binding site. However, whether these cell surface receptors mediate internalization of free ligand or RBP-bound ligand remains an area of debate. In any event, the existence of a saturable cell surface receptor for RBP has been suggested in studies with placental brush border membranes31 cultured Sertoli cells,43 stellate cells,44 peritubular cells,7 retinal pigment epithelial cells,45,46 embryonal carcinoma cells,47 and the choroid plexus.10 However, such a protein remains to be unambiguously identified. Sundaram et al,34 have put forth the hypothesis that the cell surface receptor mediates a transfer of retinol from RBP in the extracellular compartment to the intracellular retinol binding protein (cellular retinol binding protein, CRBP) a member of a distinct protein superfamily with a structural motif that is reminiscent of the lipocalin fold. The intra cellular binding proteins are composed of ten-stranded up-and-down -barrels with helical caps.48

Concluding Remarks

Although the lipocalins share a common structural motif, the biological functions of the proteins will no doubt prove to be as diverse as the sequences which adopt the characteristic fold. The serum retinol binding protein provides an excellent system in which to appreciate the complexity of the interactions a simple carrier molecule must participate in order to mediate the specific transport of a vital nutrient.

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