Conformational retinol

Van Aalten, D.M.F., Findlay, J.B.C., Amadei, A., Berendsen,H.J.C. Essential dynamics of the cellular retinol-binding protein. Evidence for ligand-induced conformational changes. Protein Engin. 8 (1995) 1129-1136. 

The failure of proteins to fold into their functional forms can occasionally lead to "misfolding" or "conformational" diseases.140 Many of these diseases are associated with the formation of amyloid protein, an insoluble material that is deposited as fibrils or plaques in different tissues and organs of the body. They include amyloid Ap protein as the major constituent of the plaques in Alzheimer patients, PrPc associated with neuro-degenerative diseases, a-synuclein (AS) associated with Parkinson s diseases, transthyretin (TTR) as a homotetrameric protein that is involved in the transport of thyroid hormones and retinol in human serum. In particular, the Ap protein is a peptide of 39-43 amino acids that is the... 

The first two of these roles appear to focus on the conformal chemistry associated with the external profile of the molecules. The latter role focuses on the internal, quantum-mechanical structure of the molecules. While retinol, in its metabolic role as a vitamin participates in the manufacture of components of the disks of the Outer Segment of the Photoreceptor cells, it primary role is the last one. It acts as the critical chromogen, independent of any vitamin or hormonal role, leading to the production of chromophores in the retinal pigment epithelium (RPE) cells of the eye. Morton noted this role specifically In the retina, retinol is indubitably a precursor. ... 

Cell surface receptors in target tissues take up retinol from the RBP-transthyretin complex, esterifying it externally, then transferring free retinol by esterase activity onto an intracellular RBP. Part of the ftmction of the receptor is to catalyze a conformational change in RBP so that the retinol held in the hydrophobic pocket can be released. There is no endocytosis of the RBP-transthyretin complex. 

In the retinal pigment epithelium, palmitate is bound to the fatty acid binding site of the interphotoreceptor RBP, and the retinoid binding site has a high affinity for 11 -ds-retinaldehyde, which is to be transported to the photoreceptor cells. In the photoreceptor cells, the palmitate is displaced by docosahex-aenoic acid, which causes a conformational change in the protein, so that it no longer binds 11 -ds-retinaldehyde, which is delivered to the photoreceptor cells and binds all-fraws-retinol for transport back to the pigment epithelium. Here, the docosahexaenoic acid is displaced by palmitate, and the affinity of the protein for 11-ds-retinaldehyde is restored (Palczewski and Saari, 1997 Tschanz and Noy, 1997). 

VKainin A (retinol) is present in many cells of the body. In the retina it is part of the rod photoreceptor pigment rhodopsin (=cis-retina] + a protein called opsin) and cone photoreceptor pigment iodopsin (= cis-retinal + a different opsin protein). When light strikes the cis-retinal part of the rhodopsin or iodopsin molecule, the "cis form changes to trans-retinal, a conformational in (he t i04 culv ti.c CIjUaU... 

A molecular dynamics study (Aqvist et al., 1986) of the conformational changes induced by removal of the retinol molecule suggests a change in the conformation in the entrance loops of the apo form. Because it has been suggested that these loops make up part of the transthyretinbinding site (Cowan et al., 1990), the study is consistent with the observation that after removal of retinol, the RBP-transthyretin complex breaks up. 

The overall folding of /3-LG is remarkably similar to that of human plasma retinol-binding protein (Papiz et al., 1986). The core is made up of an eight-stranded antiparallel /3 sheet, which forms a /3 barrel. There is also a short a helix at the C terminus. As described by Monaco et al. (1987), the interior of the /3 barrel is essentially hydrophobic. The conformational difference between the A form and B form of the protein is not significant. The most interesting observation is that the bound retinol molecule interacts with the protein in a way completely different from that of serum retinol-binding protein. The calculated difference map showed that the molecule is not located in the central j3 barrel but binds to the a-heIix//3-barrel interface delimited by about 15 residues. Most of the... 

Inactive conformation of a G-Protein coupled receptor Active conformation of a G-Protein coupled receptor Retinol-binding protein... 

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