Cellular Retinaldehyde Binding Protein—Different Binding Modes and Micro-Solvation Patterns for High-Affinity 9-<i>cis</i>- and 11-<i>cis</i>-Retinal Substrates

Helbling, Rachel E.; Bolze, Christin S.; Golczak, Marcin; Palczewski, Krzysztof; Stocker, Achim; Cascella, M.

doi:10.1021/jp405410t

Cited by 6 publications

(18 citation statements)

References 48 publications

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“…Cellular retinaldehyde-binding protein (CRALBP) in the RPE and Müller cells, and extracellular interphotoreceptor retinoidbinding protein (IRBP) are two major carriers involved. 16 The structure of CRALBP-with its unanticipated isomerase activity-has been elucidated, [271][272][273] whereas the structure of IRBP has only been partially characterized. 274 Inactivating mutations FIGURE 7.…”

Section: Restoration Of Photoactive Visual Pigments: the Retinoid (Vimentioning

confidence: 99%

Chemistry and Biology of the Initial Steps in Vision: The Friedenwald Lecture

Palczewski¹

2014

Invest. Ophthalmol. Vis. Sci.

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Visual transduction is the process in the eye whereby absorption of light in the retina is translated into electrical signals that ultimately reach the brain. The first challenge presented by visual transduction is to understand its molecular basis. We know that maintenance of vision is a continuous process requiring the activation and subsequent restoration of a vitamin A-derived chromophore through a series of chemical reactions catalyzed by enzymes in the retina and retinal pigment epithelium (RPE). Diverse biochemical approaches that identified key proteins and reactions were essential to achieve a mechanistic understanding of these visual processes. The three-dimensional arrangements of these enzymes' polypeptide chains provide invaluable insights into their mechanisms of action. A wealth of information has already been obtained by solving high-resolution crystal structures of both rhodopsin and the retinoid isomerase from pigment RPE (RPE65). Rhodopsin, which is activated by photoisomerization of its 11-cis-retinylidene chromophore, is a prototypical member of a large family of membrane-bound proteins called G protein-coupled receptors (GPCRs). RPE65 is a retinoid isomerase critical for regeneration of the chromophore. Electron microscopy (EM) and atomic force microscopy have provided insights into how certain proteins are assembled to form much larger structures such as rod photoreceptor cell outer segment membranes. A second challenge of visual transduction is to use this knowledge to devise therapeutic approaches that can prevent or reverse conditions leading to blindness. Imaging modalities like optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO) applied to appropriate animal models as well as human retinal imaging have been employed to characterize blinding diseases, monitor their progression, and evaluate the success of therapeutic agents. Lately two-photon (2-PO) imaging, together with biochemical assays, are revealing functional aspects of vision at a new molecular level. These multidisciplinary approaches combined with suitable animal models and inbred mutant species can be especially helpful in translating provocative cell and tissue culture findings into therapeutic options for further development in animals and eventually in humans. A host of different approaches and techniques is required for substantial progress in understanding fundamental properties of the visual system.

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Section: Restoration Of Photoactive Visual Pigments: the Retinoid (Vimentioning

confidence: 99%

Chemistry and Biology of the Initial Steps in Vision: The Friedenwald Lecture

Palczewski¹

2014

Invest. Ophthalmol. Vis. Sci.

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“…Residues in the βE-βF loop with higher contribution to the interaction energy with retinol (RTL) are highlighted as spheres, and retinol is shown as sticks (β-sheets C and D are not shown for the sake of clarity). While the selectivity of different members of cytosolic binding proteins toward distinct retinoidlike compounds has been related to the presence of specific residues in the -barrel, 27,28 present results point out that a seemingly minor chemical change related to the methyl isomerism between Ile and Leu at the portal site modulates the binding properties of retinol between closely related CRBP isoforms. The net effect is the enhanced free energy penalty associated to the closedopen transition, which would disfavour the release of the ligand and increase the residence time of retinol in the interior of the -barrel.…”

Section: Systemmentioning

confidence: 63%

Modulating Ligand Dissociation through Methyl Isomerism in Accessory Sites: Binding of Retinol to Cellular Carriers

Estarellas

Scaffidi

Saladino

et al. 2019

J. Phys. Chem. Lett.

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Due to the poor aqueous solubility of retinoids, evolution has tuned their binding to cellular proteins to address specialized physiological roles by modulating uptake, storage, and delivery to specific targets. With the aim to disentangle the structure-function relationships in these proteins and disclose clues for engineering selective carriers, the binding mechanism of the two most abundant retinol-binding isoforms was explored by using enhanced sampling molecular dynamics simulations and surface plasmon resonance. The distinctive dynamics of the entry portal site in the holo species was crucial to modulate retinol dissociation. Remarkably, this process is controlled at large extent by the replacement of Ile by Leu in the two isoforms, thus suggesting that a fine control of ligand release can be achieved through a rigorous selection of conservative mutations in accessory sites.

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“…However, computational studies based on classical MD simulations allowed us to confirm both the above described alternate binding mode of CRALBP to either 11- cis -retinal or 9- cis -retinal, and a not fully dehydrated cavity for the CRALBP:9- cis -retinal complex. 44 …”

Section: Resultsmentioning

confidence: 99%

“…B) Close-up view of the MD structural model of the dark state binding pocket of CRALBP:9- cis -retinal. 44 Side chains and 9- cis -retinal are shown as gray and orange sticks, respectively. Dashed black lines indicate hydrogen bonds.…”

Section: Figurementioning

confidence: 99%

Human Cellular Retinaldehyde-Binding Protein Has Secondary Thermal 9-cis-Retinal Isomerase Activity

Bolze¹,

Helbling²,

Owen

et al. 2013

J. Am. Chem. Soc.

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Cellular retinaldehyde-binding protein (CRALBP) chaperones 11-cis-retinal to convert opsin receptor molecules into photosensitive retinoid pigments of the eye. We report a thermal secondary isomerase activity of CRALBP when bound to 9-cis-retinal. UV/VIS and 1H-NMR spectroscopy were used to characterize the product as 9,13-dicis-retinal. The X-ray structure of the CRALBP mutant R234W:9-cis-retinal complex at 1.9 Å resolution revealed a niche in the binding-pocket for 9-cis-aldehyde different from that reported for 11-cis-retinal. Combined computational, kinetic, and structural data lead us to propose an isomerization mechanism catalyzed by a network of buried waters. Our findings highlight a specific role of water molecules in both CRALBP-assisted specificity towards 9-cis-retinal and its thermal isomerase activity yielding 9,13-dicis-retinal. Kinetic data from two point mutants of CRALBP support an essential role of Glu202 as the initial proton donor in this isomerization reaction.

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Cellular Retinaldehyde Binding Protein—Different Binding Modes and Micro-Solvation Patterns for High-Affinity 9-cis- and 11-cis-Retinal Substrates

Cited by 6 publications

References 48 publications

Chemistry and Biology of the Initial Steps in Vision: The Friedenwald Lecture

Chemistry and Biology of the Initial Steps in Vision: The Friedenwald Lecture

Modulating Ligand Dissociation through Methyl Isomerism in Accessory Sites: Binding of Retinol to Cellular Carriers

Human Cellular Retinaldehyde-Binding Protein Has Secondary Thermal 9-cis-Retinal Isomerase Activity

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