Abstract
Cellular retinaldehyde-binding protein (CRALBP) is a 36-kD water soluble protein with an essential chaperone function in mammalian vision (J Biol Chem 252:3267–3271, 1977). CRALBP is only found in retina and pineal gland. It functions in the retinal pigment epithelium (RPE) as a high-affinity receptor of 11-cis-retinol in the isomerization of the rod visual cycle and as a substrate carrier for 11-cis-retinol dehydrogenase. The CRALBP mutant R234W tightens retinoid interactions, which in turn compromise substrate carrier interactions with 11-cis-retinol dehydrogenase and lead to Bothnia-type retinal dystrophy (Invest Ophthalmol Vis Sci 40:995–1000, 1999). Bothnia disease makes patients suffer from night blindness and tunnel vision in earlier age and lose sight in their later life. We crystallized the CRALBP WT-11-cis-retinal complex and the mutant R234W-11-cis-retinal complex, in order to better understand CRALBP visual cycle functions, which require rapid association and dissociation of retinoid. The structures were solved at resolution of 3 and 1.7 Å, respectively (Proc Natl Acad Sci 106:18545–18550, 2009). We compared the R234W structure with wild type, and observed that a one-amino-acid mutation from arginine to tryptophan causes dramatic domino-like arrangements in the retinal-binding pocket of R234W. The volume of the ligand binding cavities was calculated using the VOIDOO program for both, wild type and R234W. We found that the mutant pocket is 7% smaller than wild type with a concomitant increase of packing density. We performed photoisomerization experiment, showing that 11-cis-retinal binds R234W five times tighter than wild type. This is consistent with our crystallographic results. Our findings provide an explanation for the disease mechanism of Bothnia-type retinal dystrophy at the molecular level and give a hint for future drug design.
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References
He X, Lobsiger J, Stocker A (2009) Bothnia dystrophy is caused by domino-like rearrangements in cellular retinaldehyde-binding protein mutant R234W. Proc Natl Acad Sci 106:18545–18550
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Acknowledgments
We thank National Eye Institute, National Institutes of Health, for the generous gift of 11-cis-retinal. Data collection was performed at the Swiss Light Source, Beam-line X06DA (PXIII), Villigen, Switzerland, and at the European Synchrotron Radiation Facility, Beamline ID29, Grenoble, France. This study was supported by the Berne University Research Foundation.
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He, X., Lobsiger, J., Stocker, A. (2012). Molecular Clues to Bothnia-Type Retinal Dystrophy. In: LaVail, M., Ash, J., Anderson, R., Hollyfield, J., Grimm, C. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 723. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-0631-0_75
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DOI: https://doi.org/10.1007/978-1-4614-0631-0_75
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