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Molecular Clues to Bothnia-Type Retinal Dystrophy

  • Xiaoqin He
  • Joel Lobsiger
  • Achim StockerEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)

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.

Keywords

Cellular retinaldehyde-binding protein 11-cis-retinal Bothnia-type retinal dystrophy X-ray crystallography structure R234W 

Notes

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.

References

  1. 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 106:18545–18550PubMedCrossRefGoogle Scholar
  2. Saari JC, Nawrot M, Kennedy BN et al (2001) Visual cycle impairment in cellular retinaldehyde binding protein (CRALBP) knockout mice results in delayed dark adaptation. Neuron 29:739–748PubMedCrossRefGoogle Scholar
  3. Burstedt MS, Sandgren O, Holmgren G et al (1999) Bothnia dystrophy caused by mutations in the cellular retinaldehyde-binding protein gene (RLBP1) on chromosome 15q26. Invest Ophthalmol Vis Sci 40:995–1000PubMedGoogle Scholar
  4. Qian B, Raman S, Das R et al (2007) High-resolution structure prediction and the crystallographic phase problem. Nature 450:259–264PubMedCrossRefGoogle Scholar
  5. Saari JC, Bredberg DL (1987) Photochemistry and stereoselectivity of cellular retinaldehyde-binding protein from bovine retina. J Biol Chem 262:7618–7622PubMedGoogle Scholar
  6. Delano ML (2002) The PyMOL Molecular Graphics System (Delano ML, Palo Alto, CA)Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Chemistry and BiochemistryUniversity of BernBernSwitzerland
  2. 2.Institute for Molecular Biology and BiophysicsETH ZürichZürichSwitzerland

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