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Chen, Yuanyuan; Jastrzebska, Beata; Cao, Pengxiu; Zhang, Jianye; Wang, Benlian; Sun, Wenyu; Yuan, Yiyuan; Feng, Zhaoyang; Palczewski, Krzysztof
The Journal of biological chemistry, 03/2014, Letnik: 289, Številka: 13Journal Article
The P23H opsin mutation is the most common cause of autosomal dominant retinitis pigmentosa. Even though the pathobiology of the resulting retinal degeneration has been characterized in several animal models, its complex molecular mechanism is not well understood. Here, we expressed P23H bovine rod opsin in the nervous system of Caenorhabditis elegans. Expression was low due to enhanced protein degradation. The mutant opsin was glycosylated, but the polysaccharide size differed from that of the normal protein. Although P23H opsin aggregated in the nervous system of C. elegans, the pharmacological chaperone 9-cis-retinal stabilized it during biogenesis, producing a variant of rhodopsin called P23H isorhodopsin. In vitro, P23H isorhodopsin folded correctly, formed the appropriate disulfide bond, could be photoactivated but with reduced sensitivity, and underwent Meta II decay at a rate similar to wild type isorhodopsin. In worm neurons, P23H isorhodopsin initiated phototransduction by coupling with the endogenous Gi/o signaling cascade that induced loss of locomotion. Using pharmacological interventions affecting protein synthesis and degradation, we showed that the chromophore could be incorporated either during or after mutant protein translation. However, regeneration of P23H isorhodopsin with chromophore was significantly slower than that of wild type isorhodopsin. This effect, combined with the inherent instability of P23H rhodopsin, could lead to the structural cellular changes and photoreceptor death found in autosomal dominant retinitis pigmentosa. These results also suggest that slow regeneration of P23H rhodopsin could prevent endogenous chromophore-mediated stabilization of rhodopsin in the retina. Background: The P23H opsin mutant causes the blinding human disease, retinitis pigmentosa. Results: Molecular properties of bovine P23H mutant opsin were characterized in both in vitro and a transgenic C. elegans model. Conclusion: Thermally unstable P23H isorhodopsin containing correct disulfide bond can be slowly regenerated in transgenic C. elegans. Significance: This study produced novel information about the disease-causing P23H mutant opsin.
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