Ramon, E;
Cordomí, A;
Aguilà, M;
Srinivasan, S;
Dong, X;
Moore, AT;
Webster, AR;
... Garriga, P; + view all
(2014)
Differential light-induced responses in sectorial inherited retinal degeneration.
Journal of Biological Chemistry
, 289
(52)
35918 - 35928.
10.1074/jbc.M114.609958.
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Abstract
Retinitis pigmentosa (RP) is a group of genetically and clinically heterogeneous inherited degenerative retinopathies caused by abnormalities of photoreceptors or retinal pigment epithelium in the retina leading to progressive sight loss. Rhodopsin is the prototypical G-protein-coupled receptor located in the vertebrate retina and is responsible for dim light vision. Here, novel M39R and N55K variants were identified as causing an intriguing sector phenotype of RP in affected patients, with selective degeneration in the inferior retina. To gain insights into the molecular aspects associated with this sector RP phenotype, whose molecular mechanism remains elusive, the mutations were constructed by site-directed mutagenesis, expressed in heterologous systems, and studied by biochemical, spectroscopic, and functional assays. M39R and N55K opsins had variable degrees of chromophore regeneration when compared with WT opsin but showed no gross structural misfolding or altered trafficking. M39R showed a faster rate for transducin activation than WT rhodopsin with a faster metarhodopsinII decay, whereas N55K presented a reduced activation rate and an altered photobleaching pattern. N55K also showed an altered retinal release from the opsin binding pocket upon light exposure, affecting its optimal functional response. Our data suggest that these sector RP mutations cause different protein phenotypes that may be related to their different clinical progression. Overall, these findings illuminate the molecular mechanisms of sector RP associated with rhodopsin mutations.
| Type: | Article |
|---|---|
| Title: | Differential light-induced responses in sectorial inherited retinal degeneration. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1074/jbc.M114.609958 |
| Publisher version: | http://dx.doi.org/10.1074/jbc.M114.609958 |
| Language: | English |
| Additional information: | Other parties are welcome to copy, distribute, transmit and adapt the work — at no cost and without permission — for noncommercial use as long as they attribute the work to the original source using the citation above. |
| Keywords: | G-protein-coupled Receptor, Light Exposure, Protein Stability, Protein Structure, Retinal Degeneration, Rhodopsin, Signal Transduction, Transducin, Visual Pigments |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1455703 |
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