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- W2079012788 abstract "Over 100 mutations in the dim-light photoreceptor rhodopsin are associated with retinitis pigmentosa (RP), a visual disorder characterized by progressive symptoms of night blindness, tunnel vision, and sometimes blindness. We studied the thermal stability of two mutations, S186W and D190N. We hypothesize that these mutations perturb an electrostatic interaction and hydrogen bonds in the active site and destabilize rhodopsin, which undermines the sensitivity to light and causes RP. We compared the rates of thermal decay, thermal isomerization, and Schiff base hydrolysis of WT, S186W, and D190N rhodopsin. Using UV-visible spectroscopy, we observed that the D190N mutant and WT rhodopsin do not decay over 24 hours at 37°C, whereas the S186W mutant decays with a half-life of 36 ± 4 min. We also measured the half-lives at 55°C, which are 70 ± 2 min for WT, 2.4 ± 0.2 for D190N, and 0.43 ± 0.03 min for S186W. Using HPLC and the acid denaturation assay, we measured the rates of thermal isomerization of 11-cis retinal and hydrolysis of the Schiff base linkage between retinal and opsin. We found that the mutations also increase these rates by 1-2 orders of magnitude. Because thermal isomerization of rhodopsin generates the same physiological response as photoisomerization, we suggest that the higher thermal isomerization rate in the mutants increases the level of dark noise, which desensitizes rhodopsin and causes the early symptom of night blindness. Because the drastic destabilizing effect of the mutations is likely correlated with the progressive deformation of the outer segment and subsequent loss of rod cells in RP, we propose that a future systematic study of the thermal stability of the RP-causing mutations can potentially provide more accurate predictions of the pace of vision loss in patients and guide strategies for treatment." @default.
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- W2079012788 date "2011-02-01" @default.
- W2079012788 modified "2023-10-14" @default.
- W2079012788 title "Thermal Stability of Rhodopsin and Implications for Retinitis Pigmentosa" @default.
- W2079012788 doi "https://doi.org/10.1016/j.bpj.2010.12.3180" @default.
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