Opsin stability

Noorwez SM, Kuksa V, Imanishi Y, Zhu L, FUipek S, Pal-czewski K, Kaushal S. Pharmacological chaperone-mediated in vivo folding and stabilization of the P23H-opsin mntant associated with autosomal dominant retinitis pigmentosa. J. Biol. Chem. 2003 278 14442-14450. 

It is important to distinguish these functional rescue studies from several other important studies showing that small molecules can stabilize or chaperone folding of mutant proteins such as mutant p53 associated with cancer [77, 78], mutant forms of V2R associated with nephrogenic diabetes insipidus [79, 80], mutant forms of opsin associated with retinitis pigmentosa [81], and ffiglucosidase mutants associated with gaucher disease [82, 83]. 

Humans deficient in vitamin A lose their ability for dark adaptation. Rod vision is affected more than cone vision. Upon depletion of retinol from liver and blood, the concentrations of retinol and rhodopsin in the retina fall. Unless the deficiency is overcome, opsin, lacking the stabilizing effect of retinal, decays and anatomical deterioration of the rods outer segments occurs. In rats maintained on a vitamin A-deficient Set, irreversible ultrastructural changes leading to blindness then supervene, a process that takes -10 months. Following short-term deprivation of vitamin A, dark adaptation can be restored to normal by the addition of retinol to the Set, but this restoration takes several weeks. The reason for this delay is unknown. 

The results of the overall treatment are represented schematically in the figure which indicates the difference in the electrostatic stabilization energy between the ground and the excited states. (The contribution of the polarisation effect is negligible.) It is observed that as an over-all result this difference is in favour of the ground state when X is in the vicinity of the N+ terminal of the chromophore (between C13 and Nie), and in favour of the excited state for positions of X between Ci and C12, and in particular for position of X in the vicinity of the region C5—C9. Thus, a bathochromic shift of the spectrum of the retinylidene iminium ion may be expected to occur, as a result of the electrostatic factor, when the X group of opsin is located in the vicinity of these atoms. 

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