Active and inactive pathways in the kinetic mechanism of the G51V retinitis pigmentosa mutant photoreaction.

Autosomal dominant retinitis pigmentosa (ADRP) is a visual disorder which can result from many different mutations of the rhodopsin gene. In most cases the mutation results in a misfolded rhodopsin protein or a protein that does not bind with the retinal chromophore. Some mutations, however, yield rhodopsins which fold properly and bind the retinal chromophore, yet still result in ADRP. Here we investigate the activation mechanism of one such mutation which produces the G51V rhodopsin variant. Human WT and G51V were recombinantly produced and embedded in identical nanodiscs. Time-resolved spectra were then measured from the nanosecond to second time scales across the near UV through the visible spectral ranges. From these measurements the activation mechanisms of the two proteins were compared. While studies of the WT protein yielded a mechanism consistent with previous determinations of human rhodopsin (15), the G51V mechanism involved multiple pathways. These results suggest multiple ways for the protein to fold, some of which are photoactivated while the majority do not activate normally.