A Phe-rich region in short-wavelength sensitive opsins is responsible for their aggregation in the absence of 11-cis-retinal

Abstract

Human blue and mouse S-opsin are prone to aggregation in the absence of 11-cis-retinal, which underlie the rapid cone degeneration in human patients and animal models of Leber congenital amaurosis (LCA). By in silico analysis and domain swapping experiments, we show that a Phe-rich region in short-wavelength sensitive (SWS) opsins, but not in medium/long-wavelength sensitive opsins, is responsible for SWS opsin aggregation. Mutagenesis studies suggest that Phe residues in this region are critical in mediating protein aggregation. Fusing the Phe-rich region of SWS opsins to GFP causes the latter to aggregate. Our findings suggest that new therapeutics can be designed to disrupt the Phe-rich region in preventing cone degeneration due to S-opsin aggregation in LCA.

Keywords: Cone degeneration; G-protein-coupled receptors (GPCRs); LRAT; Leber congenital amaurosis (LCA); Medium/long-wavelength sensitive opsins (M/LWS); Opsin aggregation; RPE65; Short-wavelength sensitive opsins (SWS).