title: 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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Fu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D055355:Opsins / Q000737:chemistry*; D010649:Phenylalanine / Q000737:chemistry*; D012172:Retinaldehyde / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid
chemical_list: D055355:Opsins; D010649:Phenylalanine; D012172:Retinaldehyde
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)