New insights into the molecular mechanism of rhodopsin retinitis pigmentosa from the biochemical and functional characterization of G90V, Y102H and I307N mutations
| Autor: | María Guadalupe Herrera-Hernández, Neda Razzaghi, Pol Fernandez-Gonzalez, Laia Bosch-Presegué, Guillem Vila-Julià, Juan Jesús Pérez, Pere Garriga |
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| Přispěvatelé: | Universitat Politècnica de Catalunya. Doctorat en Tecnologia Agroalimentària i Biotecnologia, Universitat Politècnica de Catalunya. Doctorat en Bioinformàtica, Universitat Politècnica de Catalunya. Departament d'Enginyeria Química, Universitat Politècnica de Catalunya. GBMI - Grup de Biotecnologia Molecular i Industrial |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Protein Folding Rhodopsin Retinal degenerative diseases Molecular Dynamics Simulation Cell Line Cellular and Molecular Neuroscience Mice G protein-coupled receptors Retinal Rod Photoreceptor Cells Chlorocebus aethiops Conformational stability Animals Humans Protein folding Retinal degeneration Molecular Biology Ligand binding Pharmacology Lligands (Bioquímica) Cell Biology Protein Structure Tertiary Retina -- Malalties HEK293 Cells COS Cells Mutation Molecular Medicine Ciències de la visió [Àrees temàtiques de la UPC] Cattle Original Article sense organs Ligand binding (Biochemistry) Degeneració macular Retinitis Pigmentosa |
| Zdroj: | Cellular and Molecular Life Sciences |
| ISSN: | 1420-9071 |
| Popis: | Mutations in the photoreceptor protein rhodopsin are known as one of the leading causes of retinal degeneration in humans. Two rhodopsin mutations, Y102H and I307N, obtained in chemically mutagenized mice, are currently the subject of increased interest as relevant models for studying the process of retinal degeneration in humans. Here, we report on the biochemical and functional characterization of the structural and functional alterations of these two rhodopsin mutants and we compare them with the G90V mutant previously analyzed, as a basis for a better understanding of in vivo studies. This mechanis- tic knowledge is fundamental to use it for developing novel therapeutic approaches for the treatment of inherited retinal degeneration in retinitis pigmentosa. We find that Y102H and I307N mutations affect the inactive–active equilibrium of the receptor. In this regard, the mutations reduce the stability of the inactive conformation but increase the stability of the active conformation. Furthermore, the initial rate of the functional activation of transducin, by the I307N mutant is reduced, but its kinetic profile shows an unusual increase with time suggesting a profound effect on the signal transduction process. This latter effect can be associated with a change in the flexibility of helix 7 and an indirect effect of the mutation on helix 8 and the C-terminal tail of rhodopsin, whose potential role in the functional activation of the receptor has been usually underes- timated. In the case of the Y102H mutant, the observed changes can be associated with conformational alterations affecting the folding of the rhodopsin intradiscal domain, and its presumed involvement in the retinal binding process by the receptor. This research was supported by Grant PID2019-104817GB-I00 from Ministerio de Ciencia e Innovación (MICINN) |
| Databáze: | OpenAIRE |
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