Unusual mode of dimerization of retinitis pigmentosa-associated F220C rhodopsin
| Autor: | Tylor R. Lewis, Joshua Levitz, Michel A. Cuendet, Alexander Matthew Payne, Anant K. Menon, Zarek S. Siegel, Joon Lee, Anoop Narayana Pillai, Kalpana Pandey, Vadim Y. Arshavsky, George Khelashvili, Johannes Broichhagen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Opsin Rhodopsin genetic structures Science Protomer Molecular Dynamics Simulation Article 03 medical and health sciences Computational biophysics 0302 clinical medicine Single-molecule biophysics Biophysical chemistry Retinitis pigmentosa medicine Fluorescence Resonance Energy Transfer Humans FREE-ENERGY DECOMPOSITION PROTEIN-BINDING FORCE-FIELD MM-GBSA MEMBRANE OPSIN ORGANIZATION ENERGETICS SOLVATION INSERTION Lipid bilayer Micelles G protein-coupled receptor Multidisciplinary biology Opsins Chemistry Proteins Membrane structure and assembly medicine.disease Lipids Transmembrane domain Förster resonance energy transfer 030104 developmental biology HEK293 Cells Structural biology biology.protein Biophysics Medicine sense organs Dimerization 030217 neurology & neurosurgery Retinitis Pigmentosa |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-20 (2021) Scientific Reports Scientific reports, vol. 11, no. 1, pp. 10536 |
| ISSN: | 2045-2322 |
| Popis: | Mutations in the G protein-coupled receptor (GPCR) rhodopsin are a common cause of autosomal dominant retinitis pigmentosa, a blinding disease. Rhodopsin self-associates in the membrane, and the purified monomeric apo-protein opsin dimerizes in vitro as it transitions from detergent micelles to reconstitute into a lipid bilayer. We previously reported that the retinitis pigmentosa-linked F220C opsin mutant fails to dimerize in vitro, reconstituting as a monomer. Using fluorescence-based assays and molecular dynamics simulations we now report that whereas wildtype and F220C opsin display distinct dimerization propensities in vitro as previously shown, they both dimerize in the plasma membrane of HEK293 cells. Unexpectedly, molecular dynamics simulations show that F220C opsin forms an energetically favored dimer in the membrane when compared with the wild-type protein. The conformation of the F220C dimer is unique, with transmembrane helices 5 and 6 splayed apart, promoting widening of the intracellular vestibule of each protomer and influx of water into the protein interior. FRET experiments with SNAP-tagged wild-type and F220C opsin expressed in HEK293 cells are consistent with this conformational difference. We speculate that the unusual mode of dimerization of F220C opsin in the membrane may have physiological consequences. |
| Databáze: | OpenAIRE |
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