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Stability and ligand binding properties of human cone visual pigments

by true

Institution: TDX
Department:
Degree:
Year: 2015
Keywords:
Posted: 2/5/2017 12:00:00 AM
Record ID: 2133849
Full text PDF: http://hdl.handle.net/10803/322555


Abstract

Human color perception is mediated by cone photoreceptor cells which mainly locate on the fovea of the eye. Bright light activates the photosensitive opsin pigments which are embedded in the outer segment membrane discs of cone retinal cells thereby initiating the complex process of photopic vision with a fast response. The cone visual pigments are G-protein coupled receptors which share analogous structure and functional features with rhodopsin, the most thoroughly studied G-protein coupled receptor from rod photoreceptor cells mediating scotopic vision and distributed throughout the retina. These visual pigments modulate spectral tuning of visible light depending on the molecular variance around the protein bound chromophore, 11-cis-retinal, which is a vitamin A derivative acting as an inverse agonist. Various mutations have been clinically identified in the cone opsin genes and associated with visual dysfunction ranging from mild color blindness to severe cone dystrophies. As the crystal structure of the cone pigments is yet to be resolved, identifying key molecular mechanisms that play major roles in optimal functioning of these photoreceptor proteins, should be helpful in providing a deeper understanding of their function and in designing novel therapeutic strategies for congenital retinal cone dysfunction. In order to study such light sensitive, delicate membrane proteins, the human cone opsin genes have been transiently expressed in mammalian cells, regenerated with their natural chromophore and immunopurified in dark conditions. The purified recombinant chromophore-regenerated cone opsins in solution have been characterized in detail by means of biophysical approaches, including spectroscopic, biochemical, and functional analysis, in order to uncover novel properties that help in optimizing the function of these receptors. Site-directed mutagenesis was employed to obtain the clinically identified mutations in cone opsins related to visual disorders and to compare the structure and function of these mutated opsins with the molecular properties of the wild-type cone opsins expressed in the same way. The results of the present study indicate that the cone opsins are less stable in solution and their retinal binding site is more open than rhodopsin. The ligand binding studies using retinal analogs, show that the photoactivated rhodopsin loses its ability to regenerate with its natural chromophore with time but not with an analog, 9-cis-retinal but cone opsin shows regeneration with both retinal analogs under the same experimental conditions. The highly identical red and green cone opsins exhibit different ligand binding modes during regeneration with their natural chromophore, 11-cis-retinal. A secondary retinal uptake, with a slower kinetics, has been also observed with the red and green cone pigments during regeneration with 11-cis-retinal which is altered in the case of blue cone opsin. The role of specific amino acids involved in the regeneration mechanism has also been clarified. Most of the cone…

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