Journal
EMBO REPORTS
Volume 17, Issue 10, Pages 1431-1440Publisher
WILEY
DOI: 10.15252/embr.201642671
Keywords
congenital stationary night blindness; constitutive activity; G protein-coupled receptors; rhodopsin; visual system
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Funding
- Swiss National Science Foundation [SNF 31003A_141235, SNF 31003A_159558, SNF 310030_153145]
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Congenital stationary night blindness (CSNB) is an inherited and non-progressive retinal dysfunction. Here, we present the crystal structure of CSNB-causing T94I(2.61) rhodopsin in the active conformation at 2.3 A resolution. The introduced hydrophobic side chain prolongs the lifetime of the G protein activating metarhodopsin-II state by establishing a direct van der Waals contact with K296 (7.43), the site of retinal attachment. This is in stark contrast to the light-activated state of the CSNB-causing G90D(2.57) mutation, where the charged mutation forms a salt bridge with K296(7.43). To find the common denominator between these two functional modifications, we combined our structural data with a kinetic biochemical analysis and molecular dynamics simulations. Our results indicate that both the charged G90D(2.57) and the hydrophobic T94I(2.61) mutation alter the dark state by weakening the interaction between the Schiff base (SB) and its counterion E113(3.28). We propose that this interference with the tight regulation of the dim light photoreceptor rhodopsin increases background noise in the visual system and causes the loss of night vision characteristic for CSNB patients.
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