Structure of human green cone opsin yields insights into mechanisms underlying the rapid decay of its active, signaling state
Abstract
Cone opsins enable daylight vision and color discrimination. Like their dim-light cousin rhodopsin (Rho) found in rod cells, they use a covalently attached retinal ligand to sense light and initiate visual phototransduction by activating G proteins. Unfortunately, we know less about their structural properties, in part because their activated state is unstable-cone opsins release their retinal agonist within seconds after light activation, ~100× faster than Rho. To determine what causes this rapid release and how it affects G protein activation, we solved the structure of active-state, wild-type human green cone opsin (GCOWT) stabilized with a mini-G protein and then compared its structural and biophysical properties to Rho. Our results reveal unique features in the active-state GCOWT structure. These include i) a larger water channel connected to a larger retinal binding cavity, ii) a larger "hole" near the retinal Schiff base that could facilitate both retinal escape and water access; and iii) a potential anionic residue, E102, that lies within ~3.6 Å of the Schiff base. Our biophysical assays show that neutralizing E102 (mutant GCOE102Q) slows retinal release (~8×) from the receptor and increases G protein activation. Surprisingly, our kinetic studies suggest that entropic factors are the main cause for the faster retinal release from activated GCOWT. These unique attributes in GCOWT likely facilitate its function in bright daylight. These results support the proposal…
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