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V. V. Gurevich, X. Song, S. A. Vishnivetskiy, M. Kim, S. M. Hanson, J. C. Chen, W. L. Hubbell, E. V. Gurevich; Cytotoxicity of Monomeric Arrestin1 Explains Its Robust Self-Association. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1104.
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To determine the biological role of arrestin1 self-association.
Transgenic mice expressing wild type (WT) and oligomerization-deficient arrestin1 mutant at different levels were used to determine the functionality and health of rod photoreceptors
Arrestin1 ensures timely signal shutoff by binding light-activated phosphorhodopsin. Engineered arrestin1 mutant with increased affinity for Rh* partially compensates for lack of rhodopsin phosphorylation, improving the functional performance of rhodopsin kinase knockout rods. However, self-association of this mutant is greatly impaired. We found that high expression of "enhanced" arrestin1 results in progressive light-independent rod degeneration via apoptosis involving the activation of caspases-9 and -3. In contrast, similar high expression of WT arrestin1 does not affect rod survival. Increasing co-expression of WT arrestin1 dose-dependently alleviates the damage induced by enhanced mutant. Due to "closed" shape of arrestin1 tetramer, where each monomer engages two "sister" subunits via two different interfaces, WT arrestin1 promotes self-association of the mutant with only one "damaged" interface by forming mixed oligomers. Thus, our data indicate that excess of monomeric arrestin1 induces apoptosis of rod photoreceptors in vivo.
Arrestin1 is expressed in rods at very high level, at 0.8:1 ratio to rhodopsin. Cytotoxicity of the arrestin1 monomer explains why it acquired propensity to oligomerize, even though only the monomer is the active rhodopsin-binding species. The inability of cone arrestin4 to self-associate likely explains why cones express much more arrestin1 than their "own" arrestin4 subtype.
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