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Arrestin1 self‐associates to prevent cell death induced by the cytotoxic monomer
Author(s) -
Gurevich Vsevolod V,
Song Xiufeng,
Vishnivetskiy Sergey A,
Kim Miyeon,
Hanson Susan M,
Hubbell Wayne L,
Chen Jeannie,
Gurevich Eugenia V
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.707.1
Subject(s) - rhodopsin , mutant , microbiology and biotechnology , apoptosis , monomer , phosphorylation , cytotoxic t cell , caspase , chemistry , biophysics , programmed cell death , receptor , signal transduction , biology , biochemistry , in vitro , gene , retinal , organic chemistry , polymer
Arrestin1 ensures timely signal shutoff by binding light‐activated phosphorhodopsin. Genetic defects in rhodopsin phosphorylation result in excessive signaling leading to photoreceptor death. Engineered arrestin1 mutant with increased affinity for light‐activated unphosphorylated rhodopsin partially compensates for lack of phosphorylation, improving rod function. However, this “enhanced” mutant has reduced propensity to oligomerize. Its high expression results in progressive light‐independent rod degeneration via apoptosis involving the activation of caspases‐9 and –3. In contrast, similar expression levels of wild type (WT) arrestin1 do not affect rod survival. Moreover, co‐expression of WT arrestin1 alleviates the damage induced by enhanced mutant. Since WT arrestin1 promotes self‐association of mutant by forming mixed oligomers, our data indicate that excess of monomeric arrestin1 induces apoptosis. This finding explains why arrestin1 acquired propensity to oligomerize, even though only the monomer is the active receptor‐binding species. It may also explain oligomerization of non‐visual arrestin2 and arrestin3. NIH grants EY11500 (VVG), EY005216 (WLH), NS065868 (EVG), EY012155 (JC)