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Visvanathan Ramamurthy, Jeffery R. Christiansen, Martin M. Bergo, Stephen G. Young, Saravanan Kolandaivelu; Methyl Esterification of Proteins is Essential for Effective Rod-mediated Vision. Invest. Ophthalmol. Vis. Sci. 2012;53(14):750.
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Proteins ending in a "CAAX" box are lipidated (prenylated) at their c-terminal cysteine and then RAS-converting enzyme 1 (RCE1) cleaves the final three amino acids before isoprenylcysteine methyltransferase (ICMT) catalyzes the methyl esterification of the newly lipidated cysteine residue. Some of the main players in phototransduction, transducin, phosphodiesterase and rhodopsin kinase are prenylated and further modified. Initial prenylation is crucial for a protein’s ability to interact with membrane domains. The contribution of the final two steps to a protein’s localization and function are variable and depends on the protein being studied. We recently demonstrated the importance of RCE1-mediated proteolysis in phototransduction. In the absence of Rce1, photoreceptors do not function and rapidly degenerate. To determine if the effects seen in the conditional knockout of Rce1 were related to the lack of proteolysis, lack of carboxyl methylation, or both we analyzed the retina of mice with reduced levels of Icmt.
We utilized the Icmt floxed allele as a tool to generate animals lacking Icmt in the retina. Electroretinogram (ERG) recordings were used to analyze visual function of littermate animals with a range of Icmt levels. Morphology and protein expression profiles of phototransduction proteins were investigated by immunofluoresence and immunoblotting respectively.
ERG recordings displayed reduced photoreceptor and downstream electrical responses to light stimuli. The delayed photoreceptor cell response correlates to loss in Icmt message in the retina. In agreement with reduced photoreceptor cell responses, critical phototransduction protein levels were also altered. To investigate the cause of the reduced downstream neuronal responses, we are currently verifying the development and proper synaptic stratification of inner retinal neurons.
Efficient coupling of signal transduction in photoreceptor neurons requires methyl esterification of phototransduction proteins. In comparison with Rce1 CKO, we did not observe rapid retinal degeneration or loss of visual function. In agreement with the loss of visual response phototransduction protein turnover was also increased.
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