VISION A Palmitoylated Light Switch

Vision depends on the activation of rhodopsin by light: The covalently bound rhodopsin antagonist 11-cis-retinal absorbs light, which triggers its irreversible photoisomerization to the all-trans agonist form and initiates a conformational change that allows rhodopsin to stimulate transducin. All-trans-retinal dissociates from opsin and is reduced to all-trans-retinol (vitamin A); lecithin retinol acyl transferase (LRAT) esterifies vitamin A to create all-trans-retinyl esters (mostly palmitate), which bind to a high-molecular-weight membrane-associated form of the retinal pigment epithelium protein RPE65 (mRPE65). mRPE65 mobilizes all-trans-retinyl esters, enabling their conversion into 11-cis-retinol and thereby allowing 11-cis-retinal to be regenerated and vision to continue. 11-cis-Retinol is regenerated more rapidly in the light; however, the mechanisms by which light regulates this visual cycle are poorly understood. Xue et al. used a fluorometric assay to show that soluble RPE65 (sRPE65) displayed complementary retinoid binding specificity to mRPE65, binding vitamin A with much higher affinity than all-trans-retinyl-palmitate and facilitating its conversion to all-trans-retinyl-palmitate. mRPE65 expressed in insect cells was labeled when exposed to ³H-palmitate, and mass spectroscopic analysis indicated that mRPE65 was triply palmitoylated whereas sRPE65 was not palmitoylated. LRAT reversibly transferred a palmitoyl moiety from mRPE65 to vitamin A, generating sRPE65 and all-trans-retinyl palmitate. Moreover, 11-cis-retinol served as a substrate for mRPE65- and LRAT-mediated palmitoylation as well, so that 11-cis-retinol added to retinal pigment epithelium membranes promoted mRPE65 conversion to sRPE65 and thereby inhibited its own biosynthesis. Thus, the authors propose that palmitoylation of RPE65 provides a molecular switch regulating 11-cis-retinal synthesis, which can be flipped by the light-dependent increase in the supply of all-trans-retinyl esters and the ensuing conversion of sRPE65 to mRPE65.

L. Xue, D. R. Gollapalli, P. Maiti, W. J. Jahng, R. R. Rando, A palmitoylation switch mechanism in the regulation of the visual cycle. Cell 117, 761-771 (2004). [Online Journal]