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  • Title: Delineation of the plasma membrane targeting domain of the X-linked retinitis pigmentosa protein RP2.
    Author: Chapple JP, Hardcastle AJ, Grayson C, Willison KR, Cheetham ME.
    Journal: Invest Ophthalmol Vis Sci; 2002 Jun; 43(6):2015-20. PubMed ID: 12037013.
    Abstract:
    PURPOSE: The X-linked retinitis pigmentosa protein RP2 is predominantly targeted to the plasma membrane. This study delineates the exact amino acid sequence requirements for targeting of RP2 through dual N-terminal acyl modification. METHODS: Inhibition of acyl modification with a palmitate analogue was used to confirm the mechanism of intracellular targeting. Mutagenesis of the first 15 residues in a synthetic RP2-green fluorescent protein (GFP) chimera was used to probe the precise requirements for plasma membrane targeting in Chinese hamster ovary (CHO) cells by confocal microscopy and subcellular fractionation. RESULTS: The N-terminal Met-Gly-Cys-X-Phe-Ser-Lys motif of human RP2 is necessary and sufficient for the protein's plasma membrane localization. This motif includes the accepted consensus sequence for N-myristoyl transferase (NMT) and a site for attachment of a palmitoyl moiety. An interesting feature of the motif is an essential phenylalanine at position 5. This is the first report of the requirement of a specific residue at position 5 within the N-terminal acyl modification motif for normal intracellular targeting. Arginine at position 8 is not essential for plasma membrane localization of the protein, but it improves targeting. The motif is highly conserved and is found in all vertebrate orthologues of human RP2, except mouse. In mouse, however, the Ser6Thr change is concordant with the accepted NMT consensus sequence. CONCLUSIONS: Conserved residues mediate the intracellular targeting of RP2, further highlighting the potential significance of the protein's plasma membrane localization. The delineation of this motif identifies residues in which mutations disrupt the dual acylation of RP2 and almost certainly result in disease.
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