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Originally published In Press as doi:10.1074/jbc.M210124200 on March 17, 2003

J. Biol. Chem., Vol. 278, Issue 21, 19309-19316, May 23, 2003
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Palmitoylation Regulates Regulator of G-protein Signaling (RGS) 16 Function

II. PALMITOYLATION OF A CYSTEINE RESIDUE IN THE RGS BOX IS CRITICAL FOR RGS16 GTPase ACCELERATING ACTIVITY AND REGULATION OF Gi-COUPLED SIGNALING*

James L. Osterhout {ddagger}, Abdul A. Waheed §, Abel Hiol §, Richard J. Ward ¶, Penelope C. Davey §, Lylia Nini §, Jiun Wang {ddagger}, Graeme Milligan ¶, Teresa L. Z. Jones § || and Kirk M. Druey {ddagger}

From the {ddagger} Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID, National Institutes of Health, Rockville, Maryland 20892, § Metabolic Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom

Palmitoylation is a reversible post-translational modification used by cells to regulate protein activity. The regulator of G-protein signaling (RGS) proteins RGS4 and RGS16 share conserved cysteine (Cys) residues that undergo palmitoylation. In the accompanying article (Hiol, A., Davey, P. C., Osterhout, J. L., Waheed, A. A., Fischer, E. R., Chen, C. K., Milligan, G., Druey, K. M., and Jones, T. L. Z. (2003) J. Biol. Chem. 278, 19301–19308), we determined that mutation of NH2-terminal cysteine residues in RGS16 (Cys-2 and Cys-12) reduced GTPase accelerating (GAP) activity toward a 5-hydroxytryptamine (5-HT1A)/G{alpha}o1 receptor fusion protein in cell membranes. NH2-terminal acylation also permitted palmitoylation of a cysteine residue in the RGS box of RGS16 (Cys-98). Here we investigated the role of internal palmitoylation in RGS16 localization and GAP activity. Mutation of RGS16 Cys-98 or RGS4 Cys-95 to alanine reduced GAP activity on the 5-HT1A/G{alpha}o1 fusion protein and regulation of adenylyl cyclase inhibition. The C98A mutation had no effect on RGS16 localization or GAP activity toward purified G-protein {alpha} subunits. Enzymatic palmitoylation of RGS16 resulted in internal palmitoylation on residue Cys-98. Palmitoylated RGS16 or RGS4 WT but not C98A or C95A preincubated with membranes expressing 5-HT1a/G{alpha}o1 displayed increased GAP activity over time. These results suggest that palmitoylation of a Cys residue in the RGS box is critical for RGS16 and RGS4 GAP activity and their ability to regulate Gi-coupled signaling in mammalian cells.

Received for publication, October 3, 2002 , and in revised form, March 12, 2003.

|| To whom correspondence should be addressed: Bldg. 10, Rm. 9C101, National Institutes of Health, Bethesda, MD 20892-1802. Tel.: 301-496-8711; Fax: 301-496-0200; E-mail: tlzj{at}helix.nih.gov.


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