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J. Biol. Chem., Vol. 269, Issue 45, 27791-27794, Nov, 1994
RH Stoffel, RR Randall, RT Premont, RJ Lefkowitz and J Inglese
GRK6, a 66-kDa serine/threonine protein kinase, is a recently identified
member of the G protein-coupled receptor kinase (GRK) family. GRKs are
involved in the phosphorylation of seven-transmembrane receptors, a process
mediating desensitization of signal transduction. An important feature of
these enzymes is their membrane-associated nature, which for some members
is stimulus-dependent. The structural basis for this membrane association
previously has been shown in different members of the GRK family to include
isoprenylation, G protein beta gamma-binding domains, and basic regions to
provide electrostatic interactions with phospholipids. We provide evidence
that another mechanism includes fatty acid acylation. GRK6, but not other
GRKs tested, incorporated tritium after incubation with [3H]palmitate in
Sf9 and in COS-7 cells overexpressing the kinase. The incorporated
radioactivity was released from the protein by neutral hydroxylamine,
indicating the presence of a thioester bond, and was confirmed as palmitic
acid by high performance liquid chromatography analysis. Site- directed
mutagenesis defined the region of palmitate attachment as a cluster of 3
cysteines (Cys561, Cys562, and Cys565) in the carboxyl- terminal domain of
the kinase, consistent with the location of the membrane targeting domains
of GRKs 1, 2, 3, and 5. Palmitoylation of GRK6 appears essential for
membrane association, since palmitoylated kinase was found only in the
membrane fraction. This lipid modification provides a structural basis for
potential regulation of the subcellular distribution of GRK6 through
acylation/deacylation cycles.
Palmitoylation of G protein-coupled receptor kinase, GRK6. Lipid modification diversity in the GRK family
Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710.
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