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Palmitoylation increases the kinase activity of the G protein-coupled receptor kinase, GRK6.

Publication ,  Journal Article
Stoffel, RH; Inglese, J; Macrae, AD; Lefkowitz, RJ; Premont, RT
Published in: Biochemistry
November 17, 1998

The G protein-coupled receptor kinase GRK6 undergoes posttranslational modification by palmitoylation. Palmitoylated GRK6 is associated with the membrane, while nonpalmitoylated GRK6 remains cytosolic. We have separated palmitoylated from nonpalmitoylated GRK6 to assess their relative kinase activity. Palmitoylated GRK6 is 10-fold more active at phosphorylating beta2-adrenergic receptor than nonpalmitoylated wild-type GRK6 or a nonpalmitoylatable mutant GRK6. A nonpalmitoylatable mutant GRK6 which has been further mutated to undergo posttranslational geranylgeranylation is also more active, recovering most of the activity of the palmitoylated enzyme. This activity increase by lipid modification is expected, as the lipid helps GRK6 localize to cellular membranes where its receptor substrates are found. However, when assayed using a soluble protein (casein) as a substrate, both palmitoylated and prenylated GRK6 display significantly higher activity than nonpalmitoylated wild-type or nonpalmitoylatable mutant GRK6 kinases. This increased activity is not altered by addition of exogenous palmitate or phosphatidycholine vesicles, arguing that it is not due to direct activation of GRK6 by binding palmitate, nor to nonspecific association of the GRK6 with casein. Further, chemical depalmitoylation reduces the casein phosphorylation activity of the palmitoylated, but not prenylated, GRK6 kinase. Thus, palmitoylation of GRK6 appears to play a dual role in increasing the activity of GRK6: it increases the hydrophobicity and membrane association of the GRK6 protein, which helps bring the GRK6 to its membrane-bound substrates, and it increases the kinase catalytic activity of GRK6.

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Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

November 17, 1998

Volume

37

Issue

46

Start / End Page

16053 / 16059

Location

United States

Related Subject Headings

  • Transfection
  • Receptors, Adrenergic, beta-2
  • Receptor Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Palmitic Acid
  • Lipid Metabolism
  • Hydroxylamine
  • Humans
  • GTP-Binding Proteins
 

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Stoffel, R. H., Inglese, J., Macrae, A. D., Lefkowitz, R. J., & Premont, R. T. (1998). Palmitoylation increases the kinase activity of the G protein-coupled receptor kinase, GRK6. Biochemistry, 37(46), 16053–16059. https://doi.org/10.1021/bi981432d
Stoffel, R. H., J. Inglese, A. D. Macrae, R. J. Lefkowitz, and R. T. Premont. “Palmitoylation increases the kinase activity of the G protein-coupled receptor kinase, GRK6.Biochemistry 37, no. 46 (November 17, 1998): 16053–59. https://doi.org/10.1021/bi981432d.
Stoffel RH, Inglese J, Macrae AD, Lefkowitz RJ, Premont RT. Palmitoylation increases the kinase activity of the G protein-coupled receptor kinase, GRK6. Biochemistry. 1998 Nov 17;37(46):16053–9.
Stoffel, R. H., et al. “Palmitoylation increases the kinase activity of the G protein-coupled receptor kinase, GRK6.Biochemistry, vol. 37, no. 46, Nov. 1998, pp. 16053–59. Pubmed, doi:10.1021/bi981432d.
Stoffel RH, Inglese J, Macrae AD, Lefkowitz RJ, Premont RT. Palmitoylation increases the kinase activity of the G protein-coupled receptor kinase, GRK6. Biochemistry. 1998 Nov 17;37(46):16053–16059.
Journal cover image

Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

November 17, 1998

Volume

37

Issue

46

Start / End Page

16053 / 16059

Location

United States

Related Subject Headings

  • Transfection
  • Receptors, Adrenergic, beta-2
  • Receptor Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Palmitic Acid
  • Lipid Metabolism
  • Hydroxylamine
  • Humans
  • GTP-Binding Proteins