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Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor.

Publication ,  Journal Article
Fredericks, ZL; Pitcher, JA; Lefkowitz, RJ
Published in: J Biol Chem
June 7, 1996

Rapid desensitization of G protein-coupled receptors is mediated, at least in part, by their phosphorylation by the G protein-coupled receptor kinases (GRKs). However, only in the case of rhodopsin have the actual sites of receptor phosphorylation been unambiguously determined. Although previous studies have implicated the cytoplasmic tail of the beta2-adrenergic receptor (beta2AR) as the site of GRK-mediated phosphorylation, the identities of the phosphorylated residues were unknown. Here we report the identification of the sites of GRK2- and GRK5-mediated beta2AR phosphorylation. The phosphorylation sites of both serine/threonine kinases reside exclusively in a 40-amino acid peptide located at the extreme carboxyl terminus of the beta2AR. Of the seven phosphorylatable residues within this peptide, six are phosphorylated by GRK5 (Thr-384, Thr-393, Ser-396, Ser-401, Ser-407, and Ser-411) and four are phosphorylated by GRK2 (Thr-384, Ser-396, Ser-401, and Ser-407) at equivalent phosphorylation stoichiometries (approximately 1.0 mol Pi/mol receptor). In addition to the GRK5-specific phosphorylation of Thr-393 and Ser-411, differences in the distribution of phosphate between sites are observed for GRK2 and GRK5. Increasing the stoichiometry of GRK2-mediated beta2AR phosphorylation from approximately 1.0 to 5.0 mol Pi/mol receptor increases the stoichiometry of phosphorylation of Thr-384, Ser-396, Ser-401, and Ser-407 rather than increasing the number of phosphoacceptor sites. The location of multiple GRK2 and GRK5 phosphoacceptor sites at the extreme carboxyl terminus of the beta2AR is highly reminiscent of GRK1-mediated phosphorylation of rhodopsin.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

June 7, 1996

Volume

271

Issue

23

Start / End Page

13796 / 13803

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Spodoptera
  • Sequence Homology, Amino Acid
  • Recombinant Proteins
  • Receptors, Adrenergic, beta-2
  • Receptor Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Molecular Sequence Data
  • In Vitro Techniques
 

Citation

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Fredericks, Z. L., Pitcher, J. A., & Lefkowitz, R. J. (1996). Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor. J Biol Chem, 271(23), 13796–13803. https://doi.org/10.1074/jbc.271.23.13796
Fredericks, Z. L., J. A. Pitcher, and R. J. Lefkowitz. “Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor.J Biol Chem 271, no. 23 (June 7, 1996): 13796–803. https://doi.org/10.1074/jbc.271.23.13796.
Fredericks ZL, Pitcher JA, Lefkowitz RJ. Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor. J Biol Chem. 1996 Jun 7;271(23):13796–803.
Fredericks, Z. L., et al. “Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor.J Biol Chem, vol. 271, no. 23, June 1996, pp. 13796–803. Pubmed, doi:10.1074/jbc.271.23.13796.
Fredericks ZL, Pitcher JA, Lefkowitz RJ. Identification of the G protein-coupled receptor kinase phosphorylation sites in the human beta2-adrenergic receptor. J Biol Chem. 1996 Jun 7;271(23):13796–13803.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

June 7, 1996

Volume

271

Issue

23

Start / End Page

13796 / 13803

Location

United States

Related Subject Headings

  • beta-Adrenergic Receptor Kinases
  • Spodoptera
  • Sequence Homology, Amino Acid
  • Recombinant Proteins
  • Receptors, Adrenergic, beta-2
  • Receptor Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Molecular Sequence Data
  • In Vitro Techniques