The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
Pleckstrin Homology Domain-mediated Membrane Association and Activation of the β-Adrenergic Receptor Kinase Requires Coordinate Interaction with Gβγ Subunits and Lipid
Open accessAbstract
The pleckstrin homology (PH) domain is an approximately 100-amino-acid region of sequence homology present in numerous proteins of diverse functions, which forms a discrete structural module. Several ligands capable of binding to PH domain-containing proteins have been identified including phosphatidylinositol 4,5-bisphosphate (PIP2) and the G beta gamma subunits of heterotrimeric G proteins (G beta gamma), which bind to the amino and carboxyl termini of the PH domain, respectively. Here we report that the binding of G beta gamma and lipid to the PH domain of the beta-adrenergic receptor kinase (beta ARK) synergistically enhances agonist-dependent receptor phosphorylation and that both PH domain-binding ligands are required for membrane association of the kinase. PIP2 and to a lesser extent phosphatidylinositol 4-phosphate, phosphatidylinositol, and phosphatidic acid were the only lipids tested capable, in the presence of G beta gamma, of enhancing beta ARK activity. In contrast, the Km and Vmax for phosphorylation of a soluble beta ARK substrate (casein) was not altered in either the presence or absence of G beta gamma and/or PIP2. A fusion protein of the beta ARK containing an intact PH domain inhibits G beta gamma/PIP2-dependent beta ARK activity. In contrast, a mutant fusion protein in which a tryptophan residue, invariant in all PH domain sequences, is mutated to alanine shows no inhibitory activity. The requirement for the simultaneous presence of two PH domain binding ligands represents a previously unappreciated mechanism for effecting membrane localization of a protein and may have relevance to other PH domain-containing proteins.
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Cites
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Pleckstrin homology domains bind to phosphatidylinositol-4,5-bisphosphate
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Self-citationThe PH domain: a common piece in the structural pathcwork of signalling proteins
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Cited by
Lefkowitz, R. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.30.18677 · Cited by 1,044
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Várnai, P., & Balla, T. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.143.2.501 · Cited by 859
Specific and high-affinity binding of inositol phosphates to an isolated pleckstrin homology domain
Lemmon, M. A., Ferguson, K. M., O'Brien, R., Sigler, P. B., & Schlessinger, J. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.23.10472 · Cited by 566
Martin, T. F. J. (1998) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.14.1.231 · Cited by 522
Metadata
- Authors
- Pitcher, J. A., Touhara, K., Payne, E. S., & Lefkowitz, R. J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1995-05
- Volume
- 270
- Issue
- 20
- Pages
- 11707-11710
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1967352670
- Cited by
- 366
- References
- 25
- FWCI
- 18.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Pitcher, J. A., Touhara, K., Payne, E. S., & Lefkowitz, R. J. (1995). Pleckstrin Homology Domain-mediated Membrane Association and Activation of the β-Adrenergic Receptor Kinase Requires Coordinate Interaction with Gβγ Subunits and Lipid. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.270.20.11707
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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