A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model.

Details

Serval ID
serval:BIB_559CFDBDB89B
Type
Article: article from journal or magazin.
Collection
Publications
Title
A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model.
Journal
Journal of Biological Chemistry
Author(s)
Samama P., Cotecchia S., Costa T., Lefkowitz R.J.
ISSN
0021-9258 (Print)
ISSN-L
0021-9258
Publication state
Published
Issued date
1993
Peer-reviewed
Oui
Volume
268
Number
7
Pages
4625-4636
Language
english
Abstract
We have replaced the C-terminal portion of the third intracellular loop of the beta 2-adrenergic receptor (residues 266-272) with the homologous region of the alpha 1B-adrenergic receptor. In a fashion analogous to the reciprocal mutations of the alpha 1B receptor previously described (Cotecchia, S., Exum, S., Caron, M. G., and Lefkowitz, R. J. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 2896-2900), this conservative substitution leads to agonist-independent activation of adenylyl cyclase. In addition, the constitutively active mutant receptor exhibits: (i) an increased affinity for agonists (even in the absence of guanine nucleotide-binding regulatory protein (G protein)) but not antagonists, with the extent of affinity increase being correlated with the intrinsic activity of the ligand; (ii) an increased potency of agonists for stimulation of adenylyl cyclase; and (iii) an increased intrinsic activity of partial agonists. We document that our experimental findings with the mutant receptor cannot be adequately rationalized within the theoretical framework of the Ternary Complex Model (De Lean, A., Stadel, J. M., and Lefkowitz, R. J. (1980) J. Biol. Chem. 255, 7108-7117) which postulates that receptor activation requires the agonist-promoted formation of an active, "ternary" complex of agonist, receptor, and G protein. We show, through extensive computer simulations, that an extended version of this model that includes an explicit isomerization of the receptor (R) to an active state (R*) closely models all our findings for both the mutant and the wild-type receptors. Study of such constitutively active mutant G protein-coupled receptors should help elucidate the molecular nature of the processes involved in receptor activation.
Keywords
Adenylate Cyclase/metabolism, Adrenergic beta-Agonists/metabolism, Amino Acid Sequence, Animals, CHO Cells, Cell Line, Cricetinae, Enzyme Activation, GTP-Binding Proteins/metabolism, Models, Chemical, Molecular Sequence Data, Mutagenesis, Protein Conformation, Receptors, Adrenergic, beta/chemistry, Receptors, Adrenergic, beta/genetics, Substrate Specificity
Pubmed
Web of science
Create date
24/01/2008 11:05
Last modification date
20/08/2019 14:10
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