Abstract
Heterotrimeric G-proteins, comprising Gα, Gβ, and Gγ subunits, are molecular switches that regulate numerous signaling pathways involved in cellular physiology. This characteristic is achieved by the adoption of two principal states: an inactive state in which GDP-bound Gα is complexed with the Gβγ dimer, and an active state in which GTP-bound Gα is freed of its Gβγ binding partner. Structural studies have illustrated the basis for the distinct conformations of these states which are regulated by alterations in three precise ‘switch regions’ of the Gα subunit. Discrete differences in conformation between GDP- and GTP-bound Gα underlie its nucleotide-dependent protein-protein interactions (e.g., with Gβγ/receptor and effectors, respectively) that are critical for maintaining their proper nucleotide cycling and signaling properties. Recently, several screening approaches have been used to identify peptide sequences capable of interacting with Gα (and free Gβγ) in nucleotide-dependent fashions. These peptides have demonstrated applications in direct modulation of the nucleotide cycle, assessing the structural basis for aspects of Gα and Gβγ signaling, and serving as biosensor tools in assays for Gα activation including high throughput drug screening. In this review, we highlight some of the methods used for such discoveries and discuss the insights that can be gleaned from application of these identified peptides.
Combinatorial Chemistry & High Throughput Screening
Title: State-Selective Binding Peptides for Heterotrimeric G-Protein Subunits:Novel Tools for Investigating G-Protein Signaling Dynamics
Volume: 11 Issue: 5
Author(s): Christopher A. Johnston, Francis S. Willard, J. Kevin Ramer, Rainer Blaesius, C. Natalia Roques and David P. Siderovski
Affiliation:
Abstract: Heterotrimeric G-proteins, comprising Gα, Gβ, and Gγ subunits, are molecular switches that regulate numerous signaling pathways involved in cellular physiology. This characteristic is achieved by the adoption of two principal states: an inactive state in which GDP-bound Gα is complexed with the Gβγ dimer, and an active state in which GTP-bound Gα is freed of its Gβγ binding partner. Structural studies have illustrated the basis for the distinct conformations of these states which are regulated by alterations in three precise ‘switch regions’ of the Gα subunit. Discrete differences in conformation between GDP- and GTP-bound Gα underlie its nucleotide-dependent protein-protein interactions (e.g., with Gβγ/receptor and effectors, respectively) that are critical for maintaining their proper nucleotide cycling and signaling properties. Recently, several screening approaches have been used to identify peptide sequences capable of interacting with Gα (and free Gβγ) in nucleotide-dependent fashions. These peptides have demonstrated applications in direct modulation of the nucleotide cycle, assessing the structural basis for aspects of Gα and Gβγ signaling, and serving as biosensor tools in assays for Gα activation including high throughput drug screening. In this review, we highlight some of the methods used for such discoveries and discuss the insights that can be gleaned from application of these identified peptides.
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Cite this article as:
Johnston A. Christopher, Willard S. Francis, Ramer Kevin J., Blaesius Rainer, Roques Natalia C. and Siderovski P. David, State-Selective Binding Peptides for Heterotrimeric G-Protein Subunits:Novel Tools for Investigating G-Protein Signaling Dynamics, Combinatorial Chemistry & High Throughput Screening 2008; 11 (5) . https://dx.doi.org/10.2174/138620708784534798
DOI https://dx.doi.org/10.2174/138620708784534798 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
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