Computational design of orthogonal membrane receptor-effector switches for rewiring signaling pathways.

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Download: Young et al-PNAS-2018.pdf (1097.85 [Ko])
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Version: Final published version
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Serval ID
serval:BIB_8C56DD9E0F4C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Computational design of orthogonal membrane receptor-effector switches for rewiring signaling pathways.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Young M., Dahoun T., Sokrat B., Arber C., Chen K.M., Bouvier M., Barth P.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
03/07/2018
Peer-reviewed
Oui
Volume
115
Number
27
Pages
7051-7056
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Membrane receptors regulate numerous intracellular functions. However, the molecular underpinnings remain poorly understood because most receptors initiate multiple signaling pathways through distinct interaction interfaces that are structurally uncharacterized. We present an integrated computational and experimental approach to model and rationally engineer membrane receptor-intracellular protein systems signaling with novel pathway selectivity. We targeted the dopamine D2 receptor (D2), a G-protein-coupled receptor (GPCR), which primarily signals through Gi, but triggers also the Gq and beta-arrestin pathways. Using this approach, we designed orthogonal D2-Gi complexes, which coupled with high specificity and triggered exclusively the Gi-dependent signaling pathway. We also engineered an orthogonal chimeric D2-Gs/i complex that rewired D2 signaling from a Gi-mediated inhibitory into a Gs-dependent activating pathway. Reinterpreting the evolutionary history of GPCRs in light of the designed proteins, we uncovered an unforeseen hierarchical code of GPCR-G-protein coupling selectivity determinants. The results demonstrate that membrane receptor-cytosolic protein systems can be rationally engineered to regulate mammalian cellular functions. The method should prove useful for creating orthogonal molecular switches that redirect signals at the cell surface for cell-engineering applications.
Keywords
G-protein–coupled receptor, cell signaling, membrane protein, protein binding, protein design
Pubmed
Web of science
Open Access
Yes
Create date
23/07/2018 17:04
Last modification date
01/11/2019 11:56
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