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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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Computationally designed GPCR quaternary structures bias signaling pathway activation.

Justine S Paradis1,2, Xiang Feng3,4, Brigitte Murat1,2

  • 1Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, H3T 1J4, Canada.

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Researchers developed a computational method to predict and design receptor quaternary structures, revealing their role in biased signaling. This approach reprogrammed chemokine receptor CXCR4 dimers to selectively activate distinct cellular pathways.

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Area of Science:

  • Molecular and Cellular Biology
  • Biochemistry
  • Computational Biology

Background:

  • Cellular communication relies on receptors translating external signals into internal responses.
  • Receptor quaternary structures are difficult to study, limiting understanding of their role in signal transduction.

Purpose of the Study:

  • To develop a computational approach for predicting and designing receptor quaternary structures.
  • To investigate the role of receptor oligomerization in biased signaling pathways.

Main Methods:

  • Developed a computational method to predict receptor self-associations and design novel quaternary structures.
  • Engineered chemokine receptor CXCR4 dimers with altered binding, conformations, and signaling properties.
  • Validated designed CXCR4 dimers' structural changes and signaling pathway activation (G protein Gi and β-arrestin).

Main Results:

  • Designed CXCR4 dimers exhibited distinct conformations and quaternary structural changes upon activation.
  • All engineered CXCR4 oligomers activated the G protein Gi.
  • Specific dimer structures selectively recruited β-arrestins, demonstrating biased signaling.

Conclusions:

  • Receptor quaternary structures are a critical, previously unrecognized mechanism for biased signaling.
  • A 'bias switch' at the dimer interface of G protein-coupled receptors controls selective pathway activation.
  • The computational approach enables prediction and design of receptor associations for reprogramming cellular signaling.