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Related Concept Videos

Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

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G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
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G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
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G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
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Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
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Activation and Inactivation of G Proteins01:22

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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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Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
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Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding
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Structural basis for adhesion G protein-coupled receptor Gpr126 function.

Katherine Leon1,2, Rebecca L Cunningham3, Joshua A Riback1,4

  • 1Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, 60637, USA.

Nature Communications
|January 12, 2020
PubMed
Summary
This summary is machine-generated.

Researchers determined the structure of the Gpr126 extracellular region (ECR), revealing a closed conformation critical for its function. This finding offers insights into adhesion G protein-coupled receptor (aGPCR) mechanisms and drug design.

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Area of Science:

  • Structural biology
  • Molecular pharmacology
  • Cell biology

Background:

  • Adhesion G protein-coupled receptors (aGPCRs) have crucial roles in development and disease.
  • The extracellular regions (ECRs) of aGPCRs are implicated in diverse biological processes but their structures and functions are poorly understood.
  • Gpr126 (also known as Adgrg6) is an aGPCR essential for Schwann cell myelination and other developmental processes, with mutations causing human myelination defects.

Purpose of the Study:

  • To elucidate the structure of the complete zebrafish Gpr126 extracellular region (ECR).
  • To understand the regulatory mechanisms of Gpr126 ECR conformation and signaling.
  • To provide insights for the rational design of drugs targeting aGPCRs.

Main Methods:

  • X-ray crystallography to determine the structure of the zebrafish Gpr126 ECR.
  • Site-directed mutagenesis to investigate the role of specific domains and the calcium-binding site.
  • In vivo functional assays in zebrafish to assess the impact of mutations on Gpr126 activity.

Main Results:

  • The complete zebrafish Gpr126 ECR structure was determined, revealing five distinct domains, including a novel one.
  • The Gpr126 ECR adopts a compact, closed conformation stabilized by an alternatively spliced linker and a conserved calcium-binding site.
  • Alternative splicing of the linker region was shown to regulate ECR conformation and receptor signaling.
  • Mutagenesis of the calcium-binding site abolished Gpr126 function in vivo, highlighting its critical role.

Conclusions:

  • The Gpr126 ECR employs a dynamic, multi-faceted mechanism involving alternative splicing and calcium binding to regulate receptor function.
  • The determined structure and identified regulatory mechanisms provide a foundation for understanding aGPCRs.
  • These findings offer valuable insights for developing targeted therapeutics for diseases associated with aGPCR dysfunction.