Related Experiment Video

Updated: Mar 18, 2026

Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET
10:59

Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET

Published on: August 17, 2022

3.9K

Conformational Changes in the GM-CSF Receptor Suggest a Molecular Mechanism for Affinity Conversion and Receptor

Sophie E Broughton1, Timothy R Hercus2, Tracy L Nero1

  • 1ACRF Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.

Structure (London, England : 1993)
|July 12, 2016
PubMed

Insights

Understanding how cytokine receptors signal is key. This study reveals distinct structural changes in the GM-CSF receptor, showing GMRα interactions drive signaling and βc interactions control binding affinity.

Area of Science:

  • Immunology
  • Structural Biology
  • Molecular Biology

Background:

  • The beta-c (βc) family of cytokine receptors, including GM-CSF, IL-3, and IL-5 receptors, are crucial in immune responses, inflammation, autoimmunity, and cancer.
  • Cytokine receptor signaling typically involves a heterodimeric type I cytokine receptor mechanism, requiring the recruitment of a shared subunit (βc) to a cytokine:α subunit binary complex via affinity conversion.
  • The precise mechanism of this critical process remains unclear due to limited structural data of both binary and ternary receptor complexes for specific cytokines.

Purpose of the Study:

  • To elucidate the structural basis of GM-CSF receptor activation.
  • To investigate the distinct roles of receptor subunits in signaling and binding affinity.
  • To provide insights into the signaling mechanisms of related type I cytokine receptors.

Main Methods:

  • Determined the crystal structure of the binary granulocyte-macrophage colony-stimulating factor (GM-CSF):GM-CSF receptor alpha (GMRα) complex at 2.8-Å resolution.
  • Compared the binary complex structure with existing ternary complex structures.
  • Performed mutational and functional studies to assess the impact of subunit interactions on receptor signaling and binding.

Main Results:

  • Revealed distinct conformational changes between the GM-CSF:GMRα binary complex and the ternary complex.
  • Demonstrated that interactions involving GMRα are critical for initiating receptor signaling.
  • Showed that interactions with the βc subunit are essential for high-affinity ligand binding.

Conclusions:

  • Conformational changes in the GM-CSF receptor complex are central to its activation mechanism.
  • GMRα subunit interactions primarily mediate signaling, while βc subunit interactions govern high-affinity binding.
  • The findings offer a framework for understanding signaling in related type I cytokine receptors.

More Related Videos

A Cell Free Assay System Estimating the Neutralizing Capacity of GM-CSF Antibody using Recombinant Soluble GM-CSF Receptor07:45

A Cell Free Assay System Estimating the Neutralizing Capacity of GM-CSF Antibody using Recombinant Soluble GM-CSF Receptor

Published on: June 27, 2011

13.1K
G Protein-selective GPCR Conformations Measured Using FRET Sensors in a Live Cell Suspension Fluorometer Assay09:12

G Protein-selective GPCR Conformations Measured Using FRET Sensors in a Live Cell Suspension Fluorometer Assay

Published on: September 10, 2016

10.1K

Related Concept Videos

G Protein-coupled Receptors01:15

G Protein-coupled Receptors

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.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
19.0K
GPCR Desensitization01:12

GPCR Desensitization

G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
8.6K
Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

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.
GPCRs are also called heptahelical,...
7.0K
The Two-State Receptor Model01:29

The Two-State Receptor Model

The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with...
3.4K
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

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...
19.0K
Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

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
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
7.0K