Related Experiment Video
Updated: May 15, 2026
09:40
Imaging G-protein Coupled Receptor (GPCR)-mediated Signaling Events that Control Chemotaxis of Dictyostelium Discoideum
Published on: September 20, 2011
gp130 activation is regulated by D2-D3 interdomain connectivity
Antje Schütt1, Martin Zacharias, Nico Schneider
1Christian-Albrechts-Universität zu Kiel, Institute of Biochemistry, Rudolf-Höber-Strasse 1, 24118 Kiel, Germany.
The Biochemical Journal
|January 9, 2013
Summary
Interleukin-6 (IL-6) receptor activation involves gp130 (glycoprotein 130) conformational changes, not just dimerization. Specific mutations reveal key amino acids critical for gp130 signaling in disease.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Signaling
Background:
- Interleukin-6 (IL-6) receptor activation involves gp130 (glycoprotein 130) complex formation and dimerization.
- gp130 exists as a pre-formed dimer, suggesting activation is not solely dependent on dimerization.
- The precise mechanism of gp130 activation remains unclear, particularly concerning ligand-independent activation observed in certain mutations.
Purpose of the Study:
- To investigate the role of conformational changes in gp130 activation.
- To identify critical amino acids and molecular interactions involved in gp130 signaling.
- To elucidate the mechanism of ligand-independent gp130 activation observed in inflammatory hepatocellular adenoma.
Main Methods:
- Structure-based computational analysis to identify critical amino acids.
- Investigating the role of gp130 D2-D3 interdomain connectivity and hydrophobic interactions.
- Analyzing the impact of EF loop conformation and N-terminal domain D1 residues on gp130 activation.
Main Results:
- Hydrophobic residues in gp130 D2-D3 interdomain connectivity stabilize the inactive conformation.
- Destabilization of the EF loop in domain D2 and disruption of D2-D3 hydrophobic interactions lead to ligand-independent activation.
- N-terminal residues of domain D1 are involved in the activation of gp130 deletion mutants.
Conclusions:
- Novel insights into the molecular basis of cytokine receptor signaling subunit activation.
- Identified specific amino acids and interactions critical for gp130 activation.
- Demonstrated the importance of conformational changes in gp130 activation, especially in disease-associated mutants.
Related Concept Videos
01:11IP3/DAG Signaling Pathway
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...
01:22Activation and Inactivation of G Proteins
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 affinity and are together...
01:30Assembly 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,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
01:21G-protein Coupled Receptors
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.
01:21G-protein Coupled Receptors
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.
01:09GPCRs Regulate Adenylyl Cylase Activity
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 cells.
Two...
Two...