The dynamics of signal triggering in a gp130-receptor complex

Rishi Matadeen1, Wai-Ching Hon, John K Heath

  • 1Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7BN, United Kingdom. rishi@strubi.ox.ac.uk <rishi@strubi.ox.ac.uk>

Insights

Researchers mapped the structure of the Interleukin 11 (IL-11) signaling complex. This reveals how the receptor complex changes shape to trigger cellular signals, potentially explaining cytokine signal transfer.

Area of Science:

  • Structural biology
  • Molecular and cellular biology
  • Biochemistry

Background:

  • gp130 is a crucial receptor for hematopoietic cytokines, mediating signal transduction.
  • Understanding the structure of gp130-containing complexes is key to deciphering cytokine signaling pathways.

Purpose of the Study:

  • To determine the high-resolution structure of the Interleukin 11 (IL-11) complex with its receptor and gp130.
  • To investigate the conformational dynamics and potential signal-triggering mechanisms of this complex.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) at 3.0 Å resolution.
  • Normal-mode analysis to study conformational changes.

Main Results:

  • The study determined the architecture and dynamics of the IL-11-IL-11 Receptor-gp130 extracellular complex.
  • Normal-mode analysis identified conformational changes suggesting a concerted signal triggering mechanism.

Conclusions:

  • The findings suggest a unified signaling mechanism for cytokines that use the gp130 receptor.
  • This provides insights into the general mechanism of signal transfer for cytokines utilizing the JAK-STAT signaling cascade.

Related Concept Videos

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 the...
Activation and Inactivation of G Proteins01:22

Activation 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...
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,...
G-protein Coupled Receptors01:21

G-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.
G-protein Coupled Receptors01:21

G-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.
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...