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Related Concept Videos

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.
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Covalent Binding of BMP-2 on Surfaces Using a Self-assembled Monolayer Approach
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Receptor oligomerization and beyond: a case study in bone morphogenetic proteins.

Kai Heinecke1, Axel Seher, Werner Schmitz

  • 1Physiologische Chemie II, Biozentrum, Universität Würzburg, Würzburg, Germany. kai.heinecke@biozentrum.uni-wuerzburg.de

BMC Biology
|September 9, 2009
PubMed
Summary

Transforming growth factor-beta (TGF-β) superfamily ligands exhibit promiscuous binding to type I and type II receptors. This study reveals how ligand-receptor interactions, influenced by binding affinity and stoichiometry, generate diverse cellular signals despite limited receptor availability.

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Visualization and Quantification of TGFβ/BMP/SMAD Signaling under Different Fluid Shear Stress Conditions using Proximity-Ligation-Assay

Published on: September 14, 2021

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • Transforming growth factor-beta (TGF-β) superfamily ligands signal through type I and type II serine/threonine kinase receptors.
  • Mammalian cells express a limited number of TGF-β receptors (7 type I, 5 type II) relative to the numerous ligands, suggesting significant ligand-receptor promiscuity.
  • Variations in binding affinities and specificities are crucial for generating distinct signaling outcomes from ligand-receptor complexes.

Purpose of the Study:

  • To investigate the binding kinetics and specificity of ligand-receptor interactions within the TGF-β superfamily.
  • To elucidate how different binding affinities and receptor stoichiometries contribute to distinct cellular responses.
  • To understand signal generation in a receptor-limited system characterized by ligand-receptor promiscuity.

Main Methods:

  • In vitro interaction analyses to determine binding kinetics (e.g., 'slow on/slow off', 'fast on/fast off').
  • Avidity studies using immobilized receptors to assess cooperative binding of dimeric ligands.
  • In vivo binding studies on whole cells using homodimeric and heterodimeric bone morphogenetic protein 2 (BMP2) mutants to identify binding sites and affinities.

Main Results:

  • Two binding kinetic prototypes were observed: 'slow on/slow off' and 'fast on/fast off'.
  • Ligand binding specificity to receptors of a single subtype was only moderate, with bivalent interactions contributing to avidity.
  • In vivo studies identified low and high affinity binding sites for BMP2, correlating with the presence of one or two BMP receptor (BMPR)-IA chains, respectively.
  • High affinity sites mediated rapid, transient responses at low ligand concentrations, while low affinity sites supported sustained signaling at higher concentrations.

Conclusions:

  • Ligand binding to a high-affinity receptor chain initiates signaling complex formation, enabling subsequent recruitment of other receptor subtypes.
  • Receptor complexes can comprise up to four receptors, consistent with observed low ligand-receptor specificity within subtypes.
  • Heterooligomeric signaling complexes with a single type I receptor chain are possible for BMP2, adding complexity.
  • Despite ligand-receptor promiscuity, a diverse range of signals can be generated within this receptor-limited system.