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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.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
Cooperative Binding of Transcription Regulators02:13

Cooperative Binding of Transcription Regulators

Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome.  Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form dimers that...
Enzyme-linked Receptors01:00

Enzyme-linked Receptors

Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
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Diversity of Antigen Receptors01:28

Diversity of Antigen Receptors

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TGF - β Signaling Pathway01:16

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The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...

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Related Experiment Video

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A TIRF Microscopy Technique for Real-time, Simultaneous Imaging of the TCR and its Associated Signaling Proteins
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A TIRF Microscopy Technique for Real-time, Simultaneous Imaging of the TCR and its Associated Signaling Proteins

Published on: March 22, 2012

The TLR3 signaling complex forms by cooperative receptor dimerization.

Joshua N Leonard1, Rodolfo Ghirlando, Janine Askins

  • 1Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 4, 2008
PubMed
Summary

Toll-like receptor 3 (TLR3) uses double-stranded RNA (dsRNA) to form signaling dimers. This dimer is the smallest unit that activates immune responses in cells.

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Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling

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Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
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Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling

Published on: July 26, 2017

Area of Science:

  • Immunology
  • Molecular Biology
  • Structural Biology

Background:

  • Toll-like receptors (TLRs) are crucial for innate immunity, recognizing pathogen-associated molecular patterns.
  • The precise molecular mechanisms of TLR ligand recognition and signaling complex formation remain incompletely understood.
  • Specifically, how TLR3 interacts with its ligand, double-stranded RNA (dsRNA), to initiate downstream signaling is unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism of double-stranded RNA (dsRNA) recognition by Toll-like receptor 3 (TLR3).
  • To determine the stoichiometry and structural basis of the active TLR3 signaling complex.

Main Methods:

  • Biochemical characterization of purified TLR3 ectodomain (TLR3ecd) protein.
  • Analysis of dsRNA binding kinetics, affinity, and specificity to TLR3ecd.
  • Investigation of TLR3ecd oligomerization state in response to dsRNA binding.

Main Results:

  • dsRNA binds specifically and saturably to defined sites on the TLR3 ectodomain.
  • TLR3ecd exists as a monomer in solution but forms stable dimers upon dsRNA binding.
  • The smallest dsRNA oligonucleotides (40-50 bp) capable of stable complex formation with TLR3ecd are also sufficient for efficient TLR3 activation in cells.
  • Multiple TLR3ecd dimers can assemble on longer dsRNA molecules.

Conclusions:

  • Toll-like receptor 3 (TLR3) assembles into stable dimers on double-stranded RNA (dsRNA).
  • A single TLR3 dimer represents the minimal functional unit required for initiating downstream signaling.
  • This provides a molecular framework for understanding TLR3-mediated innate immune responses to viral RNA.