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Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
Published on: July 26, 2017
Ligand-induced conformational changes allosterically activate Toll-like receptor 9.
Eicke Latz1, Anjali Verma, Alberto Visintin
1Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. eicke.latz@umassmed.edu
Nature Immunology
|June 19, 2007
Summary
CpG-rich DNA activates Toll-like receptor 9 (TLR9) by inducing conformational changes. TLR9 activation requires specific DNA binding, not just dimerization, highlighting a key regulatory mechanism for immune responses.
Area of Science:
- Immunology
- Molecular Biology
- Structural Biology
Background:
- Toll-like receptor 9 (TLR9) plays a crucial role in innate immunity, recognizing microbial DNA containing CpG motifs.
- The precise molecular mechanisms governing TLR9 activation and inhibition by different DNA sequences remain incompletely understood.
- Understanding TLR9 signaling is vital for developing immunotherapies and vaccines.
Purpose of the Study:
- To elucidate the structural and conformational changes in TLR9 upon binding to stimulatory (CpG-rich) and inhibitory (CpG-lacking) DNA.
- To investigate the role of TLR9 dimerization and conformational dynamics in receptor activation.
- To clarify the molecular basis for TLR9-mediated immune stimulation.
Main Methods:
- Biochemical assays to study TLR9 binding to various DNA substrates.
- Conformational analysis of the TLR9 ectodomain and cytoplasmic domains.
- In vitro studies to assess TLR9 dimerization and signaling complex formation.
Main Results:
- TLR9 binds to both stimulatory and inhibitory DNA, but only stimulatory DNA induces significant conformational changes in the TLR9 ectodomain.
- In its resting state, TLR9 exists as inactive homodimers with an inactivated conformation.
- CpG-containing DNA binding induces allosteric conformational shifts in the TLR9 cytoplasmic domains, leading to their close apposition in endosomes, which is likely essential for downstream signaling adaptor recruitment.
Conclusions:
- TLR9 activation is critically dependent on specific conformational changes induced by CpG-rich DNA, not solely on receptor dimerization.
- The observed conformational dynamics provide a molecular explanation for how TLR9 distinguishes between stimulatory and inhibitory DNA.
- These findings offer insights into the regulation of TLR9 signaling and its implications in immune responses.
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