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Toll-like receptors as molecular switches

Abstract

Members of the Toll family of single-pass transmembrane receptors are key mediators of innate immunity in both vertebrates and invertebrates. They respond to various pathogen-associated stimuli and transduce the complex signalling responses that are required for inflammation and for the subsequent development of adaptive immunity. Here, we propose a molecular mechanism for signalling by the Toll and Toll-like receptors that involves a series of protein conformational changes initiated by dimerization of their extracellular domains. The initial dimerization event, which is triggered by the interaction of the receptor with its ligand, might disrupt a pre-formed but non-functional dimer. Formation of a stable receptor–ligand complex then relieves constitutive autoinhibition, enabling receptor–receptor association of the extracellular juxtamembrane regions and cytoplasmic signalling domains. This activation process constitutes a tightly regulated, unidirectional molecular switch.

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Figure 1: Basic architecture of Toll and Toll-like receptors.
Figure 2: Ligand binding by a leucine-rich-repeat-containing protein.
Figure 3: Toll-like-receptor ectodomain and ligands (stimuli).
Figure 4: Model for Drosophila Toll activation by Spätzle.
Figure 5: Compartmentalization of Toll-like receptors, signalling and termination of signalling.

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Acknowledgements

The authors thank the Medical Research Council (UK), the Biotechnology and Biological Sciences Research Council (UK) and the Wellcome Trust (UK) for grant support.

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Correspondence to Nicholas J. Gay.

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Gay, N., Gangloff, M. & Weber, A. Toll-like receptors as molecular switches. Nat Rev Immunol 6, 693–698 (2006). https://doi.org/10.1038/nri1916

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