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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The authors thank the Medical Research Council (UK), the Biotechnology and Biological Sciences Research Council (UK) and the Wellcome Trust (UK) for grant support.
The authors declare no competing financial interests.
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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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