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.

Author affiliations

1. Nicholas J. Gay and Monique Gangloff are at the Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
2. Alexander N. R. Weber is at the German Cancer Research Centre (DKFZ), Angewandte Tumorvirologie (ATV), Im Neuenheimer Feld, 69242 Heidelberg, Germany.

Correspondence to: Nicholas J. Gay¹ Email: njg11@mole.bio.cam.ac.uk

Published online 18 August 2006

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