Toll-like receptors as molecular switches.
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.
Gay
Nicholas J
NJ
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. njg11@mole.bio.cam.ac.uk
Gangloff
Monique
M
Weber
Alexander N R
AN
D000818:Animals; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*
D008024:Ligands; D051193:Toll-Like Receptors