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Dynamics and structure of concerted protein conformational changes during activation of Toll and Toll-like receptors

Reference	BB/D003970/1
Principal Investigator / Supervisor	Professor Nicholas Gay
Co-Investigators / Co-Supervisors	Professor Sir Tom Blundell
Institution	University of Cambridge
Department	Biochemistry
Funding type	Research
Value (£)	217,902
Status	Completed
Type	Research Grant
Start date	01/11/2005
End date	31/10/2008
Duration	36 months

Abstract

Drosophila Toll is a type I transmembrane receptor required for dorsoventral patterning and innate immunity. Related receptors in vertebrates are critical mediators of responses to pathogenic bacteria and viruses and probably have realated mechanisms of signalling. Recent work from our lab has shown that the mechanism of activation of Drosophila Toll is complex. Rather than simple crosslinking formation of active signalling complexes appears to require concerted protein conformational changes involving ligand-receptor and receptor-receptor interactions. Here we propose to elucidate the nature of the changes firstly by a structural approach using X-ray crystallography and secondly in vivo using single molecule fluorescent microscopy techniques developed by collaborators at the Daresbury Laboratory. Single pair fluorescence resonance energy transfer (spFRET) and single molecule fluorescence polarisation (smFP) data can be acquired simultaneously and will provide information about conformational changes that occur during activation in real time. We plan to carry out in parallel studies of the related human LPS sensor, the Toll-like receptor 4/MD-2 complex.

Summary

Cells in living organisms are able to sense external stimuli and adopt particular responses to them. In this research we seek to understand how cells of the immune system are able to detect and respond to the bacteria and viruses that cause human disease. In particular we want to understand at the molecular level the changes that occur in specific proteins on the surface of the cell, called receptors that are responsible for transmitting a signal when exposed to bacterial products. We will use the techniques of X-ray crystallography and fluorescent microscopy to study this problem.

Committee	Closed Committee - Biomolecular Sciences (BMS)
Research Topics	Immunology, Structural Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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