Many cell types in vertebrates express proteins which are capable of detecting the presence of a diverse array of pathogens, including bacteria, mycoplasmas, and fungi, a capacity which is known as innate immunity. Upon recognition of invading pathogens, these cells produce specific inflammatory cytokines which signal the immune system to mount a response. A small class of proteins called toll-like receptors (TLRs) has recently been shown to play a central role in transducing the signal from invading pathogens across the plasma membrane. The mechanism of pathogen recognition is not presently understood from a structural perspective. The objective of the research propsed here is to characterize the interaction between TLRs and various ligands using biophysical and structural approaches according to the following specific aims: (1) overexpression and purification of the extracellular domains of human TLR2 or TLR4 along with the adaptor proteins CD14 and MD-2; (2) biophysical characterization of the binding affinities of various ligands and adaptor proteins using analytical ultracentrifugation, fluorescence anisotropy, and surface plasmon resonance; (3) determination of the atomic structure of the extracellular domains of TLR2 or TLR4 using x-ray crystallography.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AI049695-02
Application #
6622300
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Prograis, Lawrence J
Project Start
2002-02-01
Project End
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
2
Fiscal Year
2003
Total Cost
$49,864
Indirect Cost
Name
University of California San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Lawton, Jeffrey A; Ghosh, Partho (2003) Novel therapeutic strategies based on toll-like receptor signaling. Curr Opin Chem Biol 7:446-51