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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
48
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pubmed:dateCreated |
2003-11-24
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pubmed:abstractText |
Three cell-surface proteins have been recognized as components of the mammalian signaling receptor for bacterial lipopolysaccharide (LPS): CD14, Toll-like receptor-4 (TLR4), and MD-2. Biochemical and visual studies shown here demonstrate that the role of CD14 in signal transduction is to enhance LPS binding to MD-2, although its expression is not essential for cellular activation. These studies clarify how MD-2 functions: we found that MD-2 enables TLR4 binding to LPS and allows the formation of stable receptor complexes. MD-2 must be bound to TLR4 on the cell surface before binding can occur. Consequently, TLR4 clusters into receptosomes (many of which are massive) that recruit intracellular toll/IL-1/resistance domain-containing adapter proteins within minutes, thus initiating signal transduction. TLR4 activation correlates with the ability of MD-2 to bind LPS, as MD-2 mutants that still bind TLR4, but are impaired in the ability to bind LPS, conferred a greatly blunted LPS response. These findings help clarify the earliest events of TLR4 triggering by LPS and identify MD-2 as an attractive target for pharmacological intervention in endotoxin-mediated diseases.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, CD14,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, Surface,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine,
http://linkedlifedata.com/resource/pubmed/chemical/LY96 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides,
http://linkedlifedata.com/resource/pubmed/chemical/Lymphocyte Antigen 96,
http://linkedlifedata.com/resource/pubmed/chemical/Lysine,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cell Surface,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/TLR4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Toll-Like Receptor 4,
http://linkedlifedata.com/resource/pubmed/chemical/Toll-Like Receptors,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
28
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pubmed:volume |
278
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
48313-20
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:12960171-Amino Acid Sequence,
pubmed-meshheading:12960171-Antigens, CD14,
pubmed-meshheading:12960171-Antigens, Surface,
pubmed-meshheading:12960171-Biotinylation,
pubmed-meshheading:12960171-Blotting, Western,
pubmed-meshheading:12960171-Cell Line,
pubmed-meshheading:12960171-Cell Membrane,
pubmed-meshheading:12960171-Cysteine,
pubmed-meshheading:12960171-Humans,
pubmed-meshheading:12960171-Lipopolysaccharides,
pubmed-meshheading:12960171-Lymphocyte Antigen 96,
pubmed-meshheading:12960171-Lysine,
pubmed-meshheading:12960171-Membrane Glycoproteins,
pubmed-meshheading:12960171-Microscopy, Electron, Scanning,
pubmed-meshheading:12960171-Microscopy, Fluorescence,
pubmed-meshheading:12960171-Molecular Sequence Data,
pubmed-meshheading:12960171-Precipitin Tests,
pubmed-meshheading:12960171-Protein Binding,
pubmed-meshheading:12960171-Protein Structure, Tertiary,
pubmed-meshheading:12960171-Receptors, Cell Surface,
pubmed-meshheading:12960171-Recombinant Proteins,
pubmed-meshheading:12960171-Sequence Homology, Amino Acid,
pubmed-meshheading:12960171-Signal Transduction,
pubmed-meshheading:12960171-Toll-Like Receptor 4,
pubmed-meshheading:12960171-Toll-Like Receptors,
pubmed-meshheading:12960171-Transfection,
pubmed-meshheading:12960171-Tyrosine
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pubmed:year |
2003
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pubmed:articleTitle |
Lysines 128 and 132 enable lipopolysaccharide binding to MD-2, leading to Toll-like receptor-4 aggregation and signal transduction.
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pubmed:affiliation |
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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