Source:http://linkedlifedata.com/resource/pubmed/id/16857668
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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
37
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pubmed:dateCreated |
2006-9-11
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pubmed:abstractText |
Toll-like receptor (TLR) 8 has an important role in initiating immune responses to viral single-stranded RNA and the antiviral compound resiquimod. Together with TLR3, -7, and -9, it forms a subgroup of the TLRs that are localized intracellularly and signal in response to pathogen-derived nucleic acids. In this work, we have used site-directed mutagenesis to identify regions of the TLR8 extracellular domain that are required for stimulus-induced signal transduction. We have shown that a cysteinerich sequence predicted to form a loop projecting from the solenoidal ectodomain structure at leucine-rich repeat 8 is essential for signaling in response to both single-stranded RNA and resiquimod. A second region, centered on an aspartic acid residue in leucine-rich repeat 17, is also required for TLR8 function. The corresponding residue in TLR9 is known to be important for pH-dependent binding and signaling in response to unmethylated CpG DNA, suggesting that the TLR7/8/9 subgroups share a common signaling mechanism. We have also shown that TLR8 is localized predominantly in the endoplasmic reticulum but that signaling is completely abolished by an inhibitor of vesicle-type H+ ATPases. This indicates that TLR8 is present at low levels in an acidified compartment and that a lowered pH is required for receptor function. We propose that pH-dependent changes in the ligand facilitate activation of the receptor. The protonated form of resiquimod, a cell-permeable weak base, is likely to concentrate significantly (approximately 100x) in acidified compartments, and this may potentiate low affinity interactions with either the receptor or a specific binding protein.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0021-9258
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
281
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
27503-11
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:16857668-Amino Acid Sequence,
pubmed-meshheading:16857668-Cell Line, Tumor,
pubmed-meshheading:16857668-CpG Islands,
pubmed-meshheading:16857668-Endoplasmic Reticulum,
pubmed-meshheading:16857668-Humans,
pubmed-meshheading:16857668-Hydrogen-Ion Concentration,
pubmed-meshheading:16857668-Molecular Sequence Data,
pubmed-meshheading:16857668-Mutagenesis, Site-Directed,
pubmed-meshheading:16857668-Protein Binding,
pubmed-meshheading:16857668-Protein Structure, Tertiary,
pubmed-meshheading:16857668-Sequence Homology, Amino Acid,
pubmed-meshheading:16857668-Signal Transduction,
pubmed-meshheading:16857668-Toll-Like Receptor 8,
pubmed-meshheading:16857668-Toll-Like Receptor 9
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pubmed:year |
2006
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pubmed:articleTitle |
Conserved features in the extracellular domain of human toll-like receptor 8 are essential for pH-dependent signaling.
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pubmed:affiliation |
Biochemistry Department, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, United Kingdom.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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