Domain exchange between human Toll-like receptors 1 and 6 reveals a region required for lipopeptide discrimination

Katherine O. Omueti, John M. Beyer, Christopher M. Johnson, Elizabeth A. Lyle, Richard I. Tapping

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

Among the 10 human Toll-like receptors (TLRs), TLR2 appears to be unique in its requirement for cooperation with other TLRs, namely TLR1 and TLR6, to mediate cell signaling. Through reconstitution experiments, we have defined more precisely the function of these human TLRs. Human colonic epithelial cells cotransfected with TLR1 and -2 preferentially respond to a synthetic tripalmitoylated bacterial lipopeptide analogue (Pam3CSK 4). However, examination of a wide variety of lipopeptide derivatives indicates that recognition by human TLR1 and -2 does not strictly correlate with the number or position of the acyl chains on the modified cysteine residue. Conversely, human TLR2 and -6 exclusively respond to lipopeptides possessing a diacylglycerol group. Most surprisingly, we have found that an R stereoisomer of diacylated macrophage-activating lipopeptide 2 (MALP-2) exclusively activates epithelial cells through TLR6 and -2 but not through TLR1 and -2. These results suggest that the chirality of the central carbon of the diacylglycerol group of these agonists is a structural determinant for human TLR recognition. Examination of chimeric receptors, generated by domain exchange between TLR1 and -6, has revealed that leucine-rich repeats 9-12 of the extracellular domain enable these receptors to discriminate between structurally similar lipopeptides. However, additional chimeric constructs reveal that this region alone is not sufficient to generate receptors that can functionally cooperate with TLR2. Our results support the idea that TLR1 and TLR6 diverged during evolution to differentially recognize natural lipoprotein structures and that this function has been conserved with respect to the human receptors.

Original languageEnglish (US)
Pages (from-to)36616-36625
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number44
DOIs
StatePublished - Nov 4 2005

Fingerprint

Toll-Like Receptor 1
Lipopeptides
Toll-Like Receptors
Diglycerides
Cell signaling
Epithelial Cells
Stereoisomerism
Macrophages
Chirality
Leucine
Lipoproteins
Cysteine
Carbon
human TLR6 protein
Derivatives

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Domain exchange between human Toll-like receptors 1 and 6 reveals a region required for lipopeptide discrimination. / Omueti, Katherine O.; Beyer, John M.; Johnson, Christopher M.; Lyle, Elizabeth A.; Tapping, Richard I.

In: Journal of Biological Chemistry, Vol. 280, No. 44, 04.11.2005, p. 36616-36625.

Research output: Contribution to journalArticle

Omueti, Katherine O. ; Beyer, John M. ; Johnson, Christopher M. ; Lyle, Elizabeth A. ; Tapping, Richard I. / Domain exchange between human Toll-like receptors 1 and 6 reveals a region required for lipopeptide discrimination. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 44. pp. 36616-36625.
@article{c862885ff6b241c092e86276c9186c4a,
title = "Domain exchange between human Toll-like receptors 1 and 6 reveals a region required for lipopeptide discrimination",
abstract = "Among the 10 human Toll-like receptors (TLRs), TLR2 appears to be unique in its requirement for cooperation with other TLRs, namely TLR1 and TLR6, to mediate cell signaling. Through reconstitution experiments, we have defined more precisely the function of these human TLRs. Human colonic epithelial cells cotransfected with TLR1 and -2 preferentially respond to a synthetic tripalmitoylated bacterial lipopeptide analogue (Pam3CSK 4). However, examination of a wide variety of lipopeptide derivatives indicates that recognition by human TLR1 and -2 does not strictly correlate with the number or position of the acyl chains on the modified cysteine residue. Conversely, human TLR2 and -6 exclusively respond to lipopeptides possessing a diacylglycerol group. Most surprisingly, we have found that an R stereoisomer of diacylated macrophage-activating lipopeptide 2 (MALP-2) exclusively activates epithelial cells through TLR6 and -2 but not through TLR1 and -2. These results suggest that the chirality of the central carbon of the diacylglycerol group of these agonists is a structural determinant for human TLR recognition. Examination of chimeric receptors, generated by domain exchange between TLR1 and -6, has revealed that leucine-rich repeats 9-12 of the extracellular domain enable these receptors to discriminate between structurally similar lipopeptides. However, additional chimeric constructs reveal that this region alone is not sufficient to generate receptors that can functionally cooperate with TLR2. Our results support the idea that TLR1 and TLR6 diverged during evolution to differentially recognize natural lipoprotein structures and that this function has been conserved with respect to the human receptors.",
author = "Omueti, {Katherine O.} and Beyer, {John M.} and Johnson, {Christopher M.} and Lyle, {Elizabeth A.} and Tapping, {Richard I.}",
year = "2005",
month = "11",
day = "4",
doi = "10.1074/jbc.M504320200",
language = "English (US)",
volume = "280",
pages = "36616--36625",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "44",

}

TY - JOUR

T1 - Domain exchange between human Toll-like receptors 1 and 6 reveals a region required for lipopeptide discrimination

AU - Omueti, Katherine O.

AU - Beyer, John M.

AU - Johnson, Christopher M.

AU - Lyle, Elizabeth A.

AU - Tapping, Richard I.

PY - 2005/11/4

Y1 - 2005/11/4

N2 - Among the 10 human Toll-like receptors (TLRs), TLR2 appears to be unique in its requirement for cooperation with other TLRs, namely TLR1 and TLR6, to mediate cell signaling. Through reconstitution experiments, we have defined more precisely the function of these human TLRs. Human colonic epithelial cells cotransfected with TLR1 and -2 preferentially respond to a synthetic tripalmitoylated bacterial lipopeptide analogue (Pam3CSK 4). However, examination of a wide variety of lipopeptide derivatives indicates that recognition by human TLR1 and -2 does not strictly correlate with the number or position of the acyl chains on the modified cysteine residue. Conversely, human TLR2 and -6 exclusively respond to lipopeptides possessing a diacylglycerol group. Most surprisingly, we have found that an R stereoisomer of diacylated macrophage-activating lipopeptide 2 (MALP-2) exclusively activates epithelial cells through TLR6 and -2 but not through TLR1 and -2. These results suggest that the chirality of the central carbon of the diacylglycerol group of these agonists is a structural determinant for human TLR recognition. Examination of chimeric receptors, generated by domain exchange between TLR1 and -6, has revealed that leucine-rich repeats 9-12 of the extracellular domain enable these receptors to discriminate between structurally similar lipopeptides. However, additional chimeric constructs reveal that this region alone is not sufficient to generate receptors that can functionally cooperate with TLR2. Our results support the idea that TLR1 and TLR6 diverged during evolution to differentially recognize natural lipoprotein structures and that this function has been conserved with respect to the human receptors.

AB - Among the 10 human Toll-like receptors (TLRs), TLR2 appears to be unique in its requirement for cooperation with other TLRs, namely TLR1 and TLR6, to mediate cell signaling. Through reconstitution experiments, we have defined more precisely the function of these human TLRs. Human colonic epithelial cells cotransfected with TLR1 and -2 preferentially respond to a synthetic tripalmitoylated bacterial lipopeptide analogue (Pam3CSK 4). However, examination of a wide variety of lipopeptide derivatives indicates that recognition by human TLR1 and -2 does not strictly correlate with the number or position of the acyl chains on the modified cysteine residue. Conversely, human TLR2 and -6 exclusively respond to lipopeptides possessing a diacylglycerol group. Most surprisingly, we have found that an R stereoisomer of diacylated macrophage-activating lipopeptide 2 (MALP-2) exclusively activates epithelial cells through TLR6 and -2 but not through TLR1 and -2. These results suggest that the chirality of the central carbon of the diacylglycerol group of these agonists is a structural determinant for human TLR recognition. Examination of chimeric receptors, generated by domain exchange between TLR1 and -6, has revealed that leucine-rich repeats 9-12 of the extracellular domain enable these receptors to discriminate between structurally similar lipopeptides. However, additional chimeric constructs reveal that this region alone is not sufficient to generate receptors that can functionally cooperate with TLR2. Our results support the idea that TLR1 and TLR6 diverged during evolution to differentially recognize natural lipoprotein structures and that this function has been conserved with respect to the human receptors.

UR - http://www.scopus.com/inward/record.url?scp=27744456905&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27744456905&partnerID=8YFLogxK

U2 - 10.1074/jbc.M504320200

DO - 10.1074/jbc.M504320200

M3 - Article

C2 - 16129684

AN - SCOPUS:27744456905

VL - 280

SP - 36616

EP - 36625

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 44

ER -