TLR2-heterodimer lipopeptide sensing module

Recognition of bacterial lipopeptides by TLR2 heterodimers and the first steps of the MyD88-dependent signal. LBP and CD14 deliver the lipopeptide; TLR2 pairs with TLR1 for triacylated or with TLR6 for diacylated lipopeptides; the PIP2-anchored sorting adaptor TIRAP recruits MYD88, which recruits the kinase IRAK4. Downstream TRAF6, TAK1 and NF-kappaB steps are shared with other MyD88-dependent TLRs and are modelled in the toll-like receptor signaling module.

MODULE:tlr2_heterodimer_lipopeptide_signalingDRAFTABSTRACTSignaling Pathwaymodules/tlr2_heterodimer_lipopeptide_signaling.yaml
toll-like receptor TLR1:TLR2 signaling pathwayGO:0038123 toll-like receptor TLR6:TLR2 signaling pathwayGO:0038124
PMID:19931471
TLR2 recognises di- and triacylated lipopeptides, and the partner (TLR1 or TLR6) sets the specificity.
Toll-like receptor 2 (TLR2) initiates potent immune responses by recognizing diacylated and triacylated lipopeptides. Its ligand specificity is controlled by whether it heterodimerizes with TLR1 or TLR6.

Written as the reference representation for GO-CAMs 5fb9cc0600000727 and 5fce9b7300000030, whose receptor activities use GO:0001875 (lipopolysaccharide immune receptor activity) for lipopeptide recognition. Here the heterodimer carries GO:0038187 and the ligand specificity is expressed by the partner subunit's binding term. Downstream steps: modules/toll_like_receptor_signaling.yaml.

7Nodes
4Parts
1Variant Sets
2Variants
7Annotons
3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:tlr2_heterodimer_lipopeptide_signaling deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ representative grounding skipped for abstract module.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

7 gene-function check(s) reflected in core functions · 0 conflict(s) · 2 evidence or coverage gap(s) (11 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
lbp_carrier LBP
UniProtKB:P18428
Gene 		molecular carrier activity
GO:0140104 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
cd14_carrier CD14
UniProtKB:P08571
Gene 		molecular carrier activity
GO:0140104 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tlr1_tlr2_receptor PROTEIN_COMPLEX
Gene 		pattern recognition receptor activity
GO:0038187 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
tlr1_tlr2_receptor/tlr1_tlr2_tlr2 TLR2
UniProtKB:O60603
Complex Unit 		lipopeptide binding
GO:0071723 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tlr1_tlr2_receptor/tlr1_tlr2_tlr1 TLR1
UniProtKB:Q15399
Complex Unit 		triacyl lipopeptide binding
GO:0042497 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tlr2_tlr6_receptor PROTEIN_COMPLEX
Gene 		pattern recognition receptor activity
GO:0038187 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
tlr2_tlr6_receptor/tlr2_tlr6_tlr2 TLR2
UniProtKB:O60603
Complex Unit 		lipopeptide binding
GO:0071723 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tlr2_tlr6_receptor/tlr2_tlr6_tlr6 TLR6
UniProtKB:Q9Y2C9
Complex Unit 		diacyl lipopeptide binding
GO:0042498 		Annotation Supported
A retained annotation or curated replacement supports this function, but core_functions does not yet reflect it.
tirap_adaptor TIRAP
UniProtKB:P58753
Gene 		signaling adaptor activity
GO:0035591 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
myd88_adaptor MYD88
UniProtKB:Q99836
Gene 		signaling adaptor activity
GO:0035591 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
irak4_kinase IRAK4
UniProtKB:Q9NWZ3
Gene 		protein serine/threonine kinase activity
GO:0004674 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).

Gene-review completeness (7/9 grounded genes reviewed)

4 complete review(s) · 7 with deep research · 2 missing review · 0 reviewed but lacking deep research

Gene Review Complete Deep research
CD14 P08571 ✓ ✓ ✓
IRAK4 Q9NWZ3 ✓ ✓ ✓
MYD88 Q99836 ✓ 228/229 ✓
LBP P18428 ✗ — —
IRAK1 P51617 ✗ — —
TIRAP P58753 ✓ 108/109 ✓
TLR1 Q15399 ✓ ✓ ✓
TLR2 O60603 ✓ 145/146 ✓
TLR6 Q9Y2C9 ✓ ✓ ✓

Details

Context
mammalsNCBITaxon:40674
TLR2-heterodimer lipopeptide sensingSignaling Pathwaytlr2_heterodimer_lipopeptide_signaling
toll-like receptor TLR1:TLR2 signaling pathwayGO:0038123 toll-like receptor TLR6:TLR2 signaling pathwayGO:0038124
Context
mammalsNCBITaxon:40674

Connections

Carriers hand the lipopeptide to the TLR2 heterodimer.
Ligand-bridged TIR domains recruit TIRAP and MYD88.
MYD88 death domains recruit IRAK4.
Part 1: ligand delivery (optional)
Lipid-ligand delivery by LBP and CD14Transport Steplipid_ligand_delivery

Soluble LBP and CD14 bind the acylated ligand and hand it to the receptor; neither stays in the signaling complex. Delivery enhances sensitivity but is not strictly required, so the step is optional.

Annotons

LBP lipid carrier
lbp_carrier
Participant: Gene Product: LBP
Gene Product:
LBPUniProtKB:P18428

Function

molecular carrier activityGO:0140104
Cargo: triacyl lipopeptideCHEBI:60192 diacyl lipopeptideCHEBI:46896

Locations

extracellular regionGO:0005576

Extracellular acute-phase carrier that extracts the acylated ligand and transfers it onward.

PMID:23430250
LBP and soluble CD14 each act as mobile carriers that deliver triacylated lipopeptides to TLR1-TLR2 and are not part of the final complex.
either LBP or sCD14 can drive ternary complex formation and TLR activation by acting as mobile carriers of triacylated lipopeptides or lipoproteins
PMID:23430250
The carriers dissociate from the receptor complex.
However, neither LBP nor sCD14 was physically associated with the final ternary complex
CD14 lipid carrier
cd14_carrier
Participant: Gene Product: CD14
Gene Product:
CD14UniProtKB:P08571

Function

molecular carrier activityGO:0140104
Cargo: triacyl lipopeptideCHEBI:60192 diacyl lipopeptideCHEBI:46896

Locations

plasma membraneGO:0005886 extracellular regionGO:0005576

GPI-anchored and soluble carrier; it cannot signal across the membrane, so it is a carrier, not a receptor.

PMID:23430250
LBP and soluble CD14 each act as mobile carriers that deliver triacylated lipopeptides to TLR1-TLR2 and are not part of the final complex.
either LBP or sCD14 can drive ternary complex formation and TLR activation by acting as mobile carriers of triacylated lipopeptides or lipoproteins
PMID:23430250
The carriers dissociate from the receptor complex.
However, neither LBP nor sCD14 was physically associated with the final ternary complex
Part 2: receptor recognition
TLR2 heterodimer recognitionRegulatory Steptlr2_heterodimer_recognition

Pre-formed TLR2 heterodimers at the cell surface recognise lipopeptide; the partner chain decides which acylation pattern is accepted.

Variant set: TLR2 partner chain by TLR2 partner and lipopeptide acylation (One Or More)
PMID:16880211
TLR2 heterodimers with TLR1 and TLR6 pre-exist on the cell surface.
Our data show that TLR2 forms heterodimers with TLR1 and TLR6 and that these heterodimer pre-exist and are not induced by the ligand.

Both heterodimers can be present on the same cell; which one fires depends on the lipopeptide.

TLR1-TLR2Protein Complextlr1_tlr2

TLR2 pairs with TLR1 to recognise triacylated lipopeptides. The ligand bridges the two ectodomains and brings the TIR domains together.

Annotons

TLR1-TLR2 receptor
tlr1_tlr2_receptor
Participant: Protein Complex: Toll-like receptor 1-Toll-like receptor 2 protein complex
Protein Complex:
Toll-like receptor 1-Toll-like receptor 2 protein complexGO:0035354
Active units:
TLR2
Participant: Gene Product: TLR2
Gene Product:
TLR2UniProtKB:O60603
Role: Shared lipopeptide-binding subunit; its pocket takes the two ester-linked acyl chains.
Function:
lipopeptide bindingGO:0071723
TLR1
Participant: Gene Product: TLR1
Gene Product:
TLR1UniProtKB:Q15399
Role: Takes the amide-linked third acyl chain in its hydrophobic channel, which is why this pair senses triacylated lipopeptides.
Function:
triacyl lipopeptide bindingGO:0042497

Function

pattern recognition receptor activityGO:0038187 Recognises triacylated lipopeptides. Not GO:0001875, which is defined by lipopolysaccharide binding; GO has no lipopeptide-specific immune receptor term.

Processes

toll-like receptor TLR1:TLR2 signaling pathwayGO:0038123

Locations

plasma membraneGO:0005886

Heterodimeric pattern recognition receptor at the cell surface.

PMID:17889651
The three acyl chains of a triacyl lipopeptide bridge TLR2 and TLR1.
the two ester-bound lipid chains are inserted into a pocket in TLR2, while the amide-bound lipid chain is inserted into a hydrophobic channel in TLR1
TLR2-TLR6Protein Complextlr2_tlr6

TLR2 pairs with TLR6 to recognise diacylated lipopeptides. The ligand bridges the two ectodomains and brings the TIR domains together.

Annotons

TLR2-TLR6 receptor
tlr2_tlr6_receptor
Participant: Protein Complex: Toll-like receptor 2-Toll-like receptor 6 protein complex
Protein Complex:
Toll-like receptor 2-Toll-like receptor 6 protein complexGO:0035355
Active units:
TLR2
Participant: Gene Product: TLR2
Gene Product:
TLR2UniProtKB:O60603
Role: Shared lipopeptide-binding subunit; its pocket takes the two ester-linked acyl chains.
Function:
lipopeptide bindingGO:0071723
TLR6
Participant: Gene Product: TLR6
Gene Product:
TLR6UniProtKB:Q9Y2C9
Role: Its lipid channel is blocked, so the pair accepts diacylated but not triacylated lipopeptides.
Function:
diacyl lipopeptide bindingGO:0042498

Function

pattern recognition receptor activityGO:0038187 Recognises diacylated lipopeptides. Not GO:0001875, which is defined by lipopolysaccharide binding; GO has no lipopeptide-specific immune receptor term.

Processes

toll-like receptor TLR6:TLR2 signaling pathwayGO:0038124

Locations

plasma membraneGO:0005886

Heterodimeric pattern recognition receptor at the cell surface.

PMID:19931471
A blocked lipid channel in TLR6 restricts TLR2-TLR6 to diacylated lipopeptides.
First, the lipid channel of TLR6 is blocked by two phenylalanines
Part 3: adaptor recruitment
TIRAP-MYD88 adaptor assemblyRegulatory Steptirap_myd88_adaptors

TIRAP, anchored to plasma-membrane PIP2, engages the TLR2 TIR domains and recruits MYD88.

Annotons

TIRAP sorting adaptor
tirap_adaptor
Participant: Gene Product: TIRAP
Gene Product:
TIRAPUniProtKB:P58753

Function

signaling adaptor activityGO:0035591

Processes

MyD88-dependent toll-like receptor signaling pathwayGO:0002755

Locations

plasma membraneGO:0005886

Bridges TLR2 (and TLR4) to MYD88; PIP2 binding places it at the plasma membrane.

PMID:17258210
Mal/TIRAP links MyD88 to TLR2 and TLR4.
We show that the TLR adaptor Mal is critical for linking Myeloid Differentiation primary response protein 88 (MyD88) to TLR2 and TLR4.
PMID:16751103
TIRAP is recruited to the plasma membrane by PIP2 binding.
We find that TIRAP contains a phosphatidylinositol 4,5-bisphosphate (PIP2) binding domain, which mediates TIRAP recruitment to the plasma membrane.
MYD88 adaptor
myd88_adaptor
Participant: Gene Product: MYD88
Gene Product:
MYD88UniProtKB:Q99836

Function

signaling adaptor activityGO:0035591

Processes

MyD88-dependent toll-like receptor signaling pathwayGO:0002755

Death-domain adaptor that couples the receptor complex to IRAK kinases.

PMID:16751103
TIRAP delivers MyD88 to the activated receptor.
TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction.
PMID:9430229
MyD88 recruits IRAK to the receptor complex.
MyD88 binds to both IRAK (IL-1 receptor-associated kinase) and the heterocomplex (the signaling complex) of the two receptor chains and thereby mediates the association of IRAK with the receptor.
Part 4: receptor-proximal kinase
IRAK4 kinase activationRegulatory Stepirak4_kinase_step

MYD88 recruits IRAK4, which phosphorylates IRAK1 and starts the shared IRAK-TRAF6 relay.

Annotons

IRAK4 kinase
irak4_kinase
Participant: Gene Product: IRAK4
Gene Product:
IRAK4UniProtKB:Q9NWZ3

Function

protein serine/threonine kinase activityGO:0004674
Targets: IRAK1UniProtKB:P51617

Processes

MyD88-dependent toll-like receptor signaling pathwayGO:0002755

Receptor-proximal kinase of the myddosome.

PMID:11960013
IRAK4 phosphorylates IRAK1.
Here we show that recombinant IRAK-1 is a substrate for IRAK-4, whereas IRAK-1 is not able to phosphorylate IRAK-4 in vitro