LY96 (lymphocyte antigen 96, also called MD-2) is a small secreted glycoprotein of the ML (MD-2-related lipid-recognition) family that serves as the lipopolysaccharide (LPS)-binding coreceptor of Toll-like receptor 4 (TLR4). MD-2 has a signal peptide and no transmembrane segment; it is secreted as disulfide-linked oligomers and is held at the cell surface by binding to the concave face of the TLR4 ectodomain. Its beta-cup fold encloses a deep hydrophobic pocket that accommodates the acyl chains of lipid A, the conserved endotoxic core of LPS; TLR4 by itself does not bind LPS. Agonist binding leaves one acyl chain and the phosphate groups exposed to contact a second TLR4 chain, driving assembly of an m-shaped 2:2:2 TLR4-MD-2-LPS complex that brings the TLR4 TIR domains together to recruit TIRAP/MYD88 and, after CD14-dependent endocytosis, TRAM/TRIF. Together with CD14 it forms the LPS receptor complex. The pocket also binds under-acylated lipid A analogues such as lipid IVa and eritoran, which act as species-dependent antagonists, and has been reported to bind other ligands including morphine and heme. MD-2 is thereby essential for innate immune detection of Gram-negative bacteria and for endotoxin-induced inflammatory cytokine production.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001530 lipopolysaccharide binding | IEA GO_REF:0000002 | ACCEPT | Summary: MD-2 binds the lipid A moiety of LPS in a deep hydrophobic pocket formed by its ML (MD-2-related lipid-recognition) fold. Reason: Direct lipid A binding by MD-2 is shown by crosslinking and by several crystal structures; TLR4 alone does not bind LPS. The InterPro mapping from the LY96 family (IPR039217) is correct and this is a core molecular function. Supporting Evidence: PMID:22532668 MD-2 has a unique hydrophobic cavity that directly binds to lipid A, the active center of LPS. PMID:22532668 TLR4 alone does not directly bind LPS and requires the coreceptor MD-2 PMID:19252480 LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. |
| GO:0001875 lipopolysaccharide immune receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: MD-2 is the ligand-binding subunit of the TLR4-MD-2 LPS receptor. The PAINT node PTN000390890 places this activity on the LY96 clade, with the human protein among the experimental descendants. Reason: GO:0001875 describes combining with LPS and transmitting the signal across the membrane. MD-2 performs the combining step (lipid A sits in its pocket and bridges the two TLR4-MD-2 heterodimers), while TLR4 supplies the transmembrane and TIR signalling part. The activity therefore belongs to the heterodimer, to which MD-2 contributes the recognition half. The annotation is accepted as correct for the receptor subunit that recognises the ligand; in core_functions it is recorded as a contribution to the heteromeric receptor activity, with LPS binding and coreceptor activity as the activities MD-2 has on its own. Supporting Evidence: PMID:19252480 form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:19252480 LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. PMID:22532668 TLR4 alone does not directly bind LPS and requires the coreceptor MD-2 |
| GO:0001875 lipopolysaccharide immune receptor activity | IDA PMID:19252480 The structural basis of lipopolysaccharide recognition by th... | ACCEPT | Summary: The TLR4-MD-2-LPS crystal structure shows LPS bound in the MD-2 pocket, bridging two TLR4-MD-2 heterodimers into the m-shaped signalling multimer. Reason: Direct structural evidence that MD-2 is the LPS-binding component of the heterodimeric LPS receptor. As for the IBA row, MD-2 carries out the recognition step of a receptor activity whose transmembrane transmission is performed by TLR4; accepted, with the contributes-to nuance recorded in core_functions. Supporting Evidence: PMID:19252480 form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:19252480 LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. PMID:22532668 TLR4 alone does not directly bind LPS and requires the coreceptor MD-2 |
| GO:0002221 pattern recognition receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: MD-2 is part of the TLR4 receptor that initiates this pattern recognition receptor signalling pathway. Reason: Correct but general; TLR4 signalling (GO:0034142) is the specific pathway and is annotated separately. An ARBA IEA at this level is acceptable. Supporting Evidence: PMID:10359581 Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. PMID:19252480 form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules |
| GO:0002224 toll-like receptor signaling pathway | IDA PMID:14607928 Separate functional domains of human MD-2 mediate Toll-like ... | ACCEPT | Summary: Mutagenesis of MD-2 separated its TLR4-binding surface from the surface needed for LPS responsiveness; both are needed for TLR4 signalling. Reason: MD-2 is a component of the receptor that initiates TLR4 signalling. The more specific GO:0034142 is also annotated. Supporting Evidence: PMID:14607928 MD-2 binding to TLR4 was dependent on Cys(95) and Cys(105), which might form an intramolecular disulfide bond. PMID:14607928 Thus, our data indicate that MD-2 interaction with TLR4 is necessary but not sufficient for cellular response to LPS. |
| GO:0005515 protein binding | IPI PMID:15728506 Human TLR10 is a functional receptor, expressed by B cells a... | MODIFY | Summary: MD-2 binds the extracellular domain of TLR4. This IPI comes from a TLR10 characterisation paper (abstract-only in cache); the abstract does not describe the MD-2 experiment, but the partner recorded by the curator is TLR4. Reason: The partner is TLR4 (O00206). MD-2 binding to the concave face of the TLR4 ectodomain is established by coimmunoprecipitation, mutagenesis and crystal structures, and is how MD-2 functions (it is retained at the cell surface only through TLR4). Generic protein binding is replaced by the informative term Toll-like receptor 4 binding. Proposed replacements: Toll-like receptor 4 binding Supporting Evidence: PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. PMID:14607928 MD-2 binding to TLR4 was dependent on Cys(95) and Cys(105), which might form an intramolecular disulfide bond. |
| GO:0005515 protein binding | IPI PMID:17803912 Crystal structure of the TLR4-MD-2 complex with bound endoto... | MODIFY | Summary: MD-2 binds the extracellular domain of TLR4. The TLR4-MD-2 ectodomain structure with Eritoran shows MD-2 bound to the concave surface of the TLR4 N-terminal and central domains. Reason: The partner is TLR4 (O00206). MD-2 binding to the concave face of the TLR4 ectodomain is established by coimmunoprecipitation, mutagenesis and crystal structures, and is how MD-2 functions (it is retained at the cell surface only through TLR4). Generic protein binding is replaced by the informative term Toll-like receptor 4 binding. Proposed replacements: Toll-like receptor 4 binding Supporting Evidence: PMID:17803912 MD-2 binds to the concave surface of the N-terminal and central domains. PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. PMID:14607928 MD-2 binding to TLR4 was dependent on Cys(95) and Cys(105), which might form an intramolecular disulfide bond. |
| GO:0005515 protein binding | IPI PMID:19060881 Allergenicity resulting from functional mimicry of a Toll-li... | MODIFY | Summary: MD-2 binds the extracellular domain of TLR4. In the Der p 2 study, MD-2-TLR4 coimmunoprecipitation was measured and was increased by Der p 2 coexpression. Reason: The partner is TLR4 (O00206). MD-2 binding to the concave face of the TLR4 ectodomain is established by coimmunoprecipitation, mutagenesis and crystal structures, and is how MD-2 functions (it is retained at the cell surface only through TLR4). Generic protein binding is replaced by the informative term Toll-like receptor 4 binding. Proposed replacements: Toll-like receptor 4 binding Supporting Evidence: PMID:19060881 Notably, co-expression of Der p 2 with MD-2 and TLR4 increased the co-immunoprecipitation of TLR4 with MD-2 PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. PMID:14607928 MD-2 binding to TLR4 was dependent on Cys(95) and Cys(105), which might form an intramolecular disulfide bond. |
| GO:0005515 protein binding | IPI PMID:19060881 Allergenicity resulting from functional mimicry of a Toll-li... | REMOVE | Summary: Coimmunoprecipitation of the house dust mite allergen Der p 2 (an MD-2 structural homolog) with MD-2. Reason: Generic protein binding with a xenogeneic allergen that mimics MD-2. The interaction is reported but it is not a physiological function of MD-2 and protein binding conveys no functional information. Removal does not mean the interaction is false. Supporting Evidence: PMID:19060881 Direct association of Der p 2-HA and MD-2-FLAG was shown by co-immunoprecipitation in cell lysates using antibodies to HA and FLAG |
| GO:0005515 protein binding | IPI PMID:19252480 The structural basis of lipopolysaccharide recognition by th... | MODIFY | Summary: MD-2 binds the extracellular domain of TLR4. The TLR4-MD-2-LPS structure shows the MD-2-TLR4 heterodimer interface and the LPS-induced dimer interface. Reason: The partner is TLR4 (O00206). MD-2 binding to the concave face of the TLR4 ectodomain is established by coimmunoprecipitation, mutagenesis and crystal structures, and is how MD-2 functions (it is retained at the cell surface only through TLR4). Generic protein binding is replaced by the informative term Toll-like receptor 4 binding. Proposed replacements: Toll-like receptor 4 binding Supporting Evidence: PMID:19252480 form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. PMID:14607928 MD-2 binding to TLR4 was dependent on Cys(95) and Cys(105), which might form an intramolecular disulfide bond. |
| GO:0005515 protein binding | IPI PMID:19252480 The structural basis of lipopolysaccharide recognition by th... | MODIFY | Summary: MD-2 binds the extracellular domain of TLR4. The TLR4-MD-2-LPS structure shows the MD-2-TLR4 heterodimer interface and the LPS-induced dimer interface. Reason: The partner is TLR4 (O00206). MD-2 binding to the concave face of the TLR4 ectodomain is established by coimmunoprecipitation, mutagenesis and crystal structures, and is how MD-2 functions (it is retained at the cell surface only through TLR4). Generic protein binding is replaced by the informative term Toll-like receptor 4 binding. Proposed replacements: Toll-like receptor 4 binding Supporting Evidence: PMID:19252480 form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. PMID:14607928 MD-2 binding to TLR4 was dependent on Cys(95) and Cys(105), which might form an intramolecular disulfide bond. |
| GO:0005515 protein binding | IPI PMID:20547845 A critical cysteine is required for HMGB1 binding to Toll-li... | MODIFY | Summary: MD-2 binds the extracellular domain of TLR4. HMGB1 binding was measured by SPR against the purified TLR4/MD-2 complex, which reflects the MD-2-TLR4 heterodimer. Reason: The partner is TLR4 (O00206). MD-2 binding to the concave face of the TLR4 ectodomain is established by coimmunoprecipitation, mutagenesis and crystal structures, and is how MD-2 functions (it is retained at the cell surface only through TLR4). Generic protein binding is replaced by the informative term Toll-like receptor 4 binding. Proposed replacements: Toll-like receptor 4 binding Supporting Evidence: PMID:20547845 TLR4/MD2 complexes were coated on the sensor chip, then probed with recombinant HMGB1 or B box PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. PMID:14607928 MD-2 binding to TLR4 was dependent on Cys(95) and Cys(105), which might form an intramolecular disulfide bond. |
| GO:0005515 protein binding | IPI PMID:22474354 Morphine activates neuroinflammation in a manner parallel to... | MODIFY | Summary: MD-2 binds the extracellular domain of TLR4. Morphine binding to MD-2 was studied in the context of the TLR4/MD-2 complex, and disrupting the TLR4/MD-2 association blocked morphine signalling. Reason: The partner is TLR4 (O00206). MD-2 binding to the concave face of the TLR4 ectodomain is established by coimmunoprecipitation, mutagenesis and crystal structures, and is how MD-2 functions (it is retained at the cell surface only through TLR4). Generic protein binding is replaced by the informative term Toll-like receptor 4 binding. Proposed replacements: Toll-like receptor 4 binding Supporting Evidence: PMID:22474354 We demonstrate that morphine binds to an accessory protein of Toll-like receptor 4 (TLR4), myeloid differentiation protein 2 (MD-2), thereby inducing TLR4 oligomerization and triggering proinflammation. PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. PMID:14607928 MD-2 binding to TLR4 was dependent on Cys(95) and Cys(105), which might form an intramolecular disulfide bond. |
| GO:0005515 protein binding | IPI PMID:22532668 Structural basis of species-specific endotoxin sensing by in... | MODIFY | Summary: MD-2 binds the extracellular domain of TLR4. The mouse TLR4/MD-2 structures with LPS and lipid IVa show MD-2 bound to the TLR4 ectodomain. Reason: The partner is TLR4 (O00206). MD-2 binding to the concave face of the TLR4 ectodomain is established by coimmunoprecipitation, mutagenesis and crystal structures, and is how MD-2 functions (it is retained at the cell surface only through TLR4). Generic protein binding is replaced by the informative term Toll-like receptor 4 binding. Proposed replacements: Toll-like receptor 4 binding Supporting Evidence: PMID:22532668 MD-2 is associated with the extracellular domain of TLR4 and is indispensable for LPS recognition PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. PMID:14607928 MD-2 binding to TLR4 was dependent on Cys(95) and Cys(105), which might form an intramolecular disulfide bond. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interaction with LCN2 from the HuRI yeast two-hybrid screen. Reason: Generic protein binding from a proteome-scale yeast two-hybrid screen, with no functional follow-up linking this partner to MD-2 function. Uninformative; removal does not mean the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interaction with MESD from the HuRI yeast two-hybrid screen. Reason: Generic protein binding from a proteome-scale yeast two-hybrid screen, with no functional follow-up linking this partner to MD-2 function. Uninformative; removal does not mean the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005576 extracellular region | EXP PMID:11593030 Secreted MD-2 is a large polymeric protein that efficiently ... | ACCEPT | Summary: MD-2 is a secreted glycoprotein without a transmembrane domain; soluble MD-2 is active and confers LPS responsiveness on TLR4-expressing cells. Reason: Direct experimental evidence that MD-2 is secreted as disulfide-linked oligomers. Core location for the soluble pool. Supporting Evidence: PMID:11593030 MD-2 contains a leader sequence but lacks a transmembrane domain, and we asked whether it is secreted into the medium as an active protein. PMID:11593030 We conclude that normal and transfected cells secrete a soluble form of MD-2 that binds with high affinity to TLR4 and that could play a role in regulating responses to LPS and other pathogen-derived substances in vivo. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: MD-2 is a secreted glycoprotein without a transmembrane domain; soluble MD-2 is active and confers LPS responsiveness on TLR4-expressing cells. Reason: Consistent with the signal peptide, absence of transmembrane segment and experimental secretion data. Supporting Evidence: PMID:11593030 MD-2 contains a leader sequence but lacks a transmembrane domain, and we asked whether it is secreted into the medium as an active protein. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9707594 | ACCEPT | Summary: Reactome places secreted LY96 in the extracellular region in the heme signalling reactions, where heme binds soluble MD-2. Reason: Secreted MD-2 is experimentally established; the location is correct. Supporting Evidence: Reactome:R-HSA-9707594 Hemes can bind to secreted LY96 at a different site than LPS, resulting in comparable TLR4 activation PMID:11593030 MD-2 contains a leader sequence but lacks a transmembrane domain, and we asked whether it is secreted into the medium as an active protein. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9707659 | ACCEPT | Summary: Reactome places secreted LY96 in the extracellular region in the heme signalling reactions, where heme binds soluble MD-2. Reason: Secreted MD-2 is experimentally established; the location is correct. Supporting Evidence: Reactome:R-HSA-9707594 Hemes can bind to secreted LY96 at a different site than LPS, resulting in comparable TLR4 activation PMID:11593030 MD-2 contains a leader sequence but lacks a transmembrane domain, and we asked whether it is secreted into the medium as an active protein. |
| GO:0005886 plasma membrane | IDA PMID:11274165 Lipopolysaccharide is in close proximity to each of the prot... | ACCEPT | Summary: LPS was crosslinked to MD-2 in the CD14-TLR4-MD-2 membrane receptor complex on transfected cells. Reason: MD-2 has no transmembrane segment but is held at the outer face of the plasma membrane by TLR4; plasma membrane (as part of the receptor complex) is its functional location. Cell surface would be the more literal term, but plasma membrane is conventional for peripheral receptor subunits. Supporting Evidence: PMID:11274165 Here we show that LPS is cross-linked specifically to TLR4 and MD-2 only when co-expressed with CD14. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | NAS PMID:33576548 Structural and functional understanding of the toll-like rec... | ACCEPT | Summary: Review of TLR structures describing TLR4-MD-2 as the cell-surface LPS receptor. Reason: Correct, corroborated by primary data showing MD-2 anchored at the cell surface by TLR4. Supporting Evidence: PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS PMID:10359581 MD-2, a molecule that confers lipopolysaccharide responsiven... | ACCEPT | Summary: MD-2 appears on the cell surface only when coexpressed with TLR4. Reason: Primary evidence for surface localisation via TLR4 anchoring. Supporting Evidence: PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166041 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166072 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166082 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166091 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166119 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166284 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166286 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166362 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-166363 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2201293 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2201316 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2201322 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2262775 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2262777 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2559414 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5432825 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5432849 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5432852 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602353 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602383 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5602606 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6805943 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8870678 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937022 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937059 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-937079 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9836227 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9921458 | ACCEPT | Summary: Reactome places TLR4:LY96 complexes at the plasma membrane in the LPS recognition and TLR4 signalling reactions. Reason: MD-2 is held at the outer face of the plasma membrane by TLR4, where it binds LPS. Correct location via the receptor complex. Supporting Evidence: Reactome:R-HSA-166041 LPS binds to the hydrophobic pocket of LY96 and directly mediates the dimerization of the two TLR4:LY96 complexes in a symmetrical manner. PMID:10359581 These results are consistent with membrane anchoring of MD-2 via physical association with TLR4. |
| GO:0006968 cellular defense response | TAS PMID:10359581 MD-2, a molecule that confers lipopolysaccharide responsiven... | MODIFY | Summary: Traceable author statement from the MD-2 discovery paper about host defence against pathogens. Reason: Cellular defense response ("a defense response that is mediated by cells") is vague for a secreted/cell-surface receptor subunit. What MD-2 does is recognise LPS as part of the TLR4 receptor to initiate the innate immune response; innate immune response is the appropriate term. Proposed replacements: innate immune response Supporting Evidence: PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. |
| GO:0007166 plasma membrane receptor signaling pathway | TAS PMID:10359581 MD-2, a molecule that confers lipopolysaccharide responsiven... | MODIFY | Summary: MD-2 is part of the TLR4 cell-surface receptor that signals in response to LPS. Reason: Correct but too general; the specific pathway is toll-like receptor 4 signaling pathway. Proposed replacements: toll-like receptor 4 signaling pathway Supporting Evidence: PMID:10359581 Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-166168 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-166175 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-166245 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-166271 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-168915 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-168921 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2201293 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2201338 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2213017 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2559568 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2562541 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2562564 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-2569057 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-450358 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-5362486 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-5362500 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-936947 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-936951 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-936952 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-936985 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-937029 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-937075 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9823904 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9823906 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9823910 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9823932 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9823934 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9823939 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0010008 endosome membrane | TAS Reactome:R-HSA-9824882 | KEEP AS NON CORE | Summary: Reactome places activated TLR4:LY96:LPS:CD14 complexes on the endosome membrane after LPS-induced endocytosis, where TRAM/TRIF signalling is initiated. Reason: MD-2 travels with TLR4 into endosomes, where the TRAM/TRIF branch of TLR4 signalling is triggered. MD-2 is on the lumenal face as part of the TLR4 complex, not an integral membrane protein. Plausible as a signalling compartment, but the primary site of LPS recognition is the cell surface. Supporting Evidence: Reactome:R-HSA-2201293 Upon LPS stimulation TLR4 is internalized into endosomes where the signaling pathway is triggered through the adaptors TRAM and TRIF leading to the activation of IRF3 and induction of IFN-beta |
| GO:0015026 coreceptor activity | TAS PMID:10359581 MD-2, a molecule that confers lipopolysaccharide responsiven... | ACCEPT | Summary: MD-2 is the coreceptor of TLR4: it binds the ligand (lipid A) and cooperates with the transmembrane receptor TLR4 to initiate signalling. Reason: Coreceptor activity ("combining with an extracellular messenger, and in cooperation with a nearby primary receptor, initiating a change in cell activity") describes MD-2 precisely: TLR4 alone does not bind LPS and requires the coreceptor MD-2, and MD-2 has no transmembrane or signalling domain of its own. This is the best single term for what MD-2 does independently. Supporting Evidence: PMID:22532668 TLR4 alone does not directly bind LPS and requires the coreceptor MD-2 PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. PMID:22532668 MD-2 has a unique hydrophobic cavity that directly binds to lipid A, the active center of LPS. |
| GO:0031663 lipopolysaccharide-mediated signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: MD-2 is part of the TLR4-MD-2 receptor that initiates LPS-mediated signalling. Reason: Correct; MD-2 is required for and participates in the receptor step of LPS signalling. Supporting Evidence: PMID:10359581 Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. PMID:19252480 LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. |
| GO:0031666 positive regulation of lipopolysaccharide-mediated signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: MD-2 enhances TLR4-dependent signalling and soluble MD-2 confers LPS responsiveness on TLR4-expressing cells. Reason: MD-2 is a component of the receptor, so strictly it is part of LPS signalling rather than a regulator of it. However, soluble MD-2 availability does set the LPS responsiveness of TLR4-bearing cells, which gives the regulatory reading some basis. MD-2 also raises TLR4 surface expression, a second route by which MD-2 levels can tune LPS responsiveness. Not wrong, but secondary to the receptor role. Supporting Evidence: PMID:11593030 We conclude that normal and transfected cells secrete a soluble form of MD-2 that binds with high affinity to TLR4 and that could play a role in regulating responses to LPS and other pathogen-derived substances in vivo. PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. PMID:11593030 MD-2 binds to the extracellular domains of both TLRs 2 and 4 and causes their surface expression levels to increase file:human/LY96/LY96-deep-research-falcon.md MD-2 is processed through the secretory pathway and supports TLR4 maturation, glycosylation, and surface delivery. |
| GO:0032496 response to lipopolysaccharide | IDA PMID:12594207 Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Stap... | ACCEPT | Summary: The paper tested MD-2 in LPS and lipoteichoic acid responses; MD-2 was not required for LTA responses, while LPS was a control stimulus. Reason: Abstract-only in cache; the experimental design uses TLR4/MD-2 as the LPS-responsive system. Response to LPS is correct for MD-2 and the curator read the full text. The notable finding (MD-2 is not involved in LTA sensing via TLR2) is consistent with MD-2 being LPS-specific. Supporting Evidence: PMID:12594207 Additional transfection with MD-2 did not affect stimulation of these cells by LTA. |
| GO:0032496 response to lipopolysaccharide | IDA PMID:14607928 Separate functional domains of human MD-2 mediate Toll-like ... | ACCEPT | Summary: MD-2 mutants in the putative LPS-binding region abolish LPS responsiveness without affecting TLR4 binding. Reason: Direct mutagenesis evidence for participation in the LPS response. Supporting Evidence: PMID:14607928 Thus, our data indicate that MD-2 interaction with TLR4 is necessary but not sufficient for cellular response to LPS. PMID:10359581 Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. |
| GO:0032497 detection of lipopolysaccharide | IBA GO_REF:0000033 | ACCEPT | Summary: MD-2 performs the detection step itself: lipid A is bound in the MD-2 pocket, and this ligand binding induces TLR4-MD-2 dimerisation that converts the stimulus into a signal. Reason: Core process. The IBA node PTN000390890 covers the LY96 clade and the human protein has direct experimental evidence. Supporting Evidence: PMID:22532668 TLR4 alone does not directly bind LPS and requires the coreceptor MD-2 PMID:19252480 LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. |
| GO:0032497 detection of lipopolysaccharide | IDA PMID:19252480 The structural basis of lipopolysaccharide recognition by th... | ACCEPT | Summary: MD-2 performs the detection step itself: lipid A is bound in the MD-2 pocket, and this ligand binding induces TLR4-MD-2 dimerisation that converts the stimulus into a signal. Reason: Core process, supported by the TLR4-MD-2-LPS crystal structure. Supporting Evidence: PMID:19252480 LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. PMID:19252480 form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules |
| GO:0032760 positive regulation of tumor necrosis factor production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TNF production is a downstream output of TLR4-MD-2 signalling; the annotation is transferred from mouse Ly96. Reason: MD-2 is needed for LPS-induced cytokine production but acts at the receptor step; TNF production is a distal consequence rather than a function MD-2 executes. Supporting Evidence: PMID:10359581 Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. |
| GO:0032760 positive regulation of tumor necrosis factor production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: TNF production is a downstream output of TLR4-MD-2 signalling; the annotation is transferred from mouse Ly96. Reason: Same reasoning as the IEA row; downstream consequence of receptor function. Supporting Evidence: PMID:10359581 Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. |
| GO:0034142 toll-like receptor 4 signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: MD-2 is a component of the TLR4-MD-2 receptor that initiates TLR4 signalling on LPS binding. Reason: Core process; MD-2 is the ligand-binding subunit of the receptor that initiates the pathway. Ligand specificity (LPS/lipid A) is conserved between human and mouse MD-2, so the transfer is sound. Supporting Evidence: PMID:10359581 Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. PMID:19252480 LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. |
| GO:0034142 toll-like receptor 4 signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: MD-2 is a component of the TLR4-MD-2 receptor that initiates TLR4 signalling on LPS binding. Reason: Core process; MD-2 is the ligand-binding subunit of the receptor that initiates the pathway. Ligand specificity (LPS/lipid A) is conserved between human and mouse MD-2, so the transfer is sound. Supporting Evidence: PMID:10359581 Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. PMID:19252480 LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. |
| GO:0034142 toll-like receptor 4 signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: MD-2 is a component of the TLR4-MD-2 receptor that initiates TLR4 signalling on LPS binding. Reason: Core process; MD-2 is the ligand-binding subunit of the receptor that initiates the pathway. Ligand specificity (LPS/lipid A) is conserved between human and mouse MD-2, so the transfer is sound. Supporting Evidence: PMID:10359581 Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. PMID:19252480 LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. |
| GO:0035662 Toll-like receptor 4 binding | IEA GO_REF:0000002 | ACCEPT | Summary: MD-2 binds the extracellular domain of TLR4 through a surface centred on the Cys95-Cys105 region. Reason: Core molecular function, supported by mutagenesis and structures. Supporting Evidence: PMID:14607928 MD-2 binding to TLR4 was dependent on Cys(95) and Cys(105), which might form an intramolecular disulfide bond. PMID:17803912 MD-2 binds to the concave surface of the N-terminal and central domains. PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. |
| GO:0043235 signaling receptor complex | IPI PMID:19252480 The structural basis of lipopolysaccharide recognition by th... | ACCEPT | Summary: ComplexPortal records MD-2 in the TLR4-LY96 signalling receptor complex, supported by the TLR4-MD-2-LPS structure. Reason: Correct. The more specific lipopolysaccharide receptor complex (GO:0046696) is defined to include CD14, which the crystallised TLR4-MD-2-LPS complex lacks, so the general term is appropriate here. Supporting Evidence: PMID:19252480 form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:19252480 LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. |
| GO:0045087 innate immune response | IEA GO_REF:0000002 | ACCEPT | Summary: MD-2 acts in innate immunity as the LPS-binding coreceptor of TLR4. Reason: Correct general process. Supporting Evidence: PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. PMID:22532668 TLR4 alone does not directly bind LPS and requires the coreceptor MD-2 |
| GO:0045087 innate immune response | NAS PMID:33576548 Structural and functional understanding of the toll-like rec... | ACCEPT | Summary: MD-2 acts in innate immunity as the LPS-binding coreceptor of TLR4. Reason: Correct general process. Supporting Evidence: PMID:22532668 TLR4 alone does not directly bind LPS and requires the coreceptor MD-2 PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. |
| GO:0046696 lipopolysaccharide receptor complex | IBA GO_REF:0000033 | ACCEPT | Summary: MD-2 is one of the three proteins (CD14, TLR4, MD-2) of the LPS receptor complex, and LPS is crosslinked to each of them. Reason: Core cellular component, matching the GO:0046696 definition that names MD-2 explicitly. Supporting Evidence: PMID:11274165 Thus, LPS binds directly to each of the members of the tripartite LPS receptor complex. PMID:11274165 Here we show that LPS is cross-linked specifically to TLR4 and MD-2 only when co-expressed with CD14. |
| GO:0046696 lipopolysaccharide receptor complex | IDA PMID:11274165 Lipopolysaccharide is in close proximity to each of the prot... | ACCEPT | Summary: MD-2 is one of the three proteins (CD14, TLR4, MD-2) of the LPS receptor complex, and LPS is crosslinked to each of them. Reason: Core cellular component, matching the GO:0046696 definition that names MD-2 explicitly. Supporting Evidence: PMID:11274165 Thus, LPS binds directly to each of the members of the tripartite LPS receptor complex. PMID:11274165 Here we show that LPS is cross-linked specifically to TLR4 and MD-2 only when co-expressed with CD14. |
| GO:0046696 lipopolysaccharide receptor complex | IDA PMID:19252480 The structural basis of lipopolysaccharide recognition by th... | ACCEPT | Summary: MD-2 is one of the three proteins (CD14, TLR4, MD-2) of the LPS receptor complex, and LPS is crosslinked to each of them. Reason: Core cellular component, matching the GO:0046696 definition that names MD-2 explicitly. Supporting Evidence: PMID:19252480 form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules PMID:11274165 Thus, LPS binds directly to each of the members of the tripartite LPS receptor complex. |
| GO:0046696 lipopolysaccharide receptor complex | IEA GO_REF:0000120 | ACCEPT | Summary: MD-2 is one of the three proteins (CD14, TLR4, MD-2) of the LPS receptor complex, and LPS is crosslinked to each of them. Reason: Core cellular component, matching the GO:0046696 definition that names MD-2 explicitly. Supporting Evidence: PMID:11274165 Thus, LPS binds directly to each of the members of the tripartite LPS receptor complex. PMID:11274165 Here we show that LPS is cross-linked specifically to TLR4 and MD-2 only when co-expressed with CD14. |
| GO:0071222 cellular response to lipopolysaccharide | IBA GO_REF:0000033 | ACCEPT | Summary: MD-2 is required for cellular responses to LPS as the LPS-binding component of the TLR4 receptor. Reason: Correct; MD-2 confers LPS responsiveness on TLR4-expressing cells. Supporting Evidence: PMID:10359581 Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. |
| GO:0071222 cellular response to lipopolysaccharide | IEA GO_REF:0000107 | ACCEPT | Summary: MD-2 is required for cellular responses to LPS as the LPS-binding component of the TLR4 receptor. Reason: Correct; MD-2 confers LPS responsiveness on TLR4-expressing cells. Supporting Evidence: PMID:10359581 Here, we report that a novel molecule, MD-2, is requisite for LPS signaling of TLR4. PMID:10359581 MD-2 is physically associated with TLR4 on the cell surface and confers responsiveness to LPS. |
Loading supporting content…
Download this section (compressed HTML)Q: Should MD-2 carry GO:0001875 lipopolysaccharide immune receptor activity with the enables relation, or should it be contributes_to? The term includes transmitting the signal across the membrane, which only TLR4 can do, while the ligand-binding step is performed by MD-2 alone. A GO-wide convention for two-chain receptors where one chain binds and the other transduces would settle how TLR4 and MD-2 should each be annotated.
Q: Does soluble MD-2 have physiological roles independent of TLR4 at the cell surface, for example conferring LPS responsiveness on MD-2-negative epithelial cells in vivo, or acting as an LPS-sequestering decoy? This bears on the IBA positive regulation of LPS-mediated signaling annotation.
Q: Are the reported non-LPS ligands of the MD-2 pocket (morphine, heme, oxidised phospholipids, HMGB1, and angiotensin II as cited in cardiovascular-remodelling studies) physiologically significant agonists, and do they share the lipid A binding mode? If so, is lipopolysaccharide binding too narrow a description of the MD-2 activity?
Q: Does MD-2 contribute to TLR2 responses in vivo, as reported for some Gram-positive and Gram-negative cell wall components, given that LTA responses via TLR2 were independent of MD-2?
Q: Beyond ligand recognition, MD-2 is reported to bind the TLR4 (and TLR2) ectodomain in the secretory pathway and to increase TLR4 surface expression and maturation. Is this chaperone-like role on TLR4 biogenesis strong enough, and distinct enough from the coreceptor function, to warrant its own GO representation, or is it adequately covered by Toll-like receptor 4 binding?
Experiment: Quantify the fraction of cellular MD-2 that is TLR4-bound versus free soluble oligomers in primary human monocytes and airway epithelium, and test whether soluble MD-2 from serum confers LPS responses on MD-2-deficient epithelial cells ex vivo.
Hypothesis: Soluble MD-2 is a physiological regulator of tissue LPS responsiveness, not only a secreted surplus.
Type: biochemical fractionation and ex vivo reconstitution
Experiment: Measure direct binding of morphine, heme and oxidised phospholipids to purified human MD-2 by ITC or native mass spectrometry, with pocket-lining mutants (e.g. F126 loop) and lipid IVa competition as controls, and solve co-crystal structures.
Hypothesis: Non-LPS ligands occupy the same hydrophobic pocket and trigger TLR4-MD-2 dimerisation by a lipid A-like mechanism.
Type: biophysical binding and structural analysis
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)