TLR4_HUMAN » Toll-like receptor 4

TLR4_HUMAN » Toll-like receptor 4
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
TLR4_HUMAN » Toll-like receptor 4 » hToll;
Hydrophobic Thickness 37.2 ± 2.2 Å
Tilt Angle 0 ± 2°
ΔGtransfer -35.4 kcal/mol
ΔGfold -16.5 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, Reactome, HMDB
Topology Out
TM Segments 633-659 (631-662)
Pathways

Amoebiasis (KEGG)

Chagas disease (KEGG)

Hepatitis B (KEGG)

HIF-1 signaling pathway (KEGG)

Immune System (Reactome)

Influenza A (KEGG)

Legionellosis (KEGG)

Leishmaniasis (KEGG)

Malaria (KEGG)

Measles (KEGG)

NF-kappa B signaling pathway (KEGG)

Pathogenic Escherichia coli infection (KEGG)

Pertussis (KEGG)

Phagosome (KEGG)

PI3K-Akt signaling pathway (KEGG)

Proteoglycans in cancer (KEGG)

Rheumatoid arthritis (KEGG)

Salmonella infection (KEGG)

Toll-like receptor signaling pathway (KEGG)

Toxoplasmosis (KEGG)

Tuberculosis (KEGG)

PDB 2z62 (27-228), 2z65 (27-228), 3ul8 (27-228), 2z63 (27-527), 3ul7 (28-226), 3ul9 (28-228), 2z66 (381-627), 4g8a (A/B=23-629), 3fxi (A/B=27-631), 3ula (A/C=27-228)
OPM 2z64 (MOUSE), 4g8a
Complexes none
Interactions

EGFR, Complex: TLR4:EGFR, PubMed

SIGIR, Complex: SIGIR:TRAF6:MYD88:IRAK1:TLR4, PubMed

SIGIR, Complex: TLR4:SIGIR, PubMed

TLR1, Complex: TLR1:TLR4, PubMed

TLR5, Complex: TLR5:TLR4, PubMed

TLR6, Complex: TLR6:TLR4:CD36, PubMed

TMED7, Complex: TLR4:TMED7, PubMed

TNFL9, Complex: TNFL9:TLR4

TREM1, Complex: TREM1:TLR4, PubMed

Domains

AA: 55-114, PDBID: 2Z62, Subunit A, Seq Identity:100%, Leucine rich repeat

AA: 78-138, PDBID: 2Z62, Subunit A, Seq Identity:100%, Leucine rich repeat

AA: 126-187, PDBID: 2Z62, Subunit A, Seq Identity:100%, Leucine rich repeat

AA: 150-207, PDBID: 2Z62, Subunit A, Seq Identity:100%, Leucine rich repeat

AA: 397-413, PDBID: 2Z63, Subunit A, Seq Identity:100%, Leucine Rich repeat

AA: 447-508, PDBID: 2Z63, Subunit A, Seq Identity:100%, Leucine rich repeat

AA: 485-532, PDBID: 2Z63, Subunit A, Seq Identity:100%, Leucine rich repeat

AA: 496-556, PDBID: 2Z63, Subunit A, Seq Identity:100%, Leucine rich repeat

AA: 674-839, PDBID: 1FYW, Subunit A, Seq Identity:42%, TIR domain

UniProt annotation for TLR4_HUMAN » Toll-like receptor 4
FUNCTION: Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Also involved in LPS- independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species- specific. In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion.

SUBUNIT: Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4. Binding to bacterial LPS leads to homodimerization. Interacts with LY96 via the extracellular domain. Interacts with MYD88 and TIRAP via their respective TIR domains. Interacts with NOX4. Interacts with CNPY3 (By similarity). Interacts with HSP90B1. The interaction with both CNPY3 and HSP90B1 is required for proper folding in the endoplasmic reticulum. Interacts with MLK4; this interaction leads to negative regulation of TLR4 signaling. Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR6. The trimeric complex is internalized and triggers inflammatory response. LYN kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation.

TISSUE SPECIFICITY: Highly expressed in placenta, spleen and peripheral blood leukocytes. Detected in monocytes, macrophages, dendritic cells and several types of T-cells.

DOMAIN: The TIR domain mediates interaction with NOX4.

DISEASE: Macular degeneration, age-related, 10 (ARMD10) OMIM: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.

MISCELLANEOUS: His-456 and His-458 are found in TLR4 of human and several other primate species and may be responsible for inflammatory responses triggered by nickel (Ni(2+)). Ni(2+) may cross-link the two receptor monomers through specific histidines, triggering the formation of a dimer that structurally resembles that induced by LPS. This process may be the basis for the development of contact allergy to Ni(2+). A mouse model of contact allergy to Ni(2+) in which TLR4-deficient mice expresses human TLR4 has been proposed.

UniProt features for TLR4_HUMAN » Toll-like receptor 4
SIGNAL 1 23
CHAIN 24 839 Toll-like receptor 4.
REPEAT 55 76 LRR 1.
REPEAT 79 100 LRR 2.
REPEAT 103 124 LRR 3.
REPEAT 127 148 LRR 4.
REPEAT 151 172 LRR 5.
REPEAT 176 199 LRR 6.
REPEAT 205 225 LRR 7.
REPEAT 227 247 LRR 8.
REPEAT 331 351 LRR 9.
REPEAT 352 373 LRR 10.
REPEAT 374 394 LRR 11.
REPEAT 400 422 LRR 12.
REPEAT 423 444 LRR 13.
REPEAT 448 456 LRR 14.
REPEAT 472 495 LRR 15.
REPEAT 497 518 LRR 16.
REPEAT 521 542 LRR 17.
REPEAT 545 565 LRR 18.
DOMAIN 579 629 LRRCT.
DOMAIN 672 818 TIR.
DISULFID 29 40
DISULFID 281 306
DISULFID 390 391
DISULFID 583 609
DISULFID 585 627
Amino Acid Sequence for TLR4_HUMAN » Toll-like receptor 4
MMSASRLAGT LIPAMAFLSC VRPESWEPCV EVVPNITYQC MELNFYKIPD NLPFSTKNLD LSFNPLRHLG SYSFFSFPEL QVLDLSRCEI QTIEDGAYQS LSHLSTLILT GNPIQSLALG AFSGLSSLQK LVAVETNLAS LENFPIGHLK TLKELNVAHN LIQSFKLPEY FSNLTNLEHL DLSSNKIQSI YCTDLRVLHQ MPLLNLSLDL SLNPMNFIQP GAFKEIRLHK LTLRNNFDSL NVMKTCIQGL AGLEVHRLVL GEFRNEGNLE KFDKSALEGL CNLTIEEFRL AYLDYYLDDI IDLFNCLTNV SSFSLVSVTI ERVKDFSYNF GWQHLELVNC KFGQFPTLKL KSLKRLTFTS NKGGNAFSEV DLPSLEFLDL SRNGLSFKGC CSQSDFGTTS LKYLDLSFNG VITMSSNFLG LEQLEHLDFQ HSNLKQMSEF SVFLSLRNLI YLDISHTHTR VAFNGIFNGL SSLEVLKMAG NSFQENFLPD IFTELRNLTF LDLSQCQLEQ LSPTAFNSLS SLQVLNMSHN NFFSLDTFPY KCLNSLQVLD YSLNHIMTSK KQELQHFPSS LAFLNLTQND FACTCEHQSF LQWIKDQRQL LVEVERMECA TPSDKQGMPV LSLNITCQMN KTIIGVSVLS VLVVSVVAVL VYKFYFHLML LAGCIKYGRG ENIYDAFVIY SSQDEDWVRN ELVKNLEEGV PPFQLCLHYR DFIPGVAIAA NIIHEGFHKS RKVIVVVSQH FIQSRWCIFE YEIAQTWQFL SSRAGIIFIV LQKVEKTLLR QQVELYRLLS RNTYLEWEDS VLGRHIFWRR LRKALLDGKS WNPEGTVGTG CNWQEATSI