O00206 (TLR4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Toll-like receptor 4

Alternative name(s):
hToll
CD_antigen=CD284

Gene names

Name:

TLR4

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	839 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

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 Ni2+. These responses require non-conserved histidines and are, therefore, species-specific. Ref.18
Subunit structure	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. Ref.15 Ref.16 Ref.19
Subcellular location	Membrane; Single-pass type I membrane protein.
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.
Post-translational modification	N-glycosylated. Glycosylation of Asn-526 and Asn-575 seems to be necessary for the expression of TLR4 on the cell surface and the LPS-response. Likewise, mutants lacking two or more of the other N-glycosylation sites were deficient in interaction with LPS. Ref.14 Ref.20 Ref.21 Ref.22
Polymorphism	Allele TLR4*B (Gly-299, Ile-399) is associated with a blunted response to inhaled LPS.
Involvement in disease	Age-related macular degeneration 10 (ARMD10) [MIM:611488]: 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 (Ni2+). Ni2+ 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 Ni2+. A mouse model of contact allergy to Ni2+ in which TLR4-deficient mice expresses human TLR4 has been proposed.
Sequence similarities	Belongs to the Toll-like receptor family. Contains 18 LRR (leucine-rich) repeats. Contains 1 LRRCT domain. Contains 1 TIR domain.

Ontologies

Keywords
Biological process	Immunity Inflammatory response Innate immunity
Cellular component	Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Age-related macular degeneration
Domain	Leucine-rich repeat Repeat Signal Transmembrane Transmembrane helix
Molecular function	Receptor
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	I-kappaB phosphorylation Inferred from direct assay PubMed 19740627. Source: BHF-UCL MyD88-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome T-helper 1 type immune response Non-traceable author statement PubMed 11970998. Source: UniProtKB TRIF-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome Toll signaling pathway Traceable author statement. Source: Reactome activation of MAPK activity Inferred from sequence or structural similarity. Source: BHF-UCL cellular response to lipoteichoic acid Inferred from electronic annotation. Source: Compara cellular response to mechanical stimulus Inferred from expression pattern PubMed 19593445. Source: UniProtKB defense response to Gram-negative bacterium Inferred by curator PubMed 16514062. Source: BHF-UCL detection of fungus Non-traceable author statement PubMed 11254600. Source: UniProtKB detection of lipopolysaccharide Inferred from direct assay Ref.21. Source: UniProtKB innate immune response Traceable author statement PubMed 15356140. Source: BHF-UCL interferon-gamma production Inferred from electronic annotation. Source: Compara intestinal epithelial structure maintenance Inferred from sequence or structural similarity. Source: BHF-UCL macrophage activation Inferred from mutant phenotype Ref.4. Source: UniProtKB negative regulation of ERK1 and ERK2 cascade Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of interferon-gamma production Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of interleukin-17 production Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of interleukin-23 production Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of interleukin-6 production Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of osteoclast differentiation Non-traceable author statement PubMed 12133979. Source: UniProtKB negative regulation of tumor necrosis factor production Inferred from sequence or structural similarity. Source: BHF-UCL nitric oxide production involved in inflammatory response Inferred from electronic annotation. Source: Compara positive regulation of B cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of ERK1 and ERK2 cascade Inferred from electronic annotation. Source: Compara positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from electronic annotation. Source: Compara positive regulation of JNK cascade Inferred from electronic annotation. Source: Compara positive regulation of MHC class II biosynthetic process Inferred from electronic annotation. Source: Compara positive regulation of NF-kappaB import into nucleus Inferred from direct assay PubMed 19740627. Source: BHF-UCL positive regulation of NF-kappaB transcription factor activity Inferred from direct assay PubMed 12594207. Source: MGI positive regulation of chemokine production Inferred from direct assay PubMed 19740627. Source: BHF-UCL positive regulation of inflammatory response Inferred by curator PubMed 19740627. Source: BHF-UCL positive regulation of interferon-alpha production Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of interferon-beta biosynthetic process Inferred from electronic annotation. Source: Compara positive regulation of interferon-beta production Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of interferon-gamma production Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of interleukin-1 production Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of interleukin-10 production Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of interleukin-12 biosynthetic process Inferred from direct assay PubMed 15027902. Source: UniProtKB positive regulation of interleukin-12 production Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of interleukin-6 production Inferred from direct assay PubMed 19740627. Source: BHF-UCL positive regulation of interleukin-8 biosynthetic process Inferred from direct assay PubMed 17951129. Source: UniProtKB positive regulation of interleukin-8 production Inferred from direct assay PubMed 19740627. Source: BHF-UCL positive regulation of macrophage cytokine production Inferred from electronic annotation. Source: Compara positive regulation of nitric oxide biosynthetic process Inferred from electronic annotation. Source: Compara positive regulation of nitric-oxide synthase biosynthetic process Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of platelet activation Inferred from sequence or structural similarity PubMed 16514062. Source: BHF-UCL positive regulation of transcription from RNA polymerase II promoter Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of tumor necrosis factor biosynthetic process Inferred from direct assay PubMed 17951129. Source: UniProtKB positive regulation of tumor necrosis factor production Inferred from sequence or structural similarity. Source: BHF-UCL regulation of cytokine secretion Inferred from electronic annotation. Source: InterPro toll-like receptor 1 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 3 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 4 signaling pathway Traceable author statement. Source: Reactome
Cellular_component	endosome membrane Traceable author statement. Source: Reactome external side of plasma membrane Inferred from direct assay PubMed 16514062. Source: BHF-UCL integral to plasma membrane Inferred from direct assay PubMed 15027902. Source: UniProtKB lipopolysaccharide receptor complex Inferred from direct assay Ref.21. Source: UniProtKB perinuclear region of cytoplasm Inferred from direct assay PubMed 15027902. Source: UniProtKB
Molecular_function	lipopolysaccharide binding Non-traceable author statement Ref.4. Source: UniProtKB lipopolysaccharide receptor activity Inferred from direct assay Ref.21. Source: UniProtKB transmembrane signaling receptor activity Non-traceable author statement PubMed 11970998. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
	O76552	3	EBI-528701,EBI-3870694	From a different organism.
LY96	Q9Y6Y9	3	EBI-528701,EBI-1539247
TIRAP	P58753	2	EBI-528701,EBI-528644

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O00206-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: O00206-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-40: Missing.

Isoform 3 (identifier: O00206-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-200: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 23

23

Ref.12

Chain

24 – 839

816

Toll-like receptor 4

PRO_0000034722

Regions

Topological domain

24 – 631

608

Extracellular Potential

Transmembrane

632 – 652

21

Helical; Potential

Topological domain

653 – 839

187

Cytoplasmic Potential

Repeat

55 – 76

22

LRR 1

Repeat

79 – 100

22

LRR 2

Repeat

103 – 124

22

LRR 3

Repeat

127 – 148

22

LRR 4

Repeat

151 – 172

22

LRR 5

Repeat

176 – 199

24

LRR 6

Repeat

205 – 225

21

LRR 7

Repeat

227 – 247

21

LRR 8

Repeat

331 – 351

21

LRR 9

Repeat

352 – 373

22

LRR 10

Repeat

374 – 394

21

LRR 11

Repeat

400 – 422

23

LRR 12

Repeat

423 – 444

22

LRR 13

Repeat

448 – 456

9

LRR 14

Repeat

472 – 495

24

LRR 15

Repeat

497 – 518

22

LRR 16

Repeat

521 – 542

22

LRR 17

Repeat

545 – 565

21

LRR 18

Domain

579 – 629

51

LRRCT

Domain

672 – 818

147

TIR

Amino acid modifications

Glycosylation

35

1

N-linked (GlcNAc...) Ref.14 Ref.20 Ref.22

Glycosylation

173

1

N-linked (GlcNAc...) Ref.14 Ref.20 Ref.21 Ref.22

Glycosylation

205

1

N-linked (GlcNAc...) Ref.14 Ref.20 Ref.21

Glycosylation

282

1

N-linked (GlcNAc...) Ref.14

Glycosylation

309

1

N-linked (GlcNAc...) Ref.14

Glycosylation

497

1

N-linked (GlcNAc...) Ref.14 Ref.21

Glycosylation

526

1

N-linked (GlcNAc...) Ref.14 Ref.21

Glycosylation

575

1

N-linked (GlcNAc...) Ref.14 Ref.21

Glycosylation

624

1

N-linked (GlcNAc...) Ref.14

Glycosylation

630

1

N-linked (GlcNAc...) Potential

Disulfide bond

29 ↔ 40

Ref.20 Ref.21 Ref.22

Disulfide bond

281 ↔ 306

Ref.20 Ref.21 Ref.22

Disulfide bond

390 ↔ 391

Ref.20 Ref.21 Ref.22

Disulfide bond

583 ↔ 609

Ref.20 Ref.21 Ref.22

Disulfide bond

585 ↔ 627

Ref.20 Ref.21 Ref.22

Natural variations

Alternative sequence

1 – 200

200

Missing in isoform 3.

VSP_035793

Alternative sequence

1 – 40

40

Missing in isoform 2.

VSP_035794

Natural variant

175

1

T → A.
Corresponds to variant rs16906079 [ dbSNP | Ensembl ].

VAR_021977

Natural variant

188

1

Q → R. Ref.23
Corresponds to variant rs5030713 [ dbSNP | Ensembl ].

VAR_018729

Natural variant

246

1

C → S. Ref.23
Corresponds to variant rs5030714 [ dbSNP | Ensembl ].

VAR_018730

Natural variant

299

1

D → G in allele TLR4*B; reduced LPS-response; associated with an increased risk for ARMD10 in Caucasian patients carriers. Ref.3 Ref.4 Ref.6 Ref.23 Ref.24
Corresponds to variant rs4986790 [ dbSNP | Ensembl ].

VAR_012739

Natural variant

306

1

C → W.
Corresponds to variant rs2770145 [ dbSNP | Ensembl ].

VAR_047563

Natural variant

310

1

V → G.
Corresponds to variant rs2770144 [ dbSNP | Ensembl ].

VAR_047564

Natural variant

329

1

N → S. Ref.23
Corresponds to variant rs5030715 [ dbSNP | Ensembl ].

VAR_018731

Natural variant

342

1

F → Y.
Corresponds to variant rs5031050 [ dbSNP | Ensembl ].

VAR_020334

Natural variant

385

1

L → F.
Corresponds to variant rs11536884 [ dbSNP | Ensembl ].

VAR_037668

Natural variant

399

1

T → I in allele TLR4*B; reduced LPS-response. Ref.3 Ref.4 Ref.6 Ref.23
Corresponds to variant rs4986791 [ dbSNP | Ensembl ].

VAR_012740

Natural variant

400

1

S → N.
Corresponds to variant rs4987233 [ dbSNP | Ensembl ].

VAR_020335

Natural variant

443

1

F → L. Ref.23
Corresponds to variant rs5030716 [ dbSNP | Ensembl ].

VAR_018732

Natural variant

474

1

E → K. Ref.23
Corresponds to variant rs5030718 [ dbSNP | Ensembl ].

VAR_018733

Natural variant

510

1

Q → H. Ref.23
Corresponds to variant rs5030719 [ dbSNP | Ensembl ].

VAR_018734

Natural variant

694

1

K → R. Ref.23
Corresponds to variant rs5030722 [ dbSNP | Ensembl ].

VAR_018735

Natural variant

763

1

R → H. Ref.23
Corresponds to variant rs5030723 [ dbSNP | Ensembl ].

VAR_018736

Natural variant

834

1

Q → H. Ref.23

VAR_018737

Experimental info

Mutagenesis

431

1

H → A: Partially diminishes NF-kappa-B activation induced by Ni(2+). Strongly reduces NF-kappa-B activation induced by Ni(2+); when associated with A-456 or A-458. Ref.18

Mutagenesis

456

1

H → A: Partially diminishes NF-kappa-B activation induced by Ni(2+). Strongly reduces NF-kappa-B activation induced by Ni(2+); when associated with A-431. Suppresses NF-kappa-B activation induced by Ni(2+); when associated with A-458. Ref.18

Mutagenesis

458

1

H → A: Partially diminishes NF-kappa-B activation induced by Ni(2+). Strongly reduces NF-kappa-B activation induced by Ni(2+); when associated with A-431. Suppresses NF-kappa-B activation induced by Ni(2+); when associated with A-456. Ref.18

Mutagenesis

526

1

N → A: Abolishes LPS-response and prevents the cell surface expression. Ref.14

Mutagenesis

575

1

N → A: Abolishes LPS-response and prevents the cell surface expression. Ref.14

Mutagenesis

697

1

E → R: Abolishes LPS-response. Ref.13

Mutagenesis

710

1

R → E: Abolishes LPS-response. Ref.13

Mutagenesis

711

1

D → K: Abolishes LPS-response. Ref.13

Mutagenesis

714

1

P → H, R or E: Abolishes MYD88-binding and LPS-response. Ref.13

Sequence conflict

73

1

S → R in ABU41664. Ref.11

Sequence conflict

400

1

S → C in BAF82742. Ref.7

Sequence conflict

581

1

F → S in BAG64706. Ref.7

Secondary structure

1

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839

Helix Strand Turn

Details...

Beta strand

29 – 33

5

Turn

34 – 36

3

Beta strand

37 – 39

3

Beta strand

50 – 52

3

Beta strand

58 – 60

3

Turn

71 – 76

6

Beta strand

81 – 84

4

Turn

95 – 100

6

Beta strand

106 – 108

3

Beta strand

115 – 117

3

Turn

119 – 124

6

Beta strand

130 – 132

3

Helix

141 – 143

3

Turn

145 – 148

4

Beta strand

154 – 156

3

Helix

169 – 173

5

Beta strand

179 – 181

3

Helix

192 – 195

4

Helix

196 – 199

4

Beta strand

206 – 209

4

Turn

220 – 225

6

Beta strand

227 – 235

9

Helix

242 – 248

7

Turn

249 – 252

4

Beta strand

254 – 262

9

Turn

274 – 277

4

Helix

278 – 282

5

Beta strand

283 – 292

10

Beta strand

295 – 298

4

Turn

301 – 304

4

Helix

305 – 307

3

Beta strand

311 – 317

7

Beta strand

319 – 322

4

Helix

324 – 327

4

Beta strand

333 – 339

7

Beta strand

341 – 344

4

Beta strand

355 – 360

6

Beta strand

377 – 379

3

Beta strand

387 – 392

6

Helix

393 – 396

4

Beta strand

403 – 405

3

Beta strand

410 – 419

10

Beta strand

426 – 428

3

Beta strand

432 – 437

6

Turn

438 – 445

8

Beta strand

451 – 453

3

Turn

464 – 469

6

Beta strand

475 – 477

3

Helix

484 – 486

3

Beta strand

500 – 502

3

Turn

513 – 518

6

Beta strand

524 – 526

3

Helix

538 – 540

3

Beta strand

548 – 550

3

Beta strand

560 – 563

4

Beta strand

573 – 575

3

Helix

585 – 587

3

Helix

588 – 596

9

Helix

597 – 600

4

Helix

604 – 606

3

Beta strand

608 – 612

5

Helix

613 – 615

3

Beta strand

617 – 619

3

Helix

620 – 622

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified January 1, 1998. Version 2. Checksum: 92C48F55821133E8	FASTA	839	95,680
	10 20 30 40 50 60 MMSASRLAGT LIPAMAFLSC VRPESWEPCV EVVPNITYQC MELNFYKIPD NLPFSTKNLD 70 80 90 100 110 120 LSFNPLRHLG SYSFFSFPEL QVLDLSRCEI QTIEDGAYQS LSHLSTLILT GNPIQSLALG 130 140 150 160 170 180 AFSGLSSLQK LVAVETNLAS LENFPIGHLK TLKELNVAHN LIQSFKLPEY FSNLTNLEHL 190 200 210 220 230 240 DLSSNKIQSI YCTDLRVLHQ MPLLNLSLDL SLNPMNFIQP GAFKEIRLHK LTLRNNFDSL 250 260 270 280 290 300 NVMKTCIQGL AGLEVHRLVL GEFRNEGNLE KFDKSALEGL CNLTIEEFRL AYLDYYLDDI 310 320 330 340 350 360 IDLFNCLTNV SSFSLVSVTI ERVKDFSYNF GWQHLELVNC KFGQFPTLKL KSLKRLTFTS 370 380 390 400 410 420 NKGGNAFSEV DLPSLEFLDL SRNGLSFKGC CSQSDFGTTS LKYLDLSFNG VITMSSNFLG 430 440 450 460 470 480 LEQLEHLDFQ HSNLKQMSEF SVFLSLRNLI YLDISHTHTR VAFNGIFNGL SSLEVLKMAG 490 500 510 520 530 540 NSFQENFLPD IFTELRNLTF LDLSQCQLEQ LSPTAFNSLS SLQVLNMSHN NFFSLDTFPY 550 560 570 580 590 600 KCLNSLQVLD YSLNHIMTSK KQELQHFPSS LAFLNLTQND FACTCEHQSF LQWIKDQRQL 610 620 630 640 650 660 LVEVERMECA TPSDKQGMPV LSLNITCQMN KTIIGVSVLS VLVVSVVAVL VYKFYFHLML 670 680 690 700 710 720 LAGCIKYGRG ENIYDAFVIY SSQDEDWVRN ELVKNLEEGV PPFQLCLHYR DFIPGVAIAA 730 740 750 760 770 780 NIIHEGFHKS RKVIVVVSQH FIQSRWCIFE YEIAQTWQFL SSRAGIIFIV LQKVEKTLLR 790 800 810 820 830 QQVELYRLLS RNTYLEWEDS VLGRHIFWRR LRKALLDGKS WNPEGTVGTG CNWQEATSI
	Isoform 2 [UniParc]. Checksum: 82F70995E7F2AF9D	FASTA	799	91,296
	10 20 30 40 50 60 MELNFYKIPD NLPFSTKNLD LSFNPLRHLG SYSFFSFPEL QVLDLSRCEI QTIEDGAYQS 70 80 90 100 110 120 LSHLSTLILT GNPIQSLALG AFSGLSSLQK LVAVETNLAS LENFPIGHLK TLKELNVAHN 130 140 150 160 170 180 LIQSFKLPEY FSNLTNLEHL DLSSNKIQSI YCTDLRVLHQ MPLLNLSLDL SLNPMNFIQP 190 200 210 220 230 240 GAFKEIRLHK LTLRNNFDSL NVMKTCIQGL AGLEVHRLVL GEFRNEGNLE KFDKSALEGL 250 260 270 280 290 300 CNLTIEEFRL AYLDYYLDDI IDLFNCLTNV SSFSLVSVTI ERVKDFSYNF GWQHLELVNC 310 320 330 340 350 360 KFGQFPTLKL KSLKRLTFTS NKGGNAFSEV DLPSLEFLDL SRNGLSFKGC CSQSDFGTTS 370 380 390 400 410 420 LKYLDLSFNG VITMSSNFLG LEQLEHLDFQ HSNLKQMSEF SVFLSLRNLI YLDISHTHTR 430 440 450 460 470 480 VAFNGIFNGL SSLEVLKMAG NSFQENFLPD IFTELRNLTF LDLSQCQLEQ LSPTAFNSLS 490 500 510 520 530 540 SLQVLNMSHN NFFSLDTFPY KCLNSLQVLD YSLNHIMTSK KQELQHFPSS LAFLNLTQND 550 560 570 580 590 600 FACTCEHQSF LQWIKDQRQL LVEVERMECA TPSDKQGMPV LSLNITCQMN KTIIGVSVLS 610 620 630 640 650 660 VLVVSVVAVL VYKFYFHLML LAGCIKYGRG ENIYDAFVIY SSQDEDWVRN ELVKNLEEGV 670 680 690 700 710 720 PPFQLCLHYR DFIPGVAIAA NIIHEGFHKS RKVIVVVSQH FIQSRWCIFE YEIAQTWQFL 730 740 750 760 770 780 SSRAGIIFIV LQKVEKTLLR QQVELYRLLS RNTYLEWEDS VLGRHIFWRR LRKALLDGKS 790 WNPEGTVGTG CNWQEATSI
	Isoform 3 [UniParc]. Checksum: 23C1406CE32427EC	FASTA	639	73,301
	10 20 30 40 50 60 MPLLNLSLDL SLNPMNFIQP GAFKEIRLHK LTLRNNFDSL NVMKTCIQGL AGLEVHRLVL 70 80 90 100 110 120 GEFRNEGNLE KFDKSALEGL CNLTIEEFRL AYLDYYLDDI IDLFNCLTNV SSFSLVSVTI 130 140 150 160 170 180 ERVKDFSYNF GWQHLELVNC KFGQFPTLKL KSLKRLTFTS NKGGNAFSEV DLPSLEFLDL 190 200 210 220 230 240 SRNGLSFKGC CSQSDFGTTS LKYLDLSFNG VITMSSNFLG LEQLEHLDFQ HSNLKQMSEF 250 260 270 280 290 300 SVFLSLRNLI YLDISHTHTR VAFNGIFNGL SSLEVLKMAG NSFQENFLPD IFTELRNLTF 310 320 330 340 350 360 LDLSQCQLEQ LSPTAFNSLS SLQVLNMSHN NFFSLDTFPY KCLNSLQVLD YSLNHIMTSK 370 380 390 400 410 420 KQELQHFPSS LAFLNLTQND FACTCEHQSF LQWIKDQRQL LVEVERMECA TPSDKQGMPV 430 440 450 460 470 480 LSLNITCQMN KTIIGVSVLS VLVVSVVAVL VYKFYFHLML LAGCIKYGRG ENIYDAFVIY 490 500 510 520 530 540 SSQDEDWVRN ELVKNLEEGV PPFQLCLHYR DFIPGVAIAA NIIHEGFHKS RKVIVVVSQH 550 560 570 580 590 600 FIQSRWCIFE YEIAQTWQFL SSRAGIIFIV LQKVEKTLLR QQVELYRLLS RNTYLEWEDS 610 620 630 VLGRHIFWRR LRKALLDGKS WNPEGTVGTG CNWQEATSI

References

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[1]	"A human homologue of the Drosophila Toll protein signals activation of adaptive immunity." Medzhitov R., Preston-Hurlburt P., Janeway C.A. Jr. Nature 388:394-397(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Spleen.
[2]	"A family of human receptors structurally related to Drosophila Toll." Rock F.L., Hardiman G., Timans J.C., Kastelein R.A., Bazan J.F. Proc. Natl. Acad. Sci. U.S.A. 95:588-593(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Fetal liver, Lung and Placenta.
[3]	"Phylogenetic variation and polymorphism at the Toll-like receptor 4 locus (TLR4)." Smirnova I., Poltorak A., Chan E.K.L., McBride C., Beutler B. Genome Biol. 1:RESEARCH002.1-RESEARCH002.10(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLY-299 AND ILE-399.
[4]	"TLR4 mutations are associated with endotoxin hyporesponsiveness in humans." Arbour N.C., Lorenz E., Schutte B.C., Zabner J., Kline J.N., Jones M., Frees K., Watt J.L., Schwartz D.A. Nat. Genet. 25:187-191(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLY-299 AND ILE-399.
[5]	"Natural selection in the TLR-related genes in the course of primate evolution." Nakajima T., Ohtani H., Satta Y., Uno Y., Akari H., Ishida T., Kimura A. Immunogenetics 60:727-735(2008) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[6]	"The heterogeneous allelic repertoire of human Toll-Like receptor (TLR) genes." Georgel P., Macquin C., Bahram S. PLoS ONE 4:E7803-E7803(2009) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLY-299 AND ILE-399.
[7]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3). Tissue: Hippocampus, Kidney and Uterus.
[8]	"DNA sequence and analysis of human chromosome 9." Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., Bagguley C.L. , Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., Dunham I. Nature 429:369-374(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[10]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Cerebellum.
[11]	Liu Z., Li N., Wang J., Xiao W. Submitted (MAR-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-86.
[12]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 24-38.
[13]	"Structural basis for signal transduction by the Toll/interleukin-1 receptor domains." Xu Y., Tao X., Shen B., Horng T., Medzhitov R., Manley J.L., Tong L. Nature 408:111-115(2000) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF GLU-697; ARG-710; ASP-711 AND PRO-714.
[14]	"MD-2 and TLR4 N-linked glycosylations are important for a functional lipopolysaccharide receptor." da Silva Correia J., Ulevitch R.J. J. Biol. Chem. 277:1845-1854(2002) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION AT ASN-35; ASN-173; ASN-205; ASN-282; ASN-309; ASN-497; ASN-526; ASN-575 AND ASN-624, MUTAGENESIS OF ASN-526 AND ASN-575.
[15]	"Direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kappa B." Park H.S., Jung H.Y., Park E.Y., Kim J., Lee W.J., Bae Y.S. J. Immunol. 173:3589-3593(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NOX4.
[16]	"Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone." Liu B., Yang Y., Qiu Z., Staron M., Hong F., Li Y., Wu S., Li Y., Hao B., Bona R., Han D., Li Z. Nat. Commun. 1:79-79(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HSP90B1.
[17]	Erratum Liu B., Yang Y., Qiu Z., Staron M., Hong F., Li Y., Wu S., Li Y., Hao B., Bona R., Han D., Li Z. Nat. Commun. 3:653-653(2012)
[18]	"Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel." Schmidt M., Raghavan B., Mueller V., Vogl T., Fejer G., Tchaptchet S., Keck S., Kalis C., Nielsen P.J., Galanos C., Roth J., Skerra A., Martin S.F., Freudenberg M.A., Goebeler M. Nat. Immunol. 11:814-819(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF HIS-431; HIS-456 AND HIS-458, INVOLVEMENT IN CONTACT ALLERGY TO NICKEL.
[19]	"MLK4 has negative effect on TLR4 signaling." Seit-Nebi A., Cheng W., Xu H., Han J. Cell. Mol. Immunol. 9:27-33(2012) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MLK4.
[20]	"Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran." Kim H.M., Park B.S., Kim J.-I., Kim S.E., Lee J., Oh S.C., Enkhbayar P., Matsushima N., Lee H., Yoo O.J., Lee J.-O. Cell 130:906-917(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 27-228, DISULFIDE BONDS, GLYCOSYLATION AT ASN-35; ASN-173 AND ASN-205.
[21]	"The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex." Park B.S., Song D.H., Kim H.M., Choi B.-S., Lee H., Lee J.-O. Nature 458:1191-1195(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 27-631 IN COMPLEX WITH LY96 AND LIPOPOLYSACCHARIDE, DISULFIDE BONDS, GLYCOSYLATION AT ASN-173; ASN-205; ASN-497 AND ASN-526 AND ASN-575.
[22]	"Structure-based rational design of a Toll-like receptor 4 (TLR4) decoy receptor with high binding affinity for a target protein." Han J., Kim H.J., Lee S.C., Hong S., Park K., Jeon Y.H., Kim D., Cheong H.K., Kim H.S. PLoS ONE 7:E30929-E30929(2012) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.37 ANGSTROMS) OF 28-228, GLYCOSYLATION AT ASN-35 AND ASN-173, DISULFIDE BONDS.
[23]	"Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans." Smirnova I., Hamblin M.T., McBride C., Beutler B., Di Rienzo A. Genetics 158:1657-1664(2001) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS ARG-188; SER-246; GLY-299; SER-329; ILE-399; LEU-443; LYS-474; HIS-510; ARG-694; HIS-763 AND HIS-834.
[24]	"Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration." Zareparsi S., Buraczynska M., Branham K.E.H., Shah S., Eng D., Li M., Pawar H., Yashar B.M., Moroi S.E., Lichter P.R., Petty H.R., Richards J.E., Abecasis G.R., Elner V.M., Swaroop A. Hum. Mol. Genet. 14:1449-1455(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT GLY-299, ASSOCIATION WITH ARMD SUSCEPTIBILITY.
+	Additional computationally mapped references.

Web resources

Protein Spotlight

Zips, necklaces and mobile telephones - Issue 134 of December 2011

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U93091 mRNA. Translation: AAC80227.1.
AB445638 mRNA. Translation: BAG55035.1.
DQ018107 Genomic DNA. Translation: AAY82267.1.
DQ018108 Genomic DNA. Translation: AAY82268.1.
DQ018109 Genomic DNA. Translation: AAY82269.1.
AK290053 mRNA. Translation: BAF82742.1.
AK293068 mRNA. Translation: BAF85757.1.
AK303730 mRNA. Translation: BAG64706.1.
AL160272 Genomic DNA. Translation: CAH72618.1.
AL160272 Genomic DNA. Translation: CAH72619.1.
CH471090 Genomic DNA. Translation: EAW87448.1.
CH471090 Genomic DNA. Translation: EAW87451.1.
BC117422 mRNA. Translation: AAI17423.1.
EF535831 Genomic DNA. Translation: ABU41662.1.
EF535832 Genomic DNA. Translation: ABU41663.1.
EF535833 Genomic DNA. Translation: ABU41664.1.
AF177765 Genomic DNA. Translation: AAF05316.1.
AF177766 Genomic DNA. Translation: AAF07823.1.
AF172171, AF172169, AF172170 Genomic DNA. Translation: AAF89753.1.
U88880 mRNA. Translation: AAC34135.1.

IPI

IPI00008673.
IPI00374265.
IPI00914904.

RefSeq

NP_003257.1. NM_003266.3.
NP_612564.1. NM_138554.4.
NP_612567.1. NM_138557.2.

UniGene

Hs.174312.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2Z62	X-ray	1.70	A	27-228	[»]
2Z63	X-ray	2.00	A	27-527	[»]
2Z65	X-ray	2.70	A/B	27-228	[»]
2Z66	X-ray	1.90	A/B/C/D	380-627	[»]
3FXI	X-ray	3.10	A/B	27-631	[»]
3UL7	X-ray	2.37	A	28-228	[»]
3UL8	X-ray	2.50	A	27-228	[»]
3UL9	X-ray	2.45	A	28-228	[»]
3ULA	X-ray	3.60	A/C	27-228	[»]
4G8A	X-ray	2.40	A/B	23-629	[»]

ProteinModelPortal

O00206.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-34769N.

IntAct

O00206. 11 interactions.

MINT

MINT-3981856.

PTM databases

PhosphoSite

O00206.

Proteomic databases

PaxDb

O00206.

PRIDE

O00206.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000355622; ENSP00000363089; ENSG00000136869.
ENST00000394487; ENSP00000377997; ENSG00000136869.

GeneID

7099.

KEGG

hsa:7099.

UCSC

uc004bjz.3. human.

Organism-specific databases

CTD

7099.

GeneCards

GC09P120466.

HGNC

HGNC:11850. TLR4.

HPA

CAB004025.

MIM

603030. gene+phenotype.
611488. phenotype.

neXtProt

NX_O00206.

PharmGKB

PA36552.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG249751.

HOVERGEN

HBG018823.

InParanoid

O00206.

KO

K10160.

OMA

PESWDPC.

PhylomeDB

O00206.

Enzyme and pathway databases

Reactome

REACT_6900. Immune System.

Gene expression databases

ArrayExpress

O00206.

Bgee

O00206.

Genevestigator

O00206.

GermOnline

ENSG00000136869. Homo sapiens.

Family and domain databases

InterPro

IPR000483. Cys-rich_flank_reg_C.
IPR001611. Leu-rich_rpt.
IPR025875. Leu-rich_rpt_4.
IPR003591. Leu-rich_rpt_typical-subtyp.
IPR000157. TIR_dom.
IPR027168. TLR4.
IPR017241. Toll-like_receptor.
[Graphical view]

PANTHER

PTHR24365:SF9. PTHR24365:SF9. 1 hit.

Pfam

PF12799. LRR_4. 1 hit.
PF01582. TIR. 1 hit.
[Graphical view]

PIRSF

PIRSF037595. Toll-like_receptor. 1 hit.

SMART

SM00369. LRR_TYP. 2 hits.
SM00082. LRRCT. 1 hit.
SM00255. TIR. 1 hit.
[Graphical view]

SUPFAM

SSF52200. TIR. 1 hit.

PROSITE

PS51450. LRR. 11 hits.
PS50104. TIR. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

O00206.

ChEMBL

CHEMBL5255.

EvolutionaryTrace

O00206.

GenomeRNAi

7099.

NextBio

27773.

SOURCE

Search...

Entry information

Entry name

TLR4_HUMAN

Accession

Primary (citable) accession number: O00206
Secondary accession number(s): A8K1Y8 , A9XLP9, A9XLQ0, A9XLQ1, B4E194, D1CS52, D1CS53, Q5VZI8, Q5VZI9, Q9UK78, Q9UM57

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 11, 2002
Last sequence update:	January 1, 1998
Last modified:	May 1, 2013
This is version 139 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.