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Protein

Toll/interleukin-1 receptor domain-containing adapter protein

Gene

TIRAP

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Adapter involved in TLR2 and TLR4 signaling pathways in the innate immune response. Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in cytokine secretion and the inflammatory response. Positively regulates the production of TNF-alpha and interleukin-6.2 Publications

GO - Molecular functioni

  • phosphatidylinositol-4,5-bisphosphate binding Source: BHF-UCL
  • protein binding, bridging Source: BHF-UCL
  • protein heterodimerization activity Source: BHF-UCL
  • protein homodimerization activity Source: BHF-UCL
  • protein kinase C binding Source: BHF-UCL
  • Toll-like receptor 2 binding Source: BHF-UCL
  • Toll-like receptor 4 binding Source: BHF-UCL

GO - Biological processi

  • 3'-UTR-mediated mRNA stabilization Source: BHF-UCL
  • activation of NF-kappaB-inducing kinase activity Source: AgBase
  • cell surface receptor signaling pathway Source: BHF-UCL
  • cellular response to bacterial lipopeptide Source: BHF-UCL
  • cellular response to lipoteichoic acid Source: BHF-UCL
  • defense response to Gram-positive bacterium Source: BHF-UCL
  • inflammatory response Source: UniProtKB-KW
  • innate immune response Source: UniProtKB-KW
  • MyD88-dependent toll-like receptor signaling pathway Source: BHF-UCL
  • myeloid cell differentiation Source: BHF-UCL
  • negative regulation of growth of symbiont in host Source: BHF-UCL
  • positive regulation of B cell proliferation Source: BHF-UCL
  • positive regulation of chemokine (C-X-C motif) ligand 1 production Source: BHF-UCL
  • positive regulation of chemokine (C-X-C motif) ligand 2 production Source: BHF-UCL
  • positive regulation of ERK1 and ERK2 cascade Source: BHF-UCL
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: BHF-UCL
  • positive regulation of interleukin-12 production Source: BHF-UCL
  • positive regulation of interleukin-15 production Source: BHF-UCL
  • positive regulation of interleukin-6 biosynthetic process Source: BHF-UCL
  • positive regulation of interleukin-8 production Source: BHF-UCL
  • positive regulation of JNK cascade Source: BHF-UCL
  • positive regulation of neutrophil chemotaxis Source: BHF-UCL
  • positive regulation of NF-kappaB transcription factor activity Source: BHF-UCL
  • positive regulation of protein homodimerization activity Source: BHF-UCL
  • positive regulation of toll-like receptor 2 signaling pathway Source: BHF-UCL
  • positive regulation of toll-like receptor 3 signaling pathway Source: BHF-UCL
  • positive regulation of toll-like receptor 4 signaling pathway Source: BHF-UCL
  • positive regulation of tumor necrosis factor production Source: BHF-UCL
  • regulation of innate immune response Source: BHF-UCL
  • regulation of interferon-beta production Source: BHF-UCL
  • response to lipopolysaccharide Source: BHF-UCL
  • TIRAP-dependent toll-like receptor 4 signaling pathway Source: BHF-UCL
  • toll-like receptor 4 signaling pathway Source: Reactome
Complete GO annotation...

Keywords - Biological processi

Immunity, Inflammatory response, Innate immunity

Enzyme and pathway databases

BioCyciZFISH:ENSG00000150455-MONOMER.
ReactomeiR-HSA-1236974. ER-Phagosome pathway.
R-HSA-166016. Toll Like Receptor 4 (TLR4) Cascade.
R-HSA-166058. MyD88:Mal cascade initiated on plasma membrane.
R-HSA-5602498. MyD88 deficiency (TLR2/4).
R-HSA-5603041. IRAK4 deficiency (TLR2/4).
SignaLinkiP58753.
SIGNORiP58753.

Names & Taxonomyi

Protein namesi
Recommended name:
Toll/interleukin-1 receptor domain-containing adapter protein
Short name:
TIR domain-containing adapter protein
Alternative name(s):
Adaptor protein Wyatt
MyD88 adapter-like protein
Short name:
MyD88-2
Gene namesi
Name:TIRAP
Synonyms:MAL
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

HGNCiHGNC:17192. TIRAP.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: Reactome
  • endocytic vesicle Source: BHF-UCL
  • intercellular bridge Source: HPA
  • nucleoplasm Source: HPA
  • plasma membrane Source: UniProtKB
  • ruffle membrane Source: BHF-UCL
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi125P → H: Abolishes NF-kappa-B activation. 2 Publications1

Organism-specific databases

DisGeNETi114609.
MalaCardsiTIRAP.
MIMi607948. phenotype.
610799. phenotype.
611162. phenotype.
614382. phenotype.
OpenTargetsiENSG00000150455.
PharmGKBiPA134972842.

Polymorphism and mutation databases

BioMutaiTIRAP.
DMDMi50403750.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000725471 – 221Toll/interleukin-1 receptor domain-containing adapter proteinAdd BLAST221

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi89 ↔ 1341 Publication
Disulfide bondi142 ↔ 1741 Publication

Post-translational modificationi

Phosphorylated by IRAK1 and IRAK4. Also phosphorylated by BTK.
Polyubiquitinated. Polyubiquitination follows phosphorylation by BTK and leads to TIRAP degradation.1 Publication

Keywords - PTMi

Disulfide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP58753.
PeptideAtlasiP58753.
PRIDEiP58753.

PTM databases

iPTMnetiP58753.
PhosphoSitePlusiP58753.

Expressioni

Tissue specificityi

Highly expressed in liver, kidney, spleen, skeletal muscle and heart. Also detected in peripheral blood leukocytes, lung, placenta, small intestine, thymus, colon and brain.

Gene expression databases

BgeeiENSG00000150455.
CleanExiHS_MAL.
HS_TIRAP.
ExpressionAtlasiP58753. baseline and differential.
GenevisibleiP58753. HS.

Organism-specific databases

HPAiHPA054431.

Interactioni

Subunit structurei

Homodimer. Also forms heterodimers with MYD88. May interact with PIK3AP1 (By similarity). Interacts with TLR4 and IRAK2 via their respective TIR domains. Interacts with BMX and TBK1. Interacts with EIF2AK2. Does not interact with IRAK1, nor TLR9.By similarity6 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
ARAFP103982EBI-528644,EBI-365961
CCDC47Q96A332EBI-528644,EBI-720151
IRAK1P516172EBI-528644,EBI-358664
IRAK2O431872EBI-528644,EBI-447733
IRAK4Q9NWZ32EBI-528644,EBI-448378
LTN1O948222EBI-528644,EBI-1044684
MYD88Q998368EBI-528644,EBI-447677
PIK3R1P279863EBI-528644,EBI-79464
SAMHD1Q9Y3Z32EBI-528644,EBI-1054601
TLR4O002065EBI-528644,EBI-528701

GO - Molecular functioni

  • protein binding, bridging Source: BHF-UCL
  • protein heterodimerization activity Source: BHF-UCL
  • protein homodimerization activity Source: BHF-UCL
  • protein kinase C binding Source: BHF-UCL
  • Toll-like receptor 2 binding Source: BHF-UCL
  • Toll-like receptor 4 binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi125325. 41 interactors.
DIPiDIP-33489N.
IntActiP58753. 34 interactors.
MINTiMINT-4950450.
STRINGi9606.ENSP00000376445.

Structurei

Secondary structure

1221
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi83 – 91Combined sources9
Helixi94 – 96Combined sources3
Helixi97 – 108Combined sources12
Beta strandi131 – 133Combined sources3
Beta strandi140 – 147Combined sources8
Helixi149 – 153Combined sources5
Helixi155 – 166Combined sources12
Beta strandi168 – 179Combined sources12
Helixi184 – 186Combined sources3
Helixi189 – 193Combined sources5
Helixi202 – 205Combined sources4
Helixi206 – 217Combined sources12

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2Y92X-ray3.01A79-221[»]
3UB2X-ray2.40A78-221[»]
3UB3X-ray2.75A78-221[»]
3UB4X-ray3.10A78-221[»]
4FZ5X-ray3.60A/B72-221[»]
4LQDX-ray2.45A81-221[»]
ProteinModelPortaliP58753.
SMRiP58753.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini84 – 221TIRPROSITE-ProRule annotationAdd BLAST138

Sequence similaritiesi

Contains 1 TIR domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiENOG410IVIY. Eukaryota.
ENOG411205V. LUCA.
GeneTreeiENSGT00510000048428.
HOGENOMiHOG000068972.
HOVERGENiHBG054203.
InParanoidiP58753.
KOiK05403.
OMAiAELRFMY.
OrthoDBiEOG091G0EQB.
PhylomeDBiP58753.
TreeFamiTF330734.

Family and domain databases

Gene3Di3.40.50.10140. 1 hit.
InterProiIPR000157. TIR_dom.
IPR017279. Tol-interleuk_rcpt_adapt_Tirap.
[Graphical view]
PANTHERiPTHR22662. PTHR22662. 1 hit.
PfamiPF13676. TIR_2. 1 hit.
[Graphical view]
PIRSFiPIRSF037750. TIR_Tirap. 1 hit.
SUPFAMiSSF52200. SSF52200. 1 hit.
PROSITEiPS50104. TIR. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P58753-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MASSTSLPAP GSRPKKPLGK MADWFRQTLL KKPKKRPNSP ESTSSDASQP
60 70 80 90 100
TSQDSPLPPS LSSVTSPSLP PTHASDSGSS RWSKDYDVCV CHSEEDLVAA
110 120 130 140 150
QDLVSYLEGS TASLRCFLQL RDATPGGAIV SELCQALSSS HCRVLLITPG
160 170 180 190 200
FLQDPWCKYQ MLQALTEAPG AEGCTIPLLS GLSRAAYPPE LRFMYYVDGR
210 220
GPDGGFRQVK EAVMRYLQTL S
Length:221
Mass (Da):23,883
Last modified:July 19, 2004 - v2
Checksum:i44A8454D04704540
GO
Isoform 2 (identifier: P58753-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     216-221: YLQTLS → CKLLQEGEGERDSATVSDLL

Show »
Length:235
Mass (Da):25,323
Checksum:i383386AA03B70F32
GO
Isoform 3 (identifier: P58753-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     221-221: S → WHLLYHGTPEIGVKLETENPCRASDSHKCDKRYRE

Show »
Length:255
Mass (Da):27,948
Checksum:i97287F7E2A010915
GO

Polymorphismi

Genetic variations in TIRAP may influence susceptibility or resistance to invasive pneumococcal disease [MIMi:610799], malaria [MIMi:611162], and tuberculosis [MIMi:607948]. It may define the bacteremia susceptibility locus 1 (BACTS1) [MIMi:614382].2 Publications

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0191439A → P Does not affect NF-kappa-B activation and TNF-alpha production. 2 PublicationsCorresponds to variant rs8177369dbSNPEnsembl.1
Natural variantiVAR_01914413R → W Does not affect NF-kappa-B activation and TNF-alpha production. 2 PublicationsCorresponds to variant rs8177399dbSNPEnsembl.1
Natural variantiVAR_03669155S → N Does not affect NF-kappa-B activation and TNF-alpha production. 2 PublicationsCorresponds to variant rs3802813dbSNPEnsembl.1
Natural variantiVAR_01914596D → N Hypomorphic variant resulting in impaired NF-kappa-B activation and TNF-alpha production; cannot bind MYD88. 2 PublicationsCorresponds to variant rs8177400dbSNPEnsembl.1
Natural variantiVAR_019146180S → L At heterozygosity it protects against invasive pneumococcal disease, malaria, bacteremia and tuberculosis; does not affect NF-kappa-B activation and TNF-alpha production; attenuates TLR2 signal transduction. 4 PublicationsCorresponds to variant rs8177374dbSNPEnsembl.1
Natural variantiVAR_061713197V → I Does not affect NF-kappa-B activation and TNF-alpha production. 1 PublicationCorresponds to variant rs7932976dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_010765216 – 221YLQTLS → CKLLQEGEGERDSATVSDLL in isoform 2. 4 Publications6
Alternative sequenceiVSP_017239221S → WHLLYHGTPEIGVKLETENP CRASDSHKCDKRYRE in isoform 3. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF406652 mRNA. Translation: AAL01160.1.
AF378129 mRNA. Translation: AAL05627.1.
AF410783 mRNA. Translation: AAL05036.1.
AY576785 mRNA. Translation: AAT90417.1.
AY576786 mRNA. Translation: AAT90418.1.
AY576787 mRNA. Translation: AAT90419.1.
AB446477 mRNA. Translation: BAG55254.1.
AK124298 mRNA. Translation: BAG54027.1.
AK313147 mRNA. Translation: BAG35965.1.
AY282416 Genomic DNA. Translation: AAP31973.1.
AP001318 Genomic DNA. No translation available.
CH471065 Genomic DNA. Translation: EAW67687.1.
CH471065 Genomic DNA. Translation: EAW67689.1.
BC032474 mRNA. Translation: AAH32474.1.
CCDSiCCDS41731.1. [P58753-2]
CCDS8472.1. [P58753-1]
RefSeqiNP_001034750.1. NM_001039661.1. [P58753-1]
NP_001305705.1. NM_001318776.1. [P58753-2]
NP_001305706.1. NM_001318777.1. [P58753-1]
NP_683708.1. NM_148910.2. [P58753-2]
XP_005271456.2. XM_005271399.3. [P58753-2]
XP_011540878.1. XM_011542576.2. [P58753-1]
XP_016872651.1. XM_017017162.1. [P58753-1]
UniGeneiHs.537126.

Genome annotation databases

EnsembliENST00000392678; ENSP00000376445; ENSG00000150455. [P58753-2]
ENST00000392679; ENSP00000376446; ENSG00000150455. [P58753-1]
ENST00000392680; ENSP00000376447; ENSG00000150455. [P58753-1]
ENST00000479770; ENSP00000436967; ENSG00000150455. [P58753-1]
GeneIDi114609.
KEGGihsa:114609.
UCSCiuc001qdl.2. human. [P58753-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

SeattleSNPs

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF406652 mRNA. Translation: AAL01160.1.
AF378129 mRNA. Translation: AAL05627.1.
AF410783 mRNA. Translation: AAL05036.1.
AY576785 mRNA. Translation: AAT90417.1.
AY576786 mRNA. Translation: AAT90418.1.
AY576787 mRNA. Translation: AAT90419.1.
AB446477 mRNA. Translation: BAG55254.1.
AK124298 mRNA. Translation: BAG54027.1.
AK313147 mRNA. Translation: BAG35965.1.
AY282416 Genomic DNA. Translation: AAP31973.1.
AP001318 Genomic DNA. No translation available.
CH471065 Genomic DNA. Translation: EAW67687.1.
CH471065 Genomic DNA. Translation: EAW67689.1.
BC032474 mRNA. Translation: AAH32474.1.
CCDSiCCDS41731.1. [P58753-2]
CCDS8472.1. [P58753-1]
RefSeqiNP_001034750.1. NM_001039661.1. [P58753-1]
NP_001305705.1. NM_001318776.1. [P58753-2]
NP_001305706.1. NM_001318777.1. [P58753-1]
NP_683708.1. NM_148910.2. [P58753-2]
XP_005271456.2. XM_005271399.3. [P58753-2]
XP_011540878.1. XM_011542576.2. [P58753-1]
XP_016872651.1. XM_017017162.1. [P58753-1]
UniGeneiHs.537126.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2Y92X-ray3.01A79-221[»]
3UB2X-ray2.40A78-221[»]
3UB3X-ray2.75A78-221[»]
3UB4X-ray3.10A78-221[»]
4FZ5X-ray3.60A/B72-221[»]
4LQDX-ray2.45A81-221[»]
ProteinModelPortaliP58753.
SMRiP58753.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi125325. 41 interactors.
DIPiDIP-33489N.
IntActiP58753. 34 interactors.
MINTiMINT-4950450.
STRINGi9606.ENSP00000376445.

PTM databases

iPTMnetiP58753.
PhosphoSitePlusiP58753.

Polymorphism and mutation databases

BioMutaiTIRAP.
DMDMi50403750.

Proteomic databases

PaxDbiP58753.
PeptideAtlasiP58753.
PRIDEiP58753.

Protocols and materials databases

DNASUi114609.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000392678; ENSP00000376445; ENSG00000150455. [P58753-2]
ENST00000392679; ENSP00000376446; ENSG00000150455. [P58753-1]
ENST00000392680; ENSP00000376447; ENSG00000150455. [P58753-1]
ENST00000479770; ENSP00000436967; ENSG00000150455. [P58753-1]
GeneIDi114609.
KEGGihsa:114609.
UCSCiuc001qdl.2. human. [P58753-1]

Organism-specific databases

CTDi114609.
DisGeNETi114609.
GeneCardsiTIRAP.
HGNCiHGNC:17192. TIRAP.
HPAiHPA054431.
MalaCardsiTIRAP.
MIMi606252. gene.
607948. phenotype.
610799. phenotype.
611162. phenotype.
614382. phenotype.
neXtProtiNX_P58753.
OpenTargetsiENSG00000150455.
PharmGKBiPA134972842.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IVIY. Eukaryota.
ENOG411205V. LUCA.
GeneTreeiENSGT00510000048428.
HOGENOMiHOG000068972.
HOVERGENiHBG054203.
InParanoidiP58753.
KOiK05403.
OMAiAELRFMY.
OrthoDBiEOG091G0EQB.
PhylomeDBiP58753.
TreeFamiTF330734.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000150455-MONOMER.
ReactomeiR-HSA-1236974. ER-Phagosome pathway.
R-HSA-166016. Toll Like Receptor 4 (TLR4) Cascade.
R-HSA-166058. MyD88:Mal cascade initiated on plasma membrane.
R-HSA-5602498. MyD88 deficiency (TLR2/4).
R-HSA-5603041. IRAK4 deficiency (TLR2/4).
SignaLinkiP58753.
SIGNORiP58753.

Miscellaneous databases

GenomeRNAii114609.
PROiP58753.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000150455.
CleanExiHS_MAL.
HS_TIRAP.
ExpressionAtlasiP58753. baseline and differential.
GenevisibleiP58753. HS.

Family and domain databases

Gene3Di3.40.50.10140. 1 hit.
InterProiIPR000157. TIR_dom.
IPR017279. Tol-interleuk_rcpt_adapt_Tirap.
[Graphical view]
PANTHERiPTHR22662. PTHR22662. 1 hit.
PfamiPF13676. TIR_2. 1 hit.
[Graphical view]
PIRSFiPIRSF037750. TIR_Tirap. 1 hit.
SUPFAMiSSF52200. SSF52200. 1 hit.
PROSITEiPS50104. TIR. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTIRAP_HUMAN
AccessioniPrimary (citable) accession number: P58753
Secondary accession number(s): B3KW65
, Q56UH9, Q56UI0, Q8N5E5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 27, 2002
Last sequence update: July 19, 2004
Last modified: November 2, 2016
This is version 144 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Caution

Variant Leu-180 has been reported to reduce TLR2 signal transduction (PubMed:17322885). In contrast, PubMed:19509286 reports that this variant is fully active and has no effect on signal transduction pathways and cytokine production.1 Publication

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.