Toll/interleukin-1 receptor domain-containing adapter protein

Names and origin

Protein names

Recommended name:
    Toll/interleukin-1 receptor domain-containing adapter protein
      Short name=TIR domain-containing adapter protein
Alternative name(s):
    MyD88 adapter-like protein
    Adaptor protein Wyatt

Gene names

Name:	TIRAP
Synonyms:	MAL

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	221 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Adapter involved in the TLR4 signaling pathway in the innate immune response. Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, resulting in cytokine secretion and the inflammatory response.
Subunit structure	Homodimer. Also forms heterodimers with MyD88. Binds to TLR4 and IRAK2 via their respective TIR domains. Binds to PKR and TBK1. Does not interact with IRAK1, nor TLR9. Ref.10
Subcellular location	Cytoplasm By similarity.
Tissue specificity	Highly expressed in liver, kidney, spleen, skeletal muscle and heart. Also detected in peripheral blood leukocytes, lung, placenta, small intestine, thymus, colon and brain.
Polymorphism	Genetic variation in TIRAP can influence susceptibility or resistance to invasive pneumococcal disease, bacteremia, malaria and tuberculosi.
Sequence similarities	Contains 1 TIR domain.

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Ontologies

Keywords
Biological process	Immune response Inflammatory response
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing Polymorphism
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	I-kappaB kinase/NF-kappaB cascade Inferred from Experiment. Source: Reactome inflammatory response Inferred from electronic annotation. Source: UniProtKB-KW innate immune response Inferred from electronic annotation. Source: InterPro
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell intrinsic to membrane Inferred from electronic annotation. Source: InterPro plasma membrane Inferred from Experiment. Source: Reactome
Molecular function	protein binding Ref.1 Inferred from physical interaction. Source: IntAct transmembrane receptor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct
IRAK2	O43187	1	EBI-528644,EBI-447733
MYD88	Q99836	1	EBI-528644,EBI-447677
TICAM2	Q86XR7	1	EBI-528644,EBI-525927
TLR4	O00206	1	EBI-528644,EBI-528701

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Alternative products

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

Isoform 1 (identifier: P58753-1) 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: P58753-2) The sequence of this isoform differs from the canonical sequence as follows: 216-221: YLQTLS → CKLLQEGEGERDSATVSDLL

Isoform 3 (identifier: P58753-3) The sequence of this isoform differs from the canonical sequence as follows: 221-221: S → WHLLYHGTPEIGVKLETENPCRASDSHKCDKRYRE

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 221

221

Toll/interleukin-1 receptor domain-containing adapter protein

PRO_0000072547

Regions

Domain

84 – 221

138

TIR

Natural variations

Alternative sequence

216 – 221

6

YLQTLS → CKLLQEGEGERDSATVSDLL in isoform 2.

VSP_010765

Alternative sequence

221

1

S → WHLLYHGTPEIGVKLETENP CRASDSHKCDKRYRE in isoform 3.

VSP_017239

Natural variant

9

1

A → P: dbSNP rs8177369. Ref.7

VAR_019143

Natural variant

13

1

R → W: dbSNP rs8177399. Ref.7

VAR_019144

Natural variant

55

1

S → N: dbSNP rs3802813. Ref.1 Ref.6

VAR_036691

Natural variant

96

1

D → N: dbSNP rs8177400. Ref.7

VAR_019145

Natural variant

180

1

S → L Conferres protection against invasive pneumococcal disease, malaria and tuberculosis; attenuates TLR2 signal transduction. dbSNP rs8177374. Ref.7 Ref.11

VAR_019146

Natural variant

197

1

V → I: dbSNP rs7932976.

VAR_061713

Experimental info

Mutagenesis

125

1

P → H: Abolishes NF-kappa-B activation. Ref.1 Ref.2

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Sequences

Sequence		Length	Mass (Da)
Isoform 1 [UniParc]. Last modified July 19, 2004. Version 2. Checksum: 44A8454D04704540 Show »	FASTA	221	23,883
10 20 30 40 50 60 MASSTSLPAP GSRPKKPLGK MADWFRQTLL KKPKKRPNSP ESTSSDASQP TSQDSPLPPS 70 80 90 100 110 120 LSSVTSPSLP PTHASDSGSS RWSKDYDVCV CHSEEDLVAA QDLVSYLEGS TASLRCFLQL 130 140 150 160 170 180 RDATPGGAIV SELCQALSSS HCRVLLITPG FLQDPWCKYQ MLQALTEAPG AEGCTIPLLS 190 200 210 220 GLSRAAYPPE LRFMYYVDGR GPDGGFRQVK EAVMRYLQTL S « Hide
Isoform 2. Checksum: 383386AA03B70F32 Show »	FASTA	235	25,323
10 20 30 40 50 60 MASSTSLPAP GSRPKKPLGK MADWFRQTLL KKPKKRPNSP ESTSSDASQP TSQDSPLPPS 70 80 90 100 110 120 LSSVTSPSLP PTHASDSGSS RWSKDYDVCV CHSEEDLVAA QDLVSYLEGS TASLRCFLQL 130 140 150 160 170 180 RDATPGGAIV SELCQALSSS HCRVLLITPG FLQDPWCKYQ MLQALTEAPG AEGCTIPLLS 190 200 210 220 230 GLSRAAYPPE LRFMYYVDGR GPDGGFRQVK EAVMRCKLLQ EGEGERDSAT VSDLL « Hide
Isoform 3. Checksum: 97287F7E2A010915 Show »	FASTA	255	27,948
10 20 30 40 50 60 MASSTSLPAP GSRPKKPLGK MADWFRQTLL KKPKKRPNSP ESTSSDASQP TSQDSPLPPS 70 80 90 100 110 120 LSSVTSPSLP PTHASDSGSS RWSKDYDVCV CHSEEDLVAA QDLVSYLEGS TASLRCFLQL 130 140 150 160 170 180 RDATPGGAIV SELCQALSSS HCRVLLITPG FLQDPWCKYQ MLQALTEAPG AEGCTIPLLS 190 200 210 220 230 240 GLSRAAYPPE LRFMYYVDGR GPDGGFRQVK EAVMRYLQTL WHLLYHGTPE IGVKLETENP 250 CRASDSHKCD KRYRE « Hide

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction." Fitzgerald K.A., Palsson-McDermott E.M., Bowie A.G., Jefferies C.A., Mansell A.S., Brady G., Brint E., Dunne A., Gray P., Harte M.T., McMurray D., Smith D.E., Sims J.E., Bird T.A., O'Neill L.A.J. Nature 413:78-83(2001) [PubMed: 11544529] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), MUTAGENESIS OF PRO-125, VARIANT ASN-55. Tissue: Dendritic cell.
[2]	"TIRAP: an adapter molecule in the Toll signaling pathway." Horng T., Barton G.M., Medzhitov R. Nat. Immunol. 2:835-841(2001) [PubMed: 11526399] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), MUTAGENESIS OF PRO-125.
[3]	"Characterization and structural analysis of TIR domain-containing adaptor protein Wyatt." Kirk P.B., Pereira J.P., Bazan J.F. Submitted (AUG-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]	"Two isoforms of MAL, generated by alternative splicing, are found in humans but not mice." Hardy M.P., O'Neill L.A.J. Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[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: 18810425] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[6]	"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. Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT ASN-55. Tissue: Trachea.
[7]	SeattleSNPs variation discovery resource Submitted (APR-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS PRO-9; TRP-13; ASN-96 AND LEU-180.
[8]	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. Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). Tissue: Blood.
[10]	"Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling." Sato S., Sugiyama M., Yamamoto M., Watanabe Y., Kawai T., Takeda K., Akira S. J. Immunol. 171:4304-4310(2003) [PubMed: 14530355] [Abstract] Cited for: INTERACTION WITH TBK1.
[11]	"A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis." Khor C.C., Chapman S.J., Vannberg F.O., Dunne A., Murphy C., Ling E.Y., Frodsham A.J., Walley A.J., Kyrieleis O., Khan A., Aucan C., Segal S., Moore C.E., Knox K., Campbell S.J., Lienhardt C., Scott A., Aaby P. Hill A.V.S. Nat. Genet. 39:523-528(2007) [PubMed: 17322885] [Abstract] Cited for: VARIANT LEU-180, INVOLVEMENT IN SUSCEPTIBILITY TO INFECTIOUS DISEASES.
+	Additional computationally mapped references.

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Web resources

SeattleSNPs

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Cross-references

Sequence databases
EMBL GenBank DDBJ	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. AB446477 mRNA. Translation: BAG55254.1. AK124298 mRNA. Translation: BAG54027.1. AY282416 Genomic DNA. Translation: AAP31973.1. CH471065 Genomic DNA. Translation: EAW67687.1. BC032474 mRNA. Translation: AAH32474.1.
IPI	IPI00104143. IPI00171090. IPI00718966.
RefSeq	NP_001034750.1. NP_683708.1.
UniGene	Hs.537126
3D structure databases
SMR	P58753. Positions 75-204.
ModBase	Search...
Protein-protein interaction databases
IntAct	P58753. 5 interactions.
STRING	P58753.
PTM databases
PhosphoSite	P58753.
Genome annotation databases
Ensembl	ENST00000392679; ENSP00000376446; ENSG00000150455; Homo sapiens. [Genome view] ENST00000392680; ENSP00000376447; ENSG00000150455; Homo sapiens. [Genome view]
GeneID	114609.
KEGG	hsa:114609.
UCSC	uc001qdm.1. human.
Organism-specific databases
CTD	114609.
GeneCards	GC11P125658.
H-InvDB	HIX0010254.
HGNC	HGNC:17192. TIRAP.
MIM	606252. gene. 607948. phenotype. 610799. phenotype. 611162. phenotype.
PharmGKB	PA134972842.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG17712.
HOVERGEN	P58753.
OrthoDB	EOG9QC3RP.
PhylomeDB	P58753.
Enzyme and pathway databases
Reactome	REACT_6900. Signaling in Immune system. REACT_6968. Mal Cascade.
Gene expression databases
ArrayExpress	P58753.
Bgee	P58753.
CleanEx	HS_MAL. HS_TIRAP.
Genevestigator	P58753.
GermOnline	ENSG00000150455. Homo sapiens.
Family and domain databases
InterPro	IPR017279. Tol-interleuk_rcpt_adapt_Tirap. IPR000157. Toll-Interleukin_rcpt. [Graphical view]
Pfam	PF01582. TIR. 1 hit. [Graphical view]
PIRSF	PIRSF037750. TIR_Tirap. 1 hit.
PROSITE	PS50104. TIR. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	79099.
SOURCE	Search...

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Entry information

Entry name

TIRAP_HUMAN

Accession

Primary (citable) accession number: P58753
Secondary accession number(s): B3KW65, Q56UI0, Q8N5E5

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 27, 2002
Last sequence update:	July 19, 2004
Last modified:	January 19, 2010
This is version 78 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.

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SIMILARITY comments

Index of protein domains and families

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Alternative products

Sequence annotation (Features)

Molecule processing

Regions

Natural variations

Experimental info

Sequences

References

Web resources

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents