Q8IUC6 (TCAM1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
TIR domain-containing adapter molecule 1
Short name=TICAM-1

Alternative name(s):
Proline-rich, vinculin and TIR domain-containing protein B
Putative NF-kappa-B-activating protein 502H
Toll-interleukin-1 receptor domain-containing adapter protein inducing interferon beta
Short name=MyD88-3
Short name=TIR domain-containing adapter protein inducing IFN-beta

Gene names

Name:	TICAM1
Synonyms:	PRVTIRB, TRIF

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	712 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Involved in innate immunity against invading pathogens. Adapter used by TLR3 and TLR4 (through TICAM2) to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis. Ligand binding to these receptors results in TRIF recruitment through its TIR domain. Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively. Ref.1 Ref.2 Ref.11
Subunit structure	Homodimer Probable. Interacts (via the TIR domain) with TLR3; mediates TLR3 signaling. Interacts with AZI2, TBK1, IRF3 and IRF7. Interacts with TICAM2 in TLR4 recruitment. Interaction with PIAS4 inhibits the TICAM1-induced NF-kappa-B, IRF and IFNB1 activation. Interacts with IKBKB and IKBKE. Interaction with SARM1 blocks TICAM1-dependent transcription factor activation. Interacts with TRAF3 By similarity. Interacts with TRAF6. Interacts with TRAFD1 By similarity. Ref.1 Ref.2 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14
Tissue specificity	Ubiquitously expressed but with higher levels in liver. Ref.1 Ref.2
Domain	The N-terminal region is essential for activation of the IFNB promoter activity. Ref.1 Ref.2 Ref.11
Post-translational modification	Phosphorylated by TBK1. Ref.9
Involvement in disease	Herpes simplex encephalitis 4 (HSE4) [MIM:614850]: A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. HSE is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.18
Sequence similarities	Contains 1 TIR domain.
Sequence caution	The sequence AAO85488.1 differs from that shown. Reason: Frameshift at positions 141, 148 and 161.

Ontologies

Keywords
Biological process	Antiviral defense Apoptosis Immunity Inflammatory response Innate immunity
Coding sequence diversity	Polymorphism
Disease	Disease mutation
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	I-kappaB kinase/NF-kappaB cascade Traceable author statement. Source: Reactome TRIF-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome Toll signaling pathway Traceable author statement. Source: Reactome apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW defense response to virus Inferred from electronic annotation. Source: UniProtKB-KW inflammatory response Inferred from electronic annotation. Source: UniProtKB-KW innate immune response Traceable author statement. Source: Reactome lipopolysaccharide-mediated signaling pathway Inferred from electronic annotation. Source: Compara macrophage activation involved in immune response Inferred from electronic annotation. Source: Compara positive regulation of B cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from mutant phenotype Ref.4Ref.12. Source: UniProtKB positive regulation of NF-kappaB transcription factor activity Inferred from electronic annotation. Source: Compara positive regulation of chemokine biosynthetic process Inferred from electronic annotation. Source: Compara positive regulation of interferon-beta biosynthetic process Inferred from electronic annotation. Source: Compara positive regulation of interleukin-6 production Inferred from electronic annotation. Source: Compara positive regulation of nitric oxide biosynthetic process Inferred from electronic annotation. Source: Compara positive regulation of protein binding Inferred from electronic annotation. Source: Compara positive regulation of protein ubiquitination Inferred from electronic annotation. Source: Compara positive regulation of tumor necrosis factor production Inferred from electronic annotation. Source: Compara positive regulation of type I interferon production Inferred from electronic annotation. Source: Compara regulation of protein homodimerization activity Inferred from electronic annotation. Source: Compara response to exogenous dsRNA Inferred from electronic annotation. Source: Compara toll-like receptor 3 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 4 signaling pathway Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome endosome membrane Traceable author statement. Source: Reactome
Molecular_function	signal transducer activity Inferred from mutant phenotype Ref.4. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 712

712

TIR domain-containing adapter molecule 1

PRO_0000317663

Regions

Domain

390 – 460

71

TIR

Region

512 – 712

201

Sufficient to induce apoptosis

Motif

84 – 91

8

TRAF6-binding

Motif

248 – 255

8

TRAF6-binding

Motif

299 – 309

11

TRAF6-binding

Compositional bias

213 – 371

159

Pro-rich

Compositional bias

614 – 678

65

Pro-rich

Natural variations

Natural variant

46

1

M → I in a breast cancer sample; somatic mutation. Ref.17

VAR_038789

Natural variant

75

1

R → C.
Corresponds to variant rs11466719 [ dbSNP | Ensembl ].

VAR_051416

Natural variant

186

1

S → L in HSE4. Ref.18

VAR_069082

Natural variant

275

1

L → V.
Corresponds to variant rs11466721 [ dbSNP | Ensembl ].

VAR_051417

Natural variant

666

1

A → T.
Corresponds to variant rs11466724 [ dbSNP | Ensembl ].

VAR_051418

Experimental info

Mutagenesis

88

1

E → A: Reduces binding to TRAF6 and activation of NFKB signaling pathway; when associated with A-252 and A-303. Ref.9

Mutagenesis

252

1

E → A: Loss of TCAM1-induced NF-kappa-B activation. Reduces interaction with TRAF6 and activation of NF-kappa-B signaling pathway; when associated with A-88 and A-303. Ref.9 Ref.12

Mutagenesis

303

1

E → A: Reduces binding to TRAF6 and activation of NFKB signaling pathway; when associated with A-88 and A-252. Ref.9

Mutagenesis

434

1

P → H: Abolishes interaction with TLR3. Ref.2

Mutagenesis

493

1

E → A: Loss of TCAM1-induced NF-kappa-B and IRF3 activation. Ref.12

Sequence conflict

147

1

D → T in AAO85488. Ref.6

Sequence conflict

150

1

G → W in AAO85488. Ref.6

Sequence conflict

162

1

L → S in AAO85488. Ref.6

Sequence conflict

633 – 659

27

Missing in AAO85488. Ref.6

Sequence conflict

660

1

S → P in AAO85488. Ref.6

Secondary structure

1

.

.

.

712

Helix Strand Turn

Details...

Beta strand

369 – 371

3

Sequences

	Sequence		Length	Mass (Da)
	Q8IUC6 [UniParc]. Last modified March 1, 2003. Version 1. Checksum: 5D071E3BE9240D9A	FASTA	712	76,422
	10 20 30 40 50 60 MACTGPSLPS AFDILGAAGQ DKLLYLKHKL KTPRPGCQGQ DLLHAMVLLK LGQETEARIS 70 80 90 100 110 120 LEALKADAVA RLVARQWAGV DSTEDPEEPP DVSWAVARLY HLLAEEKLCP ASLRDVAYQE 130 140 150 160 170 180 AVRTLSSRDD HRLGELQDEA RNRCGWDIAG DPGSIRTLQS NLGCLPPSSA LPSGTRSLPR 190 200 210 220 230 240 PIDGVSDWSQ GCSLRSTGSP ASLASNLEIS QSPTMPFLSL HRSPHGPSKL CDDPQASLVP 250 260 270 280 290 300 EPVPGGCQEP EEMSWPPSGE IASPPELPSS PPPGLPEVAP DATSTGLPDT PAAPETSTNY 310 320 330 340 350 360 PVECTEGSAG PQSLPLPILE PVKNPCSVKD QTPLQLSVED TTSPNTKPCP PTPTTPETSP 370 380 390 400 410 420 PPPPPPPSST PCSAHLTPSS LFPSSLESSS EQKFYNFVIL HARADEHIAL RVREKLEALG 430 440 450 460 470 480 VPDGATFCED FQVPGRGELS CLQDAIDHSA FIILLLTSNF DCRLSLHQVN QAMMSNLTRQ 490 500 510 520 530 540 GSPDCVIPFL PLESSPAQLS SDTASLLSGL VRLDEHSQIF ARKVANTFKP HRLQARKAMW 550 560 570 580 590 600 RKEQDTRALR EQSQHLDGER MQAAALNAAY SAYLQSYLSY QAQMEQLQVA FGSHMSFGTG 610 620 630 640 650 660 APYGARMPFG GQVPLGAPPP FPTWPGCPQP PPLHAWQAGT PPPPSPQPAA FPQSLPFPQS 670 680 690 700 710 PAFPTASPAP PQSPGLQPLI IHHAQMVQLG LNNHMWNQRG SQAPEDKTQE AE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling." Yamamoto M., Sato S., Mori K., Hoshino K., Takeuchi O., Takeda K., Akira S. J. Immunol. 169:6668-6672(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, DOMAIN, INTERACTION WITH IRF3; TLR2 AND TLR3.
[2]	"TICAM-1, an adapter molecule that participates in Toll-like receptor 3 mediated interferon-beta induction." Oshiumi H., Matsumoto M., Funami K., Akazawa T., Seya T. Nat. Immunol. 4:161-167(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH TLR3, SUBUNIT, TISSUE SPECIFICITY, DOMAIN, MUTAGENESIS OF PRO-434. Tissue: Lung.
[3]	"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].
[4]	"Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways." Matsuda A., Suzuki Y., Honda G., Muramatsu S., Matsuzaki O., Nagano Y., Doi T., Shimotohno K., Harada T., Nishida E., Hayashi H., Sugano S. Oncogene 22:3307-3318(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung.
[5]	"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: Ovary and Testis.
[6]	"PRVTIRB is a differentially expressed gene." Begum N.A. Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 137-712.
[7]	Yu W., Gibbs R.A. Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 297-712. Tissue: Brain.
[8]	"TIRP, a novel Toll/interleukin-1 receptor (TIR) domain-containing adapter protein involved in TIR signaling." Bin L.-H., Xu L.-G., Shu H.-B. J. Biol. Chem. 278:24526-24532(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TICAM2.
[9]	"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] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TRAF6 AND TBK1, PHOSPHORYLATION BY TBK1, MOTIF, MUTAGENESIS OF GLU-88; GLU-252 AND GLU-303.
[10]	"PIASy represses TRIF-induced ISRE and NF-kappaB activation but not apoptosis." Zhang J., Xu L.G., Han K.J., Wei X., Shu H.B. FEBS Lett. 570:97-101(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PIAS4.
[11]	"Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways." Han K.J., Su X., Xu L.-G., Bin L.H., Zhang J., Shu H.-B. J. Biol. Chem. 279:15652-15661(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH IKBKB; IKBKE; IRF3; IRF7; TBK1 AND TRAF6, DOMAIN.
[12]	"Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta." Jiang Z., Mak T.W., Sen G., Li X. Proc. Natl. Acad. Sci. U.S.A. 101:3533-3538(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TRAF6, MUTAGENESIS OF GLU-252 AND GLU-493.
[13]	"NF-kappaB-activating kinase-associated protein 1 participates in TLR3/Toll-IL-1 homology domain-containing adapter molecule-1-mediated IFN regulatory factor 3 activation." Sasai M., Oshiumi H., Matsumoto M., Inoue N., Fujita F., Nakanishi M., Seya T. J. Immunol. 174:27-30(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH AZI2.
[14]	"The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling." Carty M., Goodbody R., Schroeder M., Stack J., Moynagh P.N., Bowie A.G. Nat. Immunol. 7:1074-1081(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SARM1.
[15]	"The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling." O'Neill L.A., Bowie A.G. Nat. Rev. Immunol. 7:353-364(2007) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[16]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[17]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] ILE-46.
[18]	"Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency." Sancho-Shimizu V., Perez de Diego R., Lorenzo L., Halwani R., Alangari A., Israelsson E., Fabrega S., Cardon A., Maluenda J., Tatematsu M., Mahvelati F., Herman M., Ciancanelli M., Guo Y., AlSum Z., Alkhamis N., Al-Makadma A.S., Ghadiri A. , Boucherit S., Plancoulaine S., Picard C., Rozenberg F., Tardieu M., Lebon P., Jouanguy E., Rezaei N., Seya T., Matsumoto M., Chaussabel D., Puel A., Zhang S.Y., Abel L., Al-Muhsen S., Casanova J.L. J. Clin. Invest. 121:4889-4902(2011) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HSE4 LEU-186.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AB093555 mRNA. Translation: BAC44839.1.
AB086380 mRNA. Translation: BAC55579.1.
AB446484 mRNA. Translation: BAG55261.1.
AB097023 mRNA. Translation: BAC77376.1.
BC009860 mRNA. Translation: AAH09860.2.
BC136556 mRNA. Translation: AAI36557.1.
BC136557 mRNA. Translation: AAI36558.1.
AF492646 mRNA. Translation: AAO85488.1. Frameshift.
AF070530 mRNA. Translation: AAC28630.1.

IPI

IPI00216715.

RefSeq

NP_891549.1. NM_182919.3.

UniGene

Hs.29344.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3RC4	X-ray	1.50	B	360-372	[»]

ProteinModelPortal

Q8IUC6.

SMR

Q8IUC6. Positions 391-518.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-33490N.

IntAct

Q8IUC6. 4 interactions.

MINT

MINT-1202912.

STRING

9606.ENSP00000248244.

PTM databases

PhosphoSite

Q8IUC6.

Polymorphism databases

DMDM

74727957.

Proteomic databases

PaxDb

Q8IUC6.

PRIDE

Q8IUC6.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000248244; ENSP00000248244; ENSG00000127666.

GeneID

148022.

KEGG

hsa:148022.

UCSC

uc002mbi.3. human.

Organism-specific databases

CTD

148022.

GeneCards

GC19M004815.

HGNC

HGNC:18348. TICAM1.

HPA

HPA042460.

MIM

607601. gene.
614850. phenotype.

neXtProt

NX_Q8IUC6.

Orphanet

1930. Herpetic encephalitis.

PharmGKB

PA142670812.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG67739.

HOGENOM

HOG000068973.

HOVERGEN

HBG108551.

InParanoid

Q8IUC6.

KO

K05842.

OMA

FCEDFQV.

OrthoDB

EOG4MKNFV.

PhylomeDB

Q8IUC6.

Enzyme and pathway databases

Reactome

REACT_6900. Immune System.

Gene expression databases

Bgee

Q8IUC6.

CleanEx

HS_TICAM1.

Genevestigator

Q8IUC6.

Family and domain databases

InterPro

IPR025735. RHIM_dom.
IPR017278. Tol-interleuk_rcpt_adapt_Ticam.
[Graphical view]

PANTHER

PTHR22811:SF1. PTHR22811:SF1. 1 hit.

Pfam

PF12721. RHIM. 1 hit.
[Graphical view]

PIRSF

PIRSF037744. TIR_Ticam. 1 hit.

PROSITE

PS50104. TIR. False negative.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

Q8IUC6.

GenomeRNAi

148022.

NextBio

85815.

SOURCE

Search...

Entry information

Entry name

TCAM1_HUMAN

Accession

Primary (citable) accession number: Q8IUC6
Secondary accession number(s): B3Y691 , O75532, Q86XP8, Q96GA0

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 5, 2008
Last sequence update:	March 1, 2003
Last modified:	May 1, 2013
This is version 88 of the entry and version 1 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.