Reviewed, UniProtKB/Swiss-Prot Q86XR7 (TCAM2_HUMAN)

Names and origin

Protein names

Recommended name:
    TIR domain-containing adapter molecule 2
      Short name=TICAM-2
Alternative name(s):
    TRIF-related adapter molecule
    Toll/interleukin-1 receptor domain-containing protein
    Toll-like receptor adaptor protein 3
    Putative NF-kappa-B-activating protein 502

Gene names

Name:	TICAM2
Synonyms:	TIRAP3, TIRP, TRAM

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

Protein attributes

Sequence length	235 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	Functions in LPS-TLR4 signaling to regulate the MYD88-independent pathway during the innate immune response to LPS. Also involved in IL1-triggered NF-kappa-B activation, functioning upstream of IRAK1, IRAK2, TRAF6, and IKBKB. Physically bridges TLR4 and TICAM1 and functionally transmits LPS-TRL4 signal to TICAM1. Ref.1 Ref.2 Ref.3 Ref.10 Ref.11
Subunit structure	Homodimer. Interacts with TLR4, TICAM1, IRF3 and IRF7 in response to LPS. Interacts with IL1R1, IL1RAP, IRAK2, IRAK3 and TRAF6. Interacts with protein kinase-inactive mutants of IRAK1 and IRAK4. Ref.1 Ref.2 Ref.3
Subcellular location	Cytoplasm. Golgi apparatus. Cell membrane. Note: Localized to the plasma membrane as a result of myristoylation. Phosphorylation on Ser-16 leads to its depletion from the membrane. Ref.10 Ref.11
Tissue specificity	Expressed in spleen, prostate, testis, uterus, small intestine, colon, peripheral blood leukocytes, heart, placenta, lung, liver, skeletal muscle, and pancreas. Ref.1 Ref.2
Domain	The TIR domain mediates the interaction with TRAF6. Ref.1
Post-translational modification	Phosphorylated by PKCE in response to LPS. Phosphorylation is essential for its function. It is depleted from the membrane upon phosphorylation. Ref.11 Myristoylated. Required for membrane association which is critical for its ability to initiate efficient signaling.
Sequence similarities	Contains 1 TIR domain.

Ontologies

Keywords
Biological process	Immune response Inflammatory response
Cellular component	Cell membrane Cytoplasm Golgi apparatus Membrane
PTM	Lipoprotein Myristate Phosphoprotein
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 positive regulation of I-kappaB kinase/NF-kappaB cascade Ref.7 Inferred from mutant phenotype. Source: UniProtKB
Cellular component	Golgi apparatus 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...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
IL1R1	P14778	1	EBI-525927,EBI-525905
IL1RAP	Q9NPH3	1	EBI-525927,EBI-525939
TICAM1	Q8IUC6	1	EBI-525927,EBI-525995
TIRAP	P58753	1	EBI-525927,EBI-528644
TRAF6	Q9Y4K3	1	EBI-525927,EBI-359276

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed By similarity
	Chain	2 – 235	234	TIR domain-containing adapter molecule 2		PRO_0000317689
Regions
	Domain	73 – 232	160	TIR
Amino acid modifications
	Modified residue	16	1	Phosphoserine; by PKC/PRKCE Ref.11
	Lipidation	2	1	N-myristoyl glycine
Experimental info
	Mutagenesis	2	1	G → A: Results in relocalization from membrane to cytosol; Loss of ability to transduce TLR4-signal. Ref.10
	Mutagenesis	6	1	S → A: Loss of phosphorylation. Significant reduction in the ability to activate IRF3 or NF-kappa-B. Ref.11
	Mutagenesis	10	1	S → A: No effect on phosphorylation and on the ability to activate IRF3 or NF-kappa-B. Ref.11
	Mutagenesis	14	1	S → A: No effect on phosphorylation and on the ability to activate IRF3 or NF-kappa-B. Ref.11
	Mutagenesis	16	1	S → A: Loss of phosphorylation. Abolishes ability to activate IRF3 or NF-kappa-B and to transduce TLR4 signal. Ref.11
	Mutagenesis	16	1	S → E: Significant decrease of localization in the membrane. Ref.11
	Mutagenesis	116	1	P → H: Loss of ability to dimerize. Significant loss of RANTES-inducing activity. Loss of ability to induce NF-kappa-B activation. Ref.2 Ref.3
	Mutagenesis	117	1	C → H: Loss of ability to dimerize. Loss of RANTES-inducing activity and ability to induce NF-kappa-B activation. Inhibition of TLR4-dependent activation of IRF3 and IRF7. Loss of interaction with TLR4. Ref.2 Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Q86XR7-1 [UniParc]. Last modified June 1, 2003. Version 1. Checksum: 2D1171F9B04D9C4C	FASTA	235	26,916
	10 20 30 40 50 60 MGIGKSKINS CPLSLSWGKR HSVDTSPGYH ESDSKKSEDL SLCNVAEHSN TTEGPTGKQE 70 80 90 100 110 120 GAQSVEEMFE EEAEEEVFLK FVILHAEDDT DEALRVQNLL QDDFGIKPGI IFAEMPCGRQ 130 140 150 160 170 180 HLQNLDDAVN GSAWTILLLT ENFLRDTWCN FQFYTSLMNS VNRQHKYNSV IPMRPLNNPL 190 200 210 220 230 PRERTPFALQ TINALEEESR GFPTQVERIF QESVYKTQQT IWKETRNMVQ RQFIA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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: 12721283] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, DOMAIN, INTERACTION WITH TRAF6; IL1R1; IL1RAP; IRAK1; IRAK2; IRAK3; IRAK4; TIRAP AND TICAM1, TISSUE SPECIFICITY.
[2]	"TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta." Oshiumi H., Sasai M., Shida K., Fujita T., Matsumoto M., Seya T. J. Biol. Chem. 278:49751-49762(2003) [PubMed: 14519765] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBUNIT, INTERACTION WITH TICAM1 AND TLR4, TISSUE SPECIFICITY, MUTAGENESIS OF PRO-116 AND CYS-117.
[3]	"LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF." Fitzgerald K.A., Rowe D.C., Barnes B.J., Caffrey D.R., Visintin A., Latz E., Monks B., Pitha P.M., Golenbock D.T. J. Exp. Med. 198:1043-1055(2003) [PubMed: 14517278] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH TICAM1; TIRAP; TLR4; IRF3 AND IRF7, MUTAGENESIS OF PRO-116 AND CYS-117.
[4]	Erratum Fitzgerald K.A., Rowe D.C., Barnes B.J., Caffrey D.R., Visintin A., Latz E., Monks B., Pitha P.M., Golenbock D.T. J. Exp. Med. 198:1451-1451(2003)
[5]	"Identification of a novel variant of the Toll-like receptor adaptor protein TIRAP3." Hardy M.P., McGettrick A.F., Ejdeback M., O'Neill L.A.J. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[6]	"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].
[7]	"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: 12761501] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung.
[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. , 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 (SEP-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].
[10]	"The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction." Rowe D.C., McGettrick A.F., Latz E., Monks B.G., Gay N.J., Yamamoto M., Akira S., O'Neill L.A., Fitzgerald K.A., Golenbock D.T. Proc. Natl. Acad. Sci. U.S.A. 103:6299-6304(2006) [PubMed: 16603631] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, MYRISTOYLATION AT GLY-2, MUTAGENESIS OF GLY-2.
[11]	"Trif-related adapter molecule is phosphorylated by PKCepsilon during Toll-like receptor 4 signaling." McGettrick A.F., Brint E.K., Palsson-McDermott E.M., Rowe D.C., Golenbock D.T., Gay N.J., Fitzgerald K.A., O'Neill L.A.J. Proc. Natl. Acad. Sci. U.S.A. 103:9196-9201(2006) [PubMed: 16757566] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-16, MUTAGENESIS OF SER-6; SER-10; SER-14 AND SER-16.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AY275836 mRNA. Translation: AAP81748.1. AB109098 mRNA. Translation: BAC98399.1. AB091054 mRNA. Translation: BAC98397.1. AY232653 mRNA. Translation: AAO74498.1. AY304582 mRNA. Translation: AAQ97431.1. AY304583 mRNA. Translation: AAQ97432.1. AB446491 mRNA. Translation: BAG55268.1. AB097022 mRNA. Translation: BAC77375.1. CH471086 Genomic DNA. Translation: EAW48960.1. BC109265 mRNA. Translation: AAI09266.1. BC109266 mRNA. Translation: AAI09267.1.
IPI	IPI00329281.
RefSeq	NP_001157941.1. NP_067681.1.
UniGene	Hs.714734
3D structure databases
ModBase	Search...
Protein-protein interaction databases
IntAct	Q86XR7. 5 interactions.
STRING	Q86XR7.
PTM databases
PhosphoSite	Q86XR7.
Proteomic databases
PRIDE	Q86XR7.
Genome annotation databases
Ensembl	ENST00000282382; ENSP00000282382; ENSG00000134970; Homo sapiens. [Genome view] ENST00000333314; ENSP00000333650; ENSG00000134970; Homo sapiens. [Genome view] ENST00000408996; ENSP00000386341; ENSG00000134970; Homo sapiens. [Genome view] ENST00000427199; ENSP00000415139; ENSG00000134970; Homo sapiens. [Genome view] ENST00000456936; ENSP00000405926; ENSG00000134970; Homo sapiens. [Genome view]
GeneID	100302736. 353376.
KEGG	hsa:353376.
UCSC	uc003krc.1. human.
Organism-specific databases
CTD	353376.
GeneCards	GC05M114942.
HGNC	HGNC:21354. TICAM2.
HPA	CAB025883.
MIM	608321. gene.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	Q86XR7.
Enzyme and pathway databases
Pathway_Interaction_DB	il1pathway. IL1-mediated signaling events.
Reactome	REACT_6900. Signaling in Immune system.
Gene expression databases
ArrayExpress	Q86XR7.
Bgee	Q86XR7.
CleanEx	HS_TICAM2.
Genevestigator	Q86XR7.
Family and domain databases
InterPro	IPR000157. Toll-Interleukin_rcpt. [Graphical view]
PROSITE	PS50104. TIR. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	99804.
SOURCE	Search...

Entry information

Entry name

TCAM2_HUMAN

Accession

Primary (citable) accession number: Q86XR7
Secondary accession number(s): B3Y698

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 5, 2008
Last sequence update:	June 1, 2003
Last modified:	November 3, 2009
This is version 62 of the entry and version 1 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.