Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

Q86XR7 (TCAM2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 114. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
TIR domain-containing adapter molecule 2

Short name=TICAM-2
Alternative name(s):
Putative NF-kappa-B-activating protein 502
TRIF-related adapter molecule
Toll-like receptor adaptor protein 3
Toll/interleukin-1 receptor domain-containing protein
Short name=MyD88-4
Gene names
Name:TICAM2
Synonyms:TIRAP3, TIRP, TRAM
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length235 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Functions as sorting adapter in LPS-TLR4 signaling to regulate the MYD88-independent pathway during the innate immune response to LPS. Physically bridges TLR4 and TICAM1 and functionally transmits LPS-TRL4 signal to TICAM1; signaling is proposed to occur in early endosomes after endocytosis of TLR4. May also be involved in IL1-triggered NF-kappa-B activation, functioning upstream of IRAK1, IRAK2, TRAF6, and IKBKB; however, reports are controversial. Involved in IL-18 signaling and is proposed to function as a sorting adaptor for MYD88 in IL-18 signaling during adaptive immune response. Ref.1 Ref.2 Ref.3 Ref.6 Ref.11 Ref.12 Ref.13

Isoform 2:Proposed to inhibit LPS-TLR4 signaling at the late endosome by interaction with isoform 1 thereby disrupting the association of isoform 1 with TICAM1. May be involved in TLR4 degradation in late endosomes. Ref.1 Ref.2 Ref.3 Ref.6 Ref.11 Ref.12 Ref.13

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. Isoform 1 interacts with isoform 2;the interaction occurs in late endosomes and disrupts the interaction between isoform 1 and TICAM1. Interacts with MYD88; the interaction decreases after IL-18 stimulation in a time-dependent manner. Interacts with IL18R1 and IL18RAP. Ref.1 Ref.2 Ref.3 Ref.13

Subcellular location

Isoform 1: Cytoplasm. Golgi apparatus. Cell membrane. Endoplasmic reticulum. Early endosome membrane. Late endosome membrane. Note: Localized to the plasma membrane as a result of myristoylation. Phosphorylation on Ser-16 leads to its depletion from the membrane. Upon LPS stimulation colcoalizes with isoform 2 in late endosomes. Ref.6 Ref.11 Ref.12

Isoform 2: Endoplasmic reticulum. Early endosome membrane. Late endosome membrane. Note: Translocates to late endosomes upon LPS stimulation where it colcoalizes with isoform 1. Ref.6 Ref.11 Ref.12

Tissue specificity

Expressed in spleen, prostate, testis, uterus, small intestine, colon, peripheral blood leukocytes, heart, placenta, lung, liver, skeletal muscle, and pancreas Isoform 2 is ubiquitously expressed (at lower levels than isoform 1) Ref.1 Ref.2 Ref.6

Domain

The TIR domain mediates the interaction with TRAF6 and MYD88. Ref.1

Post-translational modification

Phosphorylated by PRKCE in response to LPS. Phosphorylation is essential for its function. It is depleted from the membrane upon phosphorylation. Ref.12

Isoform 1 is myristoylated. Required for membrane association which is critical for its ability to initiate efficient signaling.

Sequence similarities

Contains 1 TIR domain.

Ontologies

Keywords
   Biological processImmunity
Inflammatory response
Innate immunity
   Cellular componentCell membrane
Cytoplasm
Endoplasmic reticulum
Endosome
Golgi apparatus
Membrane
   Coding sequence diversityAlternative splicing
   PTMLipoprotein
Myristate
Phosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processI-kappaB kinase/NF-kappaB signaling

Traceable author statement. Source: Reactome

MyD88-independent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

TRAM-dependent toll-like receptor 4 signaling pathway

Inferred from direct assay PubMed 194121844PubMed 194121844. Source: UniProtKB

TRIF-dependent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

cellular response to lipopolysaccharide

Inferred from direct assay PubMed 194121844PubMed 194121844. Source: UniProtKB

inflammatory response

Inferred from electronic annotation. Source: UniProtKB-KW

innate immune response

Traceable author statement. Source: Reactome

negative regulation of chemokine (C-C motif) ligand 5 production

Inferred from mutant phenotype PubMed 194121844. Source: UniProtKB

negative regulation of toll-like receptor 4 signaling pathway

Inferred from direct assay PubMed 194121844. Source: UniProtKB

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from mutant phenotype Ref.7. Source: UniProtKB

positive regulation of chemokine (C-C motif) ligand 5 production

Inferred from mutant phenotype PubMed 194121844. Source: UniProtKB

positive regulation of interleukin-18-mediated signaling pathway

Inferred from mutant phenotype Ref.13. Source: UniProtKB

positive regulation of toll-like receptor 4 signaling pathway

Inferred from direct assay PubMed 194121844. Source: UniProtKB

toll-like receptor 3 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 4 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

   Cellular_componentGolgi apparatus

Inferred from electronic annotation. Source: UniProtKB-SubCell

early endosome

Inferred from direct assay PubMed 194121844PubMed 194121844. Source: UniProtKB

early endosome membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

endoplasmic reticulum

Inferred from direct assay PubMed 194121844PubMed 194121844. Source: UniProtKB

endosome membrane

Traceable author statement. Source: Reactome

late endosome

Inferred from direct assay PubMed 194121844PubMed 194121844. Source: UniProtKB

late endosome membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

plasma membrane

Inferred from direct assay PubMed 194121844. Source: UniProtKB

   Molecular_functionsignal transducer activity

Inferred from mutant phenotype Ref.7. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q86XR7-1)

Also known as: TRAM;

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: Q86XR7-2)

Also known as: TAG; TRAM adaptor with GOLD domain;

The sequence of this isoform differs from the canonical sequence as follows:
     1-20: MGIGKSKINSCPLSLSWGKR → MPRPGSAQRW...EDLNTRVAYW

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed
Chain2 – 235234TIR domain-containing adapter molecule 2
PRO_0000317689

Regions

Domain73 – 232160TIR

Amino acid modifications

Modified residue161Phosphoserine; by PKC/PRKCE Ref.12
Lipidation21N-myristoyl glycine Ref.11

Natural variations

Alternative sequence1 – 2020MGIGK…SWGKR → MPRPGSAQRWAAVAGRWGCR LLALLLLVPGPGGASEITFE LPDNAKQCFYEDIAQGTKCT LEFQVITGGHYDVDCRLEDP DGKVLYKEMKKQYDSFTFTA SKNGTYKFCFSNEFSTFTHK TVYFDFQVGEDPPLFPSENR VSALTQMESACVSIHEALKS VIDYQTHFRLREAQGRSRAE DLNTRVAYW in isoform 2.
VSP_047437

Experimental info

Mutagenesis21G → A: Results in relocalization from membrane to cytosol; Loss of ability to transduce TLR4-signal. Ref.11
Mutagenesis61S → A: Loss of phosphorylation. Significant reduction in the ability to activate IRF3 or NF-kappa-B. Ref.12
Mutagenesis101S → A: No effect on phosphorylation and on the ability to activate IRF3 or NF-kappa-B. Ref.12
Mutagenesis141S → A: No effect on phosphorylation and on the ability to activate IRF3 or NF-kappa-B. Ref.12
Mutagenesis161S → A: Loss of phosphorylation. Abolishes ability to activate IRF3 or NF-kappa-B and to transduce TLR4 signal. Ref.12
Mutagenesis161S → E: Significant decrease of localization in the membrane. Ref.12
Mutagenesis1161P → 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
Mutagenesis1171C → 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

Secondary structure

.................................... 235
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (TRAM) [UniParc].

Last modified June 1, 2003. Version 1.
Checksum: 2D1171F9B04D9C4C

FASTA23526,916
        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 

« Hide

Isoform 2 (TAG) (TRAM adaptor with GOLD domain) [UniParc].

Checksum: C539E6D9B8185764
Show »

FASTA40446,173

References

« Hide '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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), 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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), 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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), 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]"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]"TAG, a splice variant of the adaptor TRAM, negatively regulates the adaptor MyD88-independent TLR4 pathway."
Palsson-McDermott E.M., Doyle S.L., McGettrick A.F., Hardy M., Husebye H., Banahan K., Gong M., Golenbock D., Espevik T., O'Neill L.A.
Nat. Immunol. 10:579-586(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION (ISOFORM 2), SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Lung.
[8]"The DNA sequence and comparative analysis of human chromosome 5."
Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S. expand/collapse author list , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.
Nature 431:268-274(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. expand/collapse author list , 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].
[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] (ISOFORM 1).
[11]"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] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, MYRISTOYLATION AT GLY-2, MUTAGENESIS OF GLY-2.
[12]"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] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-16, MUTAGENESIS OF SER-6; SER-10; SER-14 AND SER-16.
[13]"TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88."
Ohnishi H., Tochio H., Kato Z., Kawamoto N., Kimura T., Kubota K., Yamamoto T., Funasaka T., Nakano H., Wong R.W., Shirakawa M., Kondo N.
PLoS ONE 7:E38423-E38423(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH MYD88; IL18R1 AND IL18RAP.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AY275836 mRNA. Translation: AAP81748.1.
AB109098 mRNA. Translation: BAC98399.1.
AB091054 mRNA. Translation: BAC98397.1.
AY232653 mRNA. Translation: AAO74498.1.
AY304581 mRNA. Translation: AAQ97430.1.
AY304582 mRNA. Translation: AAQ97431.1.
AY304583 mRNA. Translation: AAQ97432.1.
AY304584 mRNA. Translation: AAQ97433.1.
AB446491 mRNA. Translation: BAG55268.1.
AB097022 mRNA. Translation: BAC77375.1.
AC010226 Genomic DNA. No translation available.
CH471086 Genomic DNA. Translation: EAW48960.1.
CH471086 Genomic DNA. Translation: EAW48961.1.
BC109265 mRNA. Translation: AAI09266.1.
BC109266 mRNA. Translation: AAI09267.1.
CCDSCCDS4119.1. [Q86XR7-1]
RefSeqNP_001157940.1. NM_001164468.3. [Q86XR7-2]
NP_001157941.1. NM_001164469.3.
NP_067681.1. NM_021649.7. [Q86XR7-1]
UniGeneHs.718838.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2M1WNMR-A75-235[»]
ProteinModelPortalQ86XR7.
SMRQ86XR7. Positions 75-235.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid131694. 9 interactions.
970651. 1 interaction.
IntActQ86XR7. 10 interactions.
STRING9606.ENSP00000386341.

PTM databases

PhosphoSiteQ86XR7.

Polymorphism databases

DMDM74727858.

Proteomic databases

MaxQBQ86XR7.
PaxDbQ86XR7.
PRIDEQ86XR7.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000408996; ENSP00000386341; ENSG00000243414. [Q86XR7-2]
ENST00000427199; ENSP00000415139; ENSG00000243414. [Q86XR7-1]
GeneID100302736.
353376.
KEGGhsa:100302736.
hsa:353376.
UCSCuc003krc.3. human. [Q86XR7-1]

Organism-specific databases

CTD100302736.
353376.
GeneCardsGC05M114942.
HGNCHGNC:21354. TICAM2.
MIM608321. gene.
neXtProtNX_Q86XR7.
PharmGKBPA134881157.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG43987.
HOGENOMHOG000068974.
HOVERGENHBG102133.
KOK05409.
OMATRVAYCH.
OrthoDBEOG70ZZP7.
PhylomeDBQ86XR7.
TreeFamTF313000.

Enzyme and pathway databases

ReactomeREACT_6900. Immune System.
SignaLinkQ86XR7.

Gene expression databases

BgeeQ86XR7.
CleanExHS_TICAM2.
GenevestigatorQ86XR7.

Family and domain databases

Gene3D3.40.50.10140. 1 hit.
InterProIPR000157. TIR_dom.
IPR015720. TMP21-related.
[Graphical view]
PANTHERPTHR22811. PTHR22811. 1 hit.
PfamPF13676. TIR_2. 1 hit.
[Graphical view]
SUPFAMSSF52200. SSF52200. 1 hit.
PROSITEPS50104. TIR. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiTICAM2.
NextBio20796124.
PROQ86XR7.
SOURCESearch...

Entry information

Entry nameTCAM2_HUMAN
AccessionPrimary (citable) accession number: Q86XR7
Secondary accession number(s): B3Y698, Q6JUT2
Entry history
Integrated into UniProtKB/Swiss-Prot: February 5, 2008
Last sequence update: June 1, 2003
Last modified: July 9, 2014
This is version 114 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 5

Human chromosome 5: entries, gene names and cross-references to MIM