TIRAP_HUMAN
ID TIRAP_HUMAN Reviewed; 221 AA.
AC P58753; B3KW65; Q56UH9; Q56UI0; Q8N5E5;
DT 27-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2004, sequence version 2.
DT 03-AUG-2022, entry version 180.
DE RecName: Full=Toll/interleukin-1 receptor domain-containing adapter protein;
DE Short=TIR domain-containing adapter protein;
DE AltName: Full=Adaptor protein Wyatt;
DE AltName: Full=MyD88 adapter-like protein;
DE Short=MyD88-2;
GN Name=TIRAP; Synonyms=MAL;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), MUTAGENESIS OF PRO-125, AND VARIANT
RP ASN-55.
RC TISSUE=Dendritic cell;
RX PubMed=11544529; DOI=10.1038/35092578;
RA Fitzgerald K.A., Palsson-McDermott E.M., Bowie A.G., Jefferies C.A.,
RA Mansell A.S., Brady G., Brint E., Dunne A., Gray P., Harte M.T.,
RA McMurray D., Smith D.E., Sims J.E., Bird T.A., O'Neill L.A.J.;
RT "Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal
RT transduction.";
RL Nature 413:78-83(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), MUTAGENESIS OF PRO-125, AND
RP INTERACTION WITH EIF2AK2.
RX PubMed=11526399; DOI=10.1038/ni0901-835;
RA Horng T., Barton G.M., Medzhitov R.;
RT "TIRAP: an adapter molecule in the Toll signaling pathway.";
RL Nat. Immunol. 2:835-841(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Kirk P.B., Pereira J.P., Bazan J.F.;
RT "Characterization and structural analysis of TIR domain-containing adaptor
RT protein Wyatt.";
RL Submitted (AUG-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RA Hardy M.P., O'Neill L.A.J.;
RT "Two isoforms of MAL, generated by alternative splicing, are found in
RT humans but not mice.";
RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=18810425; DOI=10.1007/s00251-008-0332-0;
RA Nakajima T., Ohtani H., Satta Y., Uno Y., Akari H., Ishida T., Kimura A.;
RT "Natural selection in the TLR-related genes in the course of primate
RT evolution.";
RL Immunogenetics 60:727-735(2008).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP ASN-55.
RC TISSUE=Brain, and Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS PRO-9; TRP-13; ASN-96 AND
RP LEU-180.
RG SeattleSNPs variation discovery resource;
RL Submitted (APR-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Blood;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP INTERACTION WITH TBK1.
RX PubMed=14530355; DOI=10.4049/jimmunol.171.8.4304;
RA Sato S., Sugiyama M., Yamamoto M., Watanabe Y., Kawai T., Takeda K.,
RA Akira S.;
RT "Toll/IL-1 receptor domain-containing adapter inducing IFN-beta (TRIF)
RT associates with TNF receptor-associated factor 6 and TANK-binding kinase 1,
RT and activates two distinct transcription factors, NF-kappa B and IFN-
RT regulatory factor-3, in the Toll-like receptor signaling.";
RL J. Immunol. 171:4304-4310(2003).
RN [12]
RP PHOSPHORYLATION BY BTK, AND UBIQUITINATION.
RX PubMed=16415872; DOI=10.1038/ni1299;
RA Mansell A., Smith R., Doyle S.L., Gray P., Fenner J.E., Crack P.J.,
RA Nicholson S.E., Hilton D.J., O'Neill L.A., Hertzog P.J.;
RT "Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor
RT signaling by mediating Mal degradation.";
RL Nat. Immunol. 7:148-155(2006).
RN [13]
RP FUNCTION, AND INTERACTION WITH BMX.
RX PubMed=18292575; DOI=10.4049/jimmunol.180.5.3485;
RA Semaan N., Alsaleh G., Gottenberg J.E., Wachsmann D., Sibilia J.;
RT "Etk/BMX, a Btk family tyrosine kinase, and Mal contribute to the cross-
RT talk between MyD88 and FAK pathways.";
RL J. Immunol. 180:3485-3491(2008).
RN [14]
RP FUNCTION, INTERACTION WITH MYD88, VARIANT ASN-96, AND CHARACTERIZATION OF
RP VARIANTS PRO-9; TRP-13; ASN-96; LEU-180 AND ILE-197.
RX PubMed=19509286; DOI=10.1074/jbc.m109.014886;
RA Nagpal K., Plantinga T.S., Wong J., Monks B.G., Gay N.J., Netea M.G.,
RA Fitzgerald K.A., Golenbock D.T.;
RT "A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of
RT MyD88 binding and reduced TLR2/TLR4 signaling.";
RL J. Biol. Chem. 284:25742-25748(2009).
RN [15]
RP INTERACTION WITH MYD88, AND SUBCELLULAR LOCATION.
RX PubMed=19948740; DOI=10.1074/jbc.m109.069385;
RA Wan T., Liu T., Zhang H., Tang S., Min W.;
RT "AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling.";
RL J. Biol. Chem. 285:3750-3757(2010).
RN [16]
RP PHOSPHORYLATION BY IRAK1 AND IRAK4.
RX PubMed=20400509; DOI=10.1074/jbc.m109.098137;
RA Dunne A., Carpenter S., Brikos C., Gray P., Strelow A., Wesche H.,
RA Morrice N., O'Neill L.A.;
RT "IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation
RT of MyD88 adaptor-like (Mal).";
RL J. Biol. Chem. 285:18276-18282(2010).
RN [17]
RP INTERACTION WITH BRUCELLA PROTEIN BTPA (MICROBIAL INFECTION).
RX PubMed=27311859; DOI=10.1016/j.bbrc.2016.06.064;
RA Li W., Ke Y., Wang Y., Yang M., Gao J., Zhan S., Xinying D., Huang L.,
RA Li W., Chen Z., Li J.;
RT "Brucella TIR-like protein TcpB/Btp1 specifically targets the host adaptor
RT protein MAL/TIRAP to promote infection.";
RL Biochem. Biophys. Res. Commun. 477:509-514(2016).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (3.01 ANGSTROMS) OF 79-221, SUBUNIT, AND DISULFIDE
RP BONDS.
RX PubMed=21873236; DOI=10.1073/pnas.1104780108;
RA Valkov E., Stamp A., Dimaio F., Baker D., Verstak B., Roversi P.,
RA Kellie S., Sweet M.J., Mansell A., Gay N.J., Martin J.L., Kobe B.;
RT "Crystal structure of Toll-like receptor adaptor MAL/TIRAP reveals the
RT molecular basis for signal transduction and disease protection.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:14879-14884(2011).
RN [19]
RP VARIANT LEU-180, AND POLYMORPHISM.
RX PubMed=17322885; DOI=10.1038/ng1976;
RA Khor C.C., Chapman S.J., Vannberg F.O., Dunne A., Murphy C., Ling E.Y.,
RA Frodsham A.J., Walley A.J., Kyrieleis O., Khan A., Aucan C., Segal S.,
RA Moore C.E., Knox K., Campbell S.J., Lienhardt C., Scott A., Aaby P.,
RA Sow O.Y., Grignani R.T., Sillah J., Sirugo G., Peshu N., Williams T.N.,
RA Maitland K., Davies R.J.O., Kwiatkowski D.P., Day N.P., Yala D.,
RA Crook D.W., Marsh K., Berkley J.A., O'Neill L.A.J., Hill A.V.S.;
RT "A Mal functional variant is associated with protection against invasive
RT pneumococcal disease, bacteremia, malaria and tuberculosis.";
RL Nat. Genet. 39:523-528(2007).
RN [20]
RP VARIANT LEU-180, AND POLYMORPHISM.
RX PubMed=19602285; DOI=10.1186/1471-2350-10-65;
RA Hamann L., Kumpf O., Schuring R.P., Alpsoy E., Bedu-Addo G., Bienzle U.,
RA Oskam L., Mockenhaupt F.P., Schumann R.R.;
RT "Low frequency of the TIRAP S180L polymorphism in Africa, and its potential
RT role in malaria, sepsis, and leprosy.";
RL BMC Med. Genet. 10:65-65(2009).
CC -!- FUNCTION: Adapter involved in TLR2 and TLR4 signaling pathways in the
CC innate immune response. Acts via IRAK2 and TRAF-6, leading to the
CC activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in
CC cytokine secretion and the inflammatory response. Positively regulates
CC the production of TNF-alpha and interleukin-6.
CC {ECO:0000269|PubMed:18292575, ECO:0000269|PubMed:19509286}.
CC -!- SUBUNIT: Homodimer. Also forms heterodimers with MYD88. May interact
CC with PIK3AP1 (By similarity). Interacts with TLR4 and IRAK2 via their
CC respective TIR domains. Interacts with BMX and TBK1. Interacts with
CC EIF2AK2. Does not interact with IRAK1, nor TLR9. {ECO:0000250,
CC ECO:0000269|PubMed:11526399, ECO:0000269|PubMed:14530355,
CC ECO:0000269|PubMed:18292575, ECO:0000269|PubMed:19509286,
CC ECO:0000269|PubMed:19948740, ECO:0000269|PubMed:21873236}.
CC -!- SUBUNIT: (Microbial infection) In case of infection, interacts with
CC Brucella protein BtpA. {ECO:0000269|PubMed:27311859}.
CC -!- INTERACTION:
CC P58753; Q15109: AGER; NbExp=9; IntAct=EBI-528644, EBI-1646426;
CC P58753; P10398: ARAF; NbExp=2; IntAct=EBI-528644, EBI-365961;
CC P58753; Q96A33: CCDC47; NbExp=2; IntAct=EBI-528644, EBI-720151;
CC P58753; P51617: IRAK1; NbExp=2; IntAct=EBI-528644, EBI-358664;
CC P58753; O43187: IRAK2; NbExp=2; IntAct=EBI-528644, EBI-447733;
CC P58753; Q9NWZ3: IRAK4; NbExp=2; IntAct=EBI-528644, EBI-448378;
CC P58753; O94822: LTN1; NbExp=2; IntAct=EBI-528644, EBI-1044684;
CC P58753; Q99836: MYD88; NbExp=8; IntAct=EBI-528644, EBI-447677;
CC P58753; P27986: PIK3R1; NbExp=3; IntAct=EBI-528644, EBI-79464;
CC P58753; Q9Y3Z3: SAMHD1; NbExp=2; IntAct=EBI-528644, EBI-1054601;
CC P58753; P58753: TIRAP; NbExp=2; IntAct=EBI-528644, EBI-528644;
CC P58753; O00206: TLR4; NbExp=6; IntAct=EBI-528644, EBI-528701;
CC P58753-2; P29466: CASP1; NbExp=5; IntAct=EBI-528654, EBI-516667;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19948740}. Cell
CC membrane {ECO:0000269|PubMed:19948740}. Membrane
CC {ECO:0000269|PubMed:19948740}. Note=Colocalizes with DAB2IP at the
CC plasma membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=P58753-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P58753-2; Sequence=VSP_010765;
CC Name=3;
CC IsoId=P58753-3; Sequence=VSP_017239;
CC -!- TISSUE SPECIFICITY: Highly expressed in liver, kidney, spleen, skeletal
CC muscle and heart. Also detected in peripheral blood leukocytes, lung,
CC placenta, small intestine, thymus, colon and brain.
CC -!- PTM: Phosphorylated by IRAK1 and IRAK4. Also phosphorylated by BTK.
CC -!- PTM: Polyubiquitinated. Polyubiquitination follows phosphorylation by
CC BTK and leads to TIRAP degradation. {ECO:0000269|PubMed:16415872}.
CC -!- POLYMORPHISM: Genetic variations in TIRAP may influence susceptibility
CC or resistance to invasive pneumococcal disease, malaria [MIM:611162],
CC and tuberculosis [MIM:607948]. It may define the bacteremia
CC susceptibility locus 1 (BACTS1) [MIM:614382].
CC {ECO:0000269|PubMed:17322885, ECO:0000269|PubMed:19602285}.
CC -!- CAUTION: Variant Leu-180 has been reported to reduce TLR2 signal
CC transduction (PubMed:17322885). In contrast, PubMed:19509286 reports
CC that this variant is fully active and has no effect on signal
CC transduction pathways and cytokine production.
CC {ECO:0000305|PubMed:17322885}.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/tirap/";
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DR EMBL; AF406652; AAL01160.1; -; mRNA.
DR EMBL; AF378129; AAL05627.1; -; mRNA.
DR EMBL; AF410783; AAL05036.1; -; mRNA.
DR EMBL; AY576785; AAT90417.1; -; mRNA.
DR EMBL; AY576786; AAT90418.1; -; mRNA.
DR EMBL; AY576787; AAT90419.1; -; mRNA.
DR EMBL; AB446477; BAG55254.1; -; mRNA.
DR EMBL; AK124298; BAG54027.1; -; mRNA.
DR EMBL; AK313147; BAG35965.1; -; mRNA.
DR EMBL; AY282416; AAP31973.1; -; Genomic_DNA.
DR EMBL; AP001318; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471065; EAW67687.1; -; Genomic_DNA.
DR EMBL; CH471065; EAW67689.1; -; Genomic_DNA.
DR EMBL; BC032474; AAH32474.1; -; mRNA.
DR CCDS; CCDS41731.1; -. [P58753-2]
DR CCDS; CCDS8472.1; -. [P58753-1]
DR RefSeq; NP_001034750.1; NM_001039661.1. [P58753-1]
DR RefSeq; NP_001305705.1; NM_001318776.1. [P58753-2]
DR RefSeq; NP_001305706.1; NM_001318777.1. [P58753-1]
DR RefSeq; NP_683708.1; NM_148910.2. [P58753-2]
DR RefSeq; XP_005271456.2; XM_005271399.3.
DR RefSeq; XP_011540878.1; XM_011542576.2.
DR RefSeq; XP_016872651.1; XM_017017162.1.
DR PDB; 2NDH; NMR; -; A=79-221.
DR PDB; 2Y92; X-ray; 3.01 A; A=79-221.
DR PDB; 3UB2; X-ray; 2.40 A; A=78-221.
DR PDB; 3UB3; X-ray; 2.75 A; A=78-221.
DR PDB; 3UB4; X-ray; 3.10 A; A=78-221.
DR PDB; 4FZ5; X-ray; 3.60 A; A/B=72-221.
DR PDB; 4LQD; X-ray; 2.45 A; A=81-221.
DR PDB; 5T7Q; NMR; -; A=15-35.
DR PDB; 5UZB; EM; 7.00 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N=79-221.
DR PDBsum; 2NDH; -.
DR PDBsum; 2Y92; -.
DR PDBsum; 3UB2; -.
DR PDBsum; 3UB3; -.
DR PDBsum; 3UB4; -.
DR PDBsum; 4FZ5; -.
DR PDBsum; 4LQD; -.
DR PDBsum; 5T7Q; -.
DR PDBsum; 5UZB; -.
DR AlphaFoldDB; P58753; -.
DR SMR; P58753; -.
DR BioGRID; 125325; 44.
DR DIP; DIP-33489N; -.
DR IntAct; P58753; 43.
DR MINT; P58753; -.
DR STRING; 9606.ENSP00000376445; -.
DR TCDB; 8.A.43.1.22; the neat-domain containing methaemoglobin heme sequestration (n-mhs) family.
DR GlyGen; P58753; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P58753; -.
DR PhosphoSitePlus; P58753; -.
DR BioMuta; TIRAP; -.
DR DMDM; 50403750; -.
DR jPOST; P58753; -.
DR MassIVE; P58753; -.
DR PaxDb; P58753; -.
DR PeptideAtlas; P58753; -.
DR PRIDE; P58753; -.
DR ProteomicsDB; 57101; -. [P58753-1]
DR ProteomicsDB; 57102; -. [P58753-2]
DR ProteomicsDB; 57103; -. [P58753-3]
DR Antibodypedia; 19148; 534 antibodies from 40 providers.
DR DNASU; 114609; -.
DR Ensembl; ENST00000392678.7; ENSP00000376445.3; ENSG00000150455.14. [P58753-2]
DR Ensembl; ENST00000392679.6; ENSP00000376446.1; ENSG00000150455.14. [P58753-1]
DR Ensembl; ENST00000392680.6; ENSP00000376447.2; ENSG00000150455.14. [P58753-1]
DR Ensembl; ENST00000479770.1; ENSP00000436967.1; ENSG00000150455.14. [P58753-1]
DR GeneID; 114609; -.
DR KEGG; hsa:114609; -.
DR MANE-Select; ENST00000392679.6; ENSP00000376446.1; NM_001318777.2; NP_001305706.1.
DR UCSC; uc001qdl.2; human. [P58753-1]
DR CTD; 114609; -.
DR DisGeNET; 114609; -.
DR GeneCards; TIRAP; -.
DR HGNC; HGNC:17192; TIRAP.
DR HPA; ENSG00000150455; Low tissue specificity.
DR MalaCards; TIRAP; -.
DR MIM; 606252; gene.
DR MIM; 607948; phenotype.
DR MIM; 611162; phenotype.
DR MIM; 614382; phenotype.
DR neXtProt; NX_P58753; -.
DR OpenTargets; ENSG00000150455; -.
DR PharmGKB; PA134972842; -.
DR VEuPathDB; HostDB:ENSG00000150455; -.
DR eggNOG; ENOG502S07Q; Eukaryota.
DR GeneTree; ENSGT00510000048428; -.
DR HOGENOM; CLU_091033_1_0_1; -.
DR InParanoid; P58753; -.
DR OMA; FLCDPWC; -.
DR OrthoDB; 1327598at2759; -.
DR PhylomeDB; P58753; -.
DR TreeFam; TF330734; -.
DR PathwayCommons; P58753; -.
DR Reactome; R-HSA-1236974; ER-Phagosome pathway.
DR Reactome; R-HSA-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane.
DR Reactome; R-HSA-5602498; MyD88 deficiency (TLR2/4).
DR Reactome; R-HSA-5603041; IRAK4 deficiency (TLR2/4).
DR SignaLink; P58753; -.
DR SIGNOR; P58753; -.
DR BioGRID-ORCS; 114609; 18 hits in 1082 CRISPR screens.
DR ChiTaRS; TIRAP; human.
DR GenomeRNAi; 114609; -.
DR Pharos; P58753; Tbio.
DR PRO; PR:P58753; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P58753; protein.
DR Bgee; ENSG00000150455; Expressed in oviduct epithelium and 112 other tissues.
DR ExpressionAtlas; P58753; baseline and differential.
DR Genevisible; P58753; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030139; C:endocytic vesicle; ISS:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0032587; C:ruffle membrane; ISS:BHF-UCL.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; ISS:BHF-UCL.
DR GO; GO:0005080; F:protein kinase C binding; IPI:BHF-UCL.
DR GO; GO:0030674; F:protein-macromolecule adaptor activity; NAS:BHF-UCL.
DR GO; GO:0035663; F:Toll-like receptor 2 binding; IPI:BHF-UCL.
DR GO; GO:0035662; F:Toll-like receptor 4 binding; IPI:BHF-UCL.
DR GO; GO:0070935; P:3'-UTR-mediated mRNA stabilization; IDA:BHF-UCL.
DR GO; GO:0007250; P:activation of NF-kappaB-inducing kinase activity; IMP:AgBase.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0071221; P:cellular response to bacterial lipopeptide; ISS:BHF-UCL.
DR GO; GO:0071223; P:cellular response to lipoteichoic acid; ISS:BHF-UCL.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; ISS:BHF-UCL.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; IBA:GO_Central.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:BHF-UCL.
DR GO; GO:0030099; P:myeloid cell differentiation; ISS:BHF-UCL.
DR GO; GO:0030890; P:positive regulation of B cell proliferation; ISS:BHF-UCL.
DR GO; GO:2000340; P:positive regulation of chemokine (C-X-C motif) ligand 1 production; ISS:BHF-UCL.
DR GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; ISS:BHF-UCL.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:BHF-UCL.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IMP:BHF-UCL.
DR GO; GO:0045089; P:positive regulation of innate immune response; IBA:GO_Central.
DR GO; GO:0032735; P:positive regulation of interleukin-12 production; ISS:BHF-UCL.
DR GO; GO:0032738; P:positive regulation of interleukin-15 production; IDA:BHF-UCL.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IMP:BHF-UCL.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IMP:BHF-UCL.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IMP:BHF-UCL.
DR GO; GO:0090023; P:positive regulation of neutrophil chemotaxis; ISS:BHF-UCL.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:BHF-UCL.
DR GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:BHF-UCL.
DR GO; GO:0034137; P:positive regulation of toll-like receptor 2 signaling pathway; IMP:BHF-UCL.
DR GO; GO:0034141; P:positive regulation of toll-like receptor 3 signaling pathway; ISS:BHF-UCL.
DR GO; GO:0034145; P:positive regulation of toll-like receptor 4 signaling pathway; IMP:BHF-UCL.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IMP:BHF-UCL.
DR GO; GO:0045088; P:regulation of innate immune response; IC:BHF-UCL.
DR GO; GO:0032648; P:regulation of interferon-beta production; ISS:BHF-UCL.
DR GO; GO:0032872; P:regulation of stress-activated MAPK cascade; IBA:GO_Central.
DR GO; GO:0032496; P:response to lipopolysaccharide; IDA:BHF-UCL.
DR GO; GO:0035665; P:TIRAP-dependent toll-like receptor 4 signaling pathway; IDA:BHF-UCL.
DR DisProt; DP01768; -.
DR Gene3D; 3.40.50.10140; -; 1.
DR InterPro; IPR000157; TIR_dom.
DR InterPro; IPR017279; Tol-interleuk_rcpt_adapt_Tirap.
DR InterPro; IPR035897; Toll_tir_struct_dom_sf.
DR PANTHER; PTHR22662; PTHR22662; 1.
DR Pfam; PF13676; TIR_2; 1.
DR PIRSF; PIRSF037750; TIR_Tirap; 1.
DR SUPFAM; SSF52200; SSF52200; 1.
DR PROSITE; PS50104; TIR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Cytoplasm;
KW Disulfide bond; Immunity; Inflammatory response; Innate immunity; Membrane;
KW Phosphoprotein; Reference proteome; Ubl conjugation.
FT CHAIN 1..221
FT /note="Toll/interleukin-1 receptor domain-containing
FT adapter protein"
FT /id="PRO_0000072547"
FT DOMAIN 84..213
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT REGION 1..82
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 40..82
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT DISULFID 89..134
FT /evidence="ECO:0000269|PubMed:21873236"
FT DISULFID 142..174
FT /evidence="ECO:0000269|PubMed:21873236"
FT VAR_SEQ 216..221
FT /note="YLQTLS -> CKLLQEGEGERDSATVSDLL (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11526399,
FT ECO:0000303|PubMed:11544529, ECO:0000303|PubMed:14702039,
FT ECO:0000303|Ref.4"
FT /id="VSP_010765"
FT VAR_SEQ 221
FT /note="S -> WHLLYHGTPEIGVKLETENPCRASDSHKCDKRYRE (in isoform
FT 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_017239"
FT VARIANT 9
FT /note="A -> P (does not affect NF-kappa-B activation and
FT TNF-alpha production; dbSNP:rs8177369)"
FT /evidence="ECO:0000269|PubMed:19509286, ECO:0000269|Ref.7"
FT /id="VAR_019143"
FT VARIANT 13
FT /note="R -> W (does not affect NF-kappa-B activation and
FT TNF-alpha production; dbSNP:rs8177399)"
FT /evidence="ECO:0000269|PubMed:19509286, ECO:0000269|Ref.7"
FT /id="VAR_019144"
FT VARIANT 55
FT /note="S -> N (does not affect NF-kappa-B activation and
FT TNF-alpha production; dbSNP:rs3802813)"
FT /evidence="ECO:0000269|PubMed:11544529,
FT ECO:0000269|PubMed:14702039"
FT /id="VAR_036691"
FT VARIANT 96
FT /note="D -> N (hypomorphic variant resulting in impaired
FT NF-kappa-B activation and TNF-alpha production; cannot bind
FT MYD88; dbSNP:rs8177400)"
FT /evidence="ECO:0000269|PubMed:19509286, ECO:0000269|Ref.7"
FT /id="VAR_019145"
FT VARIANT 180
FT /note="S -> L (at heterozygosity it protects against
FT invasive pneumococcal disease, malaria, bacteremia and
FT tuberculosis; does not affect NF-kappa-B activation and
FT TNF-alpha production; attenuates TLR2 signal transduction;
FT dbSNP:rs8177374)"
FT /evidence="ECO:0000269|PubMed:17322885,
FT ECO:0000269|PubMed:19509286, ECO:0000269|PubMed:19602285,
FT ECO:0000269|Ref.7"
FT /id="VAR_019146"
FT VARIANT 197
FT /note="V -> I (does not affect NF-kappa-B activation and
FT TNF-alpha production; dbSNP:rs7932976)"
FT /evidence="ECO:0000269|PubMed:19509286"
FT /id="VAR_061713"
FT MUTAGEN 125
FT /note="P->H: Abolishes NF-kappa-B activation."
FT /evidence="ECO:0000269|PubMed:11526399,
FT ECO:0000269|PubMed:11544529"
FT HELIX 17..28
FT /evidence="ECO:0007829|PDB:5T7Q"
FT STRAND 83..91
FT /evidence="ECO:0007829|PDB:3UB2"
FT HELIX 94..96
FT /evidence="ECO:0007829|PDB:3UB2"
FT HELIX 97..108
FT /evidence="ECO:0007829|PDB:3UB2"
FT TURN 109..111
FT /evidence="ECO:0007829|PDB:2NDH"
FT STRAND 131..133
FT /evidence="ECO:0007829|PDB:3UB2"
FT HELIX 135..139
FT /evidence="ECO:0007829|PDB:2NDH"
FT STRAND 140..147
FT /evidence="ECO:0007829|PDB:3UB2"
FT HELIX 149..153
FT /evidence="ECO:0007829|PDB:3UB2"
FT HELIX 155..166
FT /evidence="ECO:0007829|PDB:3UB2"
FT STRAND 168..179
FT /evidence="ECO:0007829|PDB:3UB2"
FT HELIX 184..186
FT /evidence="ECO:0007829|PDB:3UB2"
FT HELIX 189..193
FT /evidence="ECO:0007829|PDB:3UB2"
FT HELIX 202..205
FT /evidence="ECO:0007829|PDB:3UB2"
FT HELIX 206..217
FT /evidence="ECO:0007829|PDB:3UB2"
SQ SEQUENCE 221 AA; 23883 MW; 44A8454D04704540 CRC64;
MASSTSLPAP GSRPKKPLGK MADWFRQTLL KKPKKRPNSP ESTSSDASQP TSQDSPLPPS
LSSVTSPSLP PTHASDSGSS RWSKDYDVCV CHSEEDLVAA QDLVSYLEGS TASLRCFLQL
RDATPGGAIV SELCQALSSS HCRVLLITPG FLQDPWCKYQ MLQALTEAPG AEGCTIPLLS
GLSRAAYPPE LRFMYYVDGR GPDGGFRQVK EAVMRYLQTL S
