ID THA_HUMAN Reviewed; 490 AA. AC P10827; A8K3B5; P21205; Q8N6A1; Q96H73; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-1989, sequence version 1. DT 24-JAN-2024, entry version 254. DE RecName: Full=Thyroid hormone receptor alpha; DE AltName: Full=Nuclear receptor subfamily 1 group A member 1; DE AltName: Full=V-erbA-related protein 7; DE Short=EAR-7; DE AltName: Full=c-erbA-1; DE AltName: Full=c-erbA-alpha; GN Name=THRA; Synonyms=EAR7, ERBA1, NR1A1, THRA1, THRA2; 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 [GENOMIC DNA / MRNA] (ISOFORMS ALPHA-1 AND ALPHA-2). RX PubMed=1850510; DOI=10.1093/nar/19.5.1105; RA Laudet V., Begue A., Henry C., Joubel A., Martin P., Stehelin D., Saule S.; RT "Genomic organization of the human thyroid hormone receptor alpha (c-erbA- RT 1) gene."; RL Nucleic Acids Res. 19:1105-1112(1991). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS ALPHA-1 AND ALPHA-2). RX PubMed=2539258; DOI=10.1016/0092-8674(89)90169-4; RA Miyajima N., Horiuchi R., Shibuya Y., Fukushige S., Matsubara K., RA Toyoshima K., Yamamoto T.; RT "Two erbA homologs encoding proteins with different T3 binding capacities RT are transcribed from opposite DNA strands of the same genetic locus."; RL Cell 57:31-39(1989). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA-2). RC TISSUE=Kidney; RX PubMed=3357890; DOI=10.1073/pnas.85.8.2781; RA Nakai A., Seino S., Sakurai A., Szilak I., Bell G.I., Degroot L.J.; RT "Characterization of a thyroid hormone receptor expressed in human kidney RT and other tissues."; RL Proc. Natl. Acad. Sci. U.S.A. 85:2781-2785(1988). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA-2). RC TISSUE=Testis; RX PubMed=3684612; DOI=10.1093/nar/15.22.9613; RA Pfahl M., Benbrook D.; RT "Nucleotide sequence of cDNA encoding a novel human thyroid hormone RT receptor."; RL Nucleic Acids Res. 15:9613-9613(1987). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM ALPHA-1). RX PubMed=2464749; DOI=10.1210/mend-2-11-1087; RA Nakai A., Sakurai A., Bell G.I., Degroot L.J.; RT "Characterization of a third human thyroid hormone receptor coexpressed RT with other thyroid hormone receptors in several tissues."; RL Mol. Endocrinol. 2:1087-1092(1988). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA-2). RC TISSUE=Brain; 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 [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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS ALPHA-2 AND ALPHA-3). RC TISSUE=Brain, Hippocampus, and Muscle; 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 [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-370. RX PubMed=3672126; DOI=10.1126/science.3672126; RA Benbrook D., Pfahl M.; RT "A novel thyroid hormone receptor encoded by a cDNA clone from a human RT testis library."; RL Science 238:788-791(1987). RN [10] RP NUCLEOTIDE SEQUENCE [MRNA] OF 280-451 (ISOFORM ALPHA-4). RC TISSUE=Brain cortex; RA Liu C., Li L., Liu B., Zang X.; RL Submitted (JUN-2002) to the EMBL/GenBank/DDBJ databases. RN [11] RP FUNCTION (ISOFORM ALPHA-2). RX PubMed=8910441; DOI=10.1074/jbc.271.45.28235; RA Yang Y.Z., Burgos-Trinidad M., Wu Y., Koenig R.J.; RT "Thyroid hormone receptor variant alpha2. Role of the ninth heptad in dna RT binding, heterodimerization with retinoid X receptors, and dominant RT negative activity."; RL J. Biol. Chem. 271:28235-28242(1996). RN [12] RP INTERACTION WITH NCOA3. RX PubMed=9267036; DOI=10.1016/s0092-8674(00)80516-4; RA Chen H., Lin R.J., Schiltz R.L., Chakravarti D., Nash A., Nagy L., RA Privalsky M.L., Nakatani Y., Evans R.M.; RT "Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and RT forms a multimeric activation complex with P/CAF and CBP/p300."; RL Cell 90:569-580(1997). RN [13] RP INTERACTION WITH AKAP13. RX PubMed=9627117; DOI=10.1038/sj.onc.1201783; RA Rubino D., Driggers P., Arbit D., Kemp L., Miller B., Coso O., Pagliai K., RA Gray K., Gutkind S., Segars J.; RT "Characterization of Brx, a novel Dbl family member that modulates estrogen RT receptor action."; RL Oncogene 16:2513-2526(1998). RN [14] RP INTERACTION WITH NCOA6. RX PubMed=10567404; DOI=10.1074/jbc.274.48.34283; RA Lee S.-K., Anzick S.L., Choi J.-E., Bubendorf L., Guan X.-Y., Jung Y.-K., RA Kallioniemi O.-P., Kononen J., Trent J.M., Azorsa D., Jhun B.-H., RA Cheong J.H., Lee Y.C., Meltzer P.S., Lee J.W.; RT "A nuclear factor ASC-2, as a cancer-amplified transcriptional coactivator RT essential for ligand-dependent transactivation by nuclear receptors in RT vivo."; RL J. Biol. Chem. 274:34283-34293(1999). RN [15] RP FUNCTION, AND MUTAGENESIS OF SER-277. RX PubMed=14673100; DOI=10.1073/pnas.2136689100; RA Borngraeber S., Budny M.J., Chiellini G., Cunha-Lima S.T., Togashi M., RA Webb P., Baxter J.D., Scanlan T.S., Fletterick R.J.; RT "Ligand selectivity by seeking hydrophobicity in thyroid hormone RT receptor."; RL Proc. Natl. Acad. Sci. U.S.A. 100:15358-15363(2003). RN [16] RP INTERACTION WITH TP53INP2. RX PubMed=18030323; DOI=10.1371/journal.pone.0001183; RA Baumgartner B.G., Orpinell M., Duran J., Ribas V., Burghardt H.E., Bach D., RA Villar A.V., Paz J.C., Gonzalez M., Camps M., Oriola J., Rivera F., RA Palacin M., Zorzano A.; RT "Identification of a novel modulator of thyroid hormone receptor-mediated RT action."; RL PLoS ONE 2:E1183-E1183(2007). RN [17] RP INTERACTION WITH TACC1. RX PubMed=20078863; DOI=10.1186/1471-2199-11-3; RA Guyot R., Vincent S., Bertin J., Samarut J., Ravel-Chapuis P.; RT "The transforming acidic coiled coil (TACC1) protein modulates the RT transcriptional activity of the nuclear receptors TR and RAR."; RL BMC Mol. Biol. 11:3-3(2010). RN [18] RP INVOLVEMENT IN CHNG6. RX PubMed=22168587; DOI=10.1056/nejmoa1110296; RA Bochukova E., Schoenmakers N., Agostini M., Schoenmakers E., RA Rajanayagam O., Keogh J.M., Henning E., Reinemund J., Gevers E., Sarri M., RA Downes K., Offiah A., Albanese A., Halsall D., Schwabe J.W., Bain M., RA Lindley K., Muntoni F., Khadem F.V., Dattani M., Farooqi I.S., Gurnell M., RA Chatterjee K.; RT "A mutation in the thyroid hormone receptor alpha gene."; RL N. Engl. J. Med. 366:243-249(2012). RN [19] RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 148-370 IN COMPLEX WITH SYNTHETIC RP AGONIST, AND FUNCTION. RX PubMed=12699376; DOI=10.1021/jm021080f; RA Ye L., Li Y.L., Mellstrom K., Mellin C., Bladh L.G., Koehler K., Garg N., RA Garcia Collazo A.M., Litten C., Husman B., Persson K., Ljunggren J., RA Grover G., Sleph P.G., George R., Malm J.; RT "Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid RT receptor beta1."; RL J. Med. Chem. 46:1580-1588(2003). RN [20] {ECO:0007744|PDB:2H77, ECO:0007744|PDB:2H79} RP X-RAY CRYSTALLOGRAPHY (1.87 ANGSTROMS) OF 148-370 IN COMPLEX WITH RP TRIIODOTHYRONINE, AND SUBUNIT. RX PubMed=16781732; DOI=10.1016/j.jmb.2006.05.008; RA Nascimento A.S., Dias S.M., Nunes F.M., Aparicio R., Ambrosio A.L., RA Bleicher L., Figueira A.C., Santos M.A., de Oliveira Neto M., Fischer H., RA Togashi M., Craievich A.F., Garratt R.C., Baxter J.D., Webb P., RA Polikarpov I.; RT "Structural rearrangements in the thyroid hormone receptor hinge domain and RT their putative role in the receptor function."; RL J. Mol. Biol. 360:586-598(2006). RN [21] RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 148-370 IN COMPLEX WITH SYNTHETIC RP AGONIST, AND FUNCTION. RX PubMed=18237438; DOI=10.1186/1472-6807-8-8; RA Bleicher L., Aparicio R., Nunes F.M., Martinez L., Gomes Dias S.M., RA Figueira A.C., Santos M.A., Venturelli W.H., da Silva R., Donate P.M., RA Neves F.A., Simeoni L.A., Baxter J.D., Webb P., Skaf M.S., Polikarpov I.; RT "Structural basis of GC-1 selectivity for thyroid hormone receptor RT isoforms."; RL BMC Struct. Biol. 8:8-8(2008). RN [22] RP X-RAY CRYSTALLOGRAPHY (2.01 ANGSTROMS) OF 148-370 IN COMPLEX WITH SYNTHETIC RP AGONIST, FUNCTION, AND MUTAGENESIS OF SER-277. RX PubMed=19926848; DOI=10.1073/pnas.0911024106; RA Martinez L., Nascimento A.S., Nunes F.M., Phillips K., Aparicio R., RA Dias S.M., Figueira A.C., Lin J.H., Nguyen P., Apriletti J.W., Neves F.A., RA Baxter J.D., Webb P., Skaf M.S., Polikarpov I.; RT "Gaining ligand selectivity in thyroid hormone receptors via entropy."; RL Proc. Natl. Acad. Sci. U.S.A. 106:20717-20722(2009). RN [23] RP VARIANT CHNG6 VAL-263, CHARACTERIZATION OF VARIANT VAL-263 (ISOFORM RP ALPHA-1), AND CHARACTERIZATION OF VARIANT VAL-263 (ISOFORM ALPHA-2). RX PubMed=24969835; DOI=10.1016/s2213-8587(14)70111-1; RA Moran C., Agostini M., Visser W.E., Schoenmakers E., Schoenmakers N., RA Offiah A.C., Poole K., Rajanayagam O., Lyons G., Halsall D., Gurnell M., RA Chrysis D., Efthymiadou A., Buchanan C., Aylwin S., Chatterjee K.K.; RT "Resistance to thyroid hormone caused by a mutation in thyroid hormone RT receptor (TR)alpha1 and TRalpha2: clinical, biochemical, and genetic RT analyses of three related patients."; RL Lancet Diabetes Endocrinol. 2:619-626(2014). RN [24] RP VARIANT CHNG6 TYR-359, CHARACTERIZATION OF VARIANT TYR-359 (ISOFORM RP ALPHA-1), AND CHARACTERIZATION OF VARIANT TYR-359 (ISOFORM ALPHA-2). RX PubMed=26037512; DOI=10.1210/jc.2015-1120; RA Espiard S., Savagner F., Flamant F., Vlaeminck-Guillem V., Guyot R., RA Munier M., d'Herbomez M., Bourguet W., Pinto G., Rose C., Rodien P., RA Wemeau J.L.; RT "A novel mutation in THRA gene associated with an atypical phenotype of RT resistance to thyroid hormone."; RL J. Clin. Endocrinol. Metab. 100:2841-2848(2015). RN [25] RP VARIANTS CHNG6 ARG-398 AND LYS-403 (ISOFORM ALPHA-1). RX PubMed=25670821; DOI=10.1136/jmedgenet-2014-102936; RA Tylki-Szymanska A., Acuna-Hidalgo R., Krajewska-Walasek M., RA Lecka-Ambroziak A., Steehouwer M., Gilissen C., Brunner H.G., Jurecka A., RA Rozdzynska-Swiatkowska A., Hoischen A., Chrzanowska K.H.; RT "Thyroid hormone resistance syndrome due to mutations in the thyroid RT hormone receptor alpha gene (THRA)."; RL J. Med. Genet. 52:312-316(2015). CC -!- FUNCTION: [Isoform Alpha-1]: Nuclear hormone receptor that can act as a CC repressor or activator of transcription. High affinity receptor for CC thyroid hormones, including triiodothyronine and thyroxine. CC {ECO:0000269|PubMed:12699376, ECO:0000269|PubMed:14673100, CC ECO:0000269|PubMed:18237438, ECO:0000269|PubMed:19926848}. CC -!- FUNCTION: [Isoform Alpha-2]: Does not bind thyroid hormone and CC functions as a weak dominant negative inhibitor of thyroid hormone CC action. {ECO:0000269|PubMed:8910441}. CC -!- SUBUNIT: Binds DNA as a dimer; homodimer and heterodimer with RXRB. CC Interacts with NCOA3 and NCOA6 coactivators, leading to a strong CC increase of transcription of target genes. Probably interacts with CC SFPQ. Interacts with C1D. Interacts with AKAP13. Interacts with CC TP53INP2. Interacts with PER2. Isoform alpha-2 and isoform alpha-1 CC interact with TACC1, but the interaction with alpha-1 is weaker. The CC interaction with isoform alpha-1, but not alpha-2, is decreased in the CC presence of thyroid hormone T3 (PubMed:20078863). CC {ECO:0000269|PubMed:10567404, ECO:0000269|PubMed:12699376, CC ECO:0000269|PubMed:16781732, ECO:0000269|PubMed:18030323, CC ECO:0000269|PubMed:18237438, ECO:0000269|PubMed:19926848, CC ECO:0000269|PubMed:20078863, ECO:0000269|PubMed:9267036, CC ECO:0000269|PubMed:9627117}. CC -!- INTERACTION: CC P10827; Q9Y2J4: AMOTL2; NbExp=3; IntAct=EBI-286285, EBI-746752; CC P10827; Q9Y2J4-4: AMOTL2; NbExp=3; IntAct=EBI-286285, EBI-10187270; CC P10827; O95971: CD160; NbExp=3; IntAct=EBI-286285, EBI-4314390; CC P10827; Q8TAP6: CEP76; NbExp=4; IntAct=EBI-286285, EBI-742887; CC P10827; Q96JM7: L3MBTL3; NbExp=3; IntAct=EBI-286285, EBI-2686809; CC P10827; Q15648: MED1; NbExp=4; IntAct=EBI-286285, EBI-394459; CC P10827; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-286285, EBI-16439278; CC P10827; P31321: PRKAR1B; NbExp=5; IntAct=EBI-286285, EBI-2805516; CC P10827; Q96A49: SYAP1; NbExp=5; IntAct=EBI-286285, EBI-10770179; CC P10827; O75410-7: TACC1; NbExp=3; IntAct=EBI-286285, EBI-12007872; CC P10827; Q9JLI4: Ncoa6; Xeno; NbExp=2; IntAct=EBI-286285, EBI-286271; CC -!- SUBCELLULAR LOCATION: Nucleus. CC -!- SUBCELLULAR LOCATION: [Isoform Alpha-2]: Cytoplasm CC {ECO:0000250|UniProtKB:P63058}. Nucleus {ECO:0000250|UniProtKB:P63058}. CC Note=When overexpressed found in the cytoplasm where it colocalizes CC with TACC1. {ECO:0000250|UniProtKB:P63058}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=Alpha-2; CC IsoId=P10827-1; Sequence=Displayed; CC Name=Alpha-1; CC IsoId=P10827-2; Sequence=VSP_003621; CC Name=Alpha-3; CC IsoId=P10827-3; Sequence=VSP_003622; CC Name=Alpha-4; Synonyms=Alpha3; CC IsoId=P10827-4; Sequence=VSP_003623; CC -!- DOMAIN: Composed of three domains: a modulating N-terminal domain, a CC DNA-binding domain and a C-terminal ligand-binding domain. CC -!- DISEASE: Hypothyroidism, congenital, non-goitrous, 6 (CHNG6) CC [MIM:614450]: A disease characterized by growth retardation, CC developmental retardation, skeletal dysplasia, borderline low thyroxine CC levels and high triiodothyronine levels. There is differential CC sensitivity to thyroid hormone action, with retention of hormone CC responsiveness in the hypothalamic pituitary axis and liver but CC skeletal, gastrointestinal, and myocardial resistance. CC {ECO:0000269|PubMed:22168587, ECO:0000269|PubMed:24969835, CC ECO:0000269|PubMed:25670821, ECO:0000269|PubMed:26037512}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- MISCELLANEOUS: [Isoform Alpha-2]: Does not bind thyroid hormone T3. CC {ECO:0000305|PubMed:20078863}. CC -!- SIMILARITY: Belongs to the nuclear hormone receptor family. NR1 CC subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X55074; CAB57886.1; -; Genomic_DNA. DR EMBL; X55073; CAB57886.1; JOINED; Genomic_DNA. DR EMBL; X55070; CAB57886.1; JOINED; Genomic_DNA. DR EMBL; X55071; CAB57886.1; JOINED; Genomic_DNA. DR EMBL; X55004; CAB57886.1; JOINED; Genomic_DNA. DR EMBL; X55069; CAB57886.1; JOINED; Genomic_DNA. DR EMBL; X55068; CAB57886.1; JOINED; Genomic_DNA. DR EMBL; X55066; CAB57886.1; JOINED; Genomic_DNA. DR EMBL; X55005; CAA38749.1; -; mRNA. DR EMBL; X55074; CAA38899.1; -; Genomic_DNA. DR EMBL; X55073; CAA38899.1; JOINED; Genomic_DNA. DR EMBL; X55070; CAA38899.1; JOINED; Genomic_DNA. DR EMBL; X55071; CAA38899.1; JOINED; Genomic_DNA. DR EMBL; X55004; CAA38899.1; JOINED; Genomic_DNA. DR EMBL; X55069; CAA38899.1; JOINED; Genomic_DNA. DR EMBL; X55068; CAA38899.1; JOINED; Genomic_DNA. DR EMBL; M24899; AAA35783.1; -; mRNA. DR EMBL; M24900; AAA52333.1; -; mRNA. DR EMBL; J03239; AAA61176.1; -; mRNA. DR EMBL; Y00479; CAA68539.1; -; mRNA. DR EMBL; M24748; AAA66021.1; -; Genomic_DNA. DR EMBL; AK290530; BAF83219.1; -; mRNA. DR EMBL; CH471152; EAW60632.1; -; Genomic_DNA. DR EMBL; BC000261; AAH00261.1; -; mRNA. DR EMBL; BC002728; AAH02728.1; -; mRNA. DR EMBL; BC035137; AAH35137.1; -; mRNA. DR EMBL; AF522368; AAM77692.1; -; mRNA. DR CCDS; CCDS11360.1; -. [P10827-1] DR CCDS; CCDS42316.1; -. [P10827-2] DR CCDS; CCDS58546.1; -. [P10827-3] DR PIR; A30893; A30893. DR PIR; A40917; A40917. DR PIR; S06163; S06163. DR RefSeq; NP_001177847.1; NM_001190918.1. [P10827-3] DR RefSeq; NP_001177848.1; NM_001190919.1. [P10827-1] DR RefSeq; NP_003241.2; NM_003250.5. [P10827-1] DR RefSeq; NP_955366.1; NM_199334.3. [P10827-2] DR PDB; 1NAV; X-ray; 2.50 A; A=148-370. DR PDB; 2H77; X-ray; 2.33 A; A=148-370. DR PDB; 2H79; X-ray; 1.87 A; A=148-370. DR PDB; 3HZF; X-ray; 2.50 A; A=148-370. DR PDB; 3ILZ; X-ray; 1.85 A; A=148-370. DR PDB; 3JZB; X-ray; 2.01 A; A=148-370. DR PDB; 4LNW; X-ray; 1.90 A; A=148-370. DR PDB; 4LNX; X-ray; 2.05 A; A=148-370. DR PDB; 7QDT; X-ray; 3.00 A; A=156-370. DR PDBsum; 1NAV; -. DR PDBsum; 2H77; -. DR PDBsum; 2H79; -. DR PDBsum; 3HZF; -. DR PDBsum; 3ILZ; -. DR PDBsum; 3JZB; -. DR PDBsum; 4LNW; -. DR PDBsum; 4LNX; -. DR PDBsum; 7QDT; -. DR AlphaFoldDB; P10827; -. DR SMR; P10827; -. DR BioGRID; 112923; 98. DR ComplexPortal; CPX-662; RXRalpha-TRalpha nuclear hormone receptor complex. [P10827-2] DR CORUM; P10827; -. DR DIP; DIP-31452N; -. DR IntAct; P10827; 32. DR MINT; P10827; -. DR STRING; 9606.ENSP00000264637; -. DR BindingDB; P10827; -. DR ChEMBL; CHEMBL1860; -. DR DrugBank; DB01118; Amiodarone. DR DrugBank; DB00509; Dextrothyroxine. DR DrugBank; DB04855; Dronedarone. DR DrugBank; DB05035; Eprotirome. DR DrugBank; DB03176; KB-141. DR DrugBank; DB00451; Levothyroxine. DR DrugBank; DB00279; Liothyronine. DR DrugBank; DB01583; Liotrix. DR DrugBank; DB05235; NRP409. DR DrugBank; DB09100; Thyroid, porcine. DR DrugCentral; P10827; -. DR GuidetoPHARMACOLOGY; 588; -. DR iPTMnet; P10827; -. DR PhosphoSitePlus; P10827; -. DR BioMuta; THRA; -. DR DMDM; 135705; -. DR jPOST; P10827; -. DR MassIVE; P10827; -. DR MaxQB; P10827; -. DR PaxDb; 9606-ENSP00000264637; -. DR PeptideAtlas; P10827; -. DR ProteomicsDB; 52657; -. [P10827-1] DR ProteomicsDB; 52658; -. [P10827-2] DR ProteomicsDB; 52659; -. [P10827-3] DR ProteomicsDB; 52660; -. [P10827-4] DR ABCD; P10827; 2 sequenced antibodies. DR Antibodypedia; 1300; 762 antibodies from 44 providers. DR DNASU; 7067; -. DR Ensembl; ENST00000264637.8; ENSP00000264637.4; ENSG00000126351.13. [P10827-1] DR Ensembl; ENST00000394121.8; ENSP00000377679.4; ENSG00000126351.13. [P10827-1] DR Ensembl; ENST00000450525.7; ENSP00000395641.3; ENSG00000126351.13. [P10827-2] DR Ensembl; ENST00000546243.5; ENSP00000443972.1; ENSG00000126351.13. [P10827-2] DR Ensembl; ENST00000584985.5; ENSP00000463466.1; ENSG00000126351.13. [P10827-3] DR GeneID; 7067; -. DR KEGG; hsa:7067; -. DR MANE-Select; ENST00000450525.7; ENSP00000395641.3; NM_199334.5; NP_955366.1. [P10827-2] DR UCSC; uc002htw.4; human. [P10827-1] DR AGR; HGNC:11796; -. DR CTD; 7067; -. DR DisGeNET; 7067; -. DR GeneCards; THRA; -. DR HGNC; HGNC:11796; THRA. DR HPA; ENSG00000126351; Tissue enriched (brain). DR MalaCards; THRA; -. DR MIM; 190120; gene. DR MIM; 614450; phenotype. DR neXtProt; NX_P10827; -. DR OpenTargets; ENSG00000126351; -. DR Orphanet; 566231; Resistance to thyroid hormone due to a mutation in thyroid hormone receptor alpha. DR PharmGKB; PA36507; -. DR VEuPathDB; HostDB:ENSG00000126351; -. DR eggNOG; KOG3575; Eukaryota. DR GeneTree; ENSGT00940000157917; -. DR HOGENOM; CLU_007368_18_0_1; -. DR InParanoid; P10827; -. DR OMA; QCSVKSS; -. DR OrthoDB; 5390715at2759; -. DR PhylomeDB; P10827; -. DR TreeFam; TF328382; -. DR PathwayCommons; P10827; -. DR Reactome; R-HSA-383280; Nuclear Receptor transcription pathway. DR Reactome; R-HSA-4090294; SUMOylation of intracellular receptors. [P10827-2] DR SignaLink; P10827; -. DR SIGNOR; P10827; -. DR BioGRID-ORCS; 7067; 13 hits in 1192 CRISPR screens. DR ChiTaRS; THRA; human. DR EvolutionaryTrace; P10827; -. DR GeneWiki; Thyroid_hormone_receptor_alpha; -. DR GenomeRNAi; 7067; -. DR Pharos; P10827; Tclin. DR PRO; PR:P10827; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; P10827; Protein. DR Bgee; ENSG00000126351; Expressed in nucleus accumbens and 204 other cell types or tissues. DR ExpressionAtlas; P10827; baseline and differential. DR GO; GO:0000785; C:chromatin; ISA:NTNU_SB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; EXP:ComplexPortal. DR GO; GO:0031490; F:chromatin DNA binding; IEA:Ensembl. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; ISA:NTNU_SB. DR GO; GO:0140296; F:general transcription initiation factor binding; IPI:UniProtKB. DR GO; GO:0004879; F:nuclear receptor activity; IDA:UniProtKB. DR GO; GO:0019904; F:protein domain specific binding; IPI:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IBA:GO_Central. DR GO; GO:0017025; F:TBP-class protein binding; IDA:UniProtKB. DR GO; GO:0070324; F:thyroid hormone binding; IDA:UniProtKB. DR GO; GO:0000976; F:transcription cis-regulatory region binding; IDA:BHF-UCL. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0001502; P:cartilage condensation; IEA:Ensembl. DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central. DR GO; GO:0030218; P:erythrocyte differentiation; IEA:Ensembl. DR GO; GO:0008050; P:female courtship behavior; IEA:Ensembl. DR GO; GO:0009755; P:hormone-mediated signaling pathway; IDA:BHF-UCL. DR GO; GO:0007611; P:learning or memory; IEA:Ensembl. DR GO; GO:0042789; P:mRNA transcription by RNA polymerase II; IDA:ComplexPortal. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:2000143; P:negative regulation of DNA-templated transcription initiation; IDA:UniProtKB. DR GO; GO:0017055; P:negative regulation of RNA polymerase II transcription preinitiation complex assembly; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0001503; P:ossification; IEA:Ensembl. DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab. DR GO; GO:0045925; P:positive regulation of female receptivity; IEA:Ensembl. DR GO; GO:0002157; P:positive regulation of thyroid hormone mediated signaling pathway; IDA:ComplexPortal. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:ComplexPortal. DR GO; GO:0008016; P:regulation of heart contraction; IEA:Ensembl. DR GO; GO:0050994; P:regulation of lipid catabolic process; IEA:Ensembl. DR GO; GO:0033032; P:regulation of myeloid cell apoptotic process; IEA:Ensembl. DR GO; GO:0002155; P:regulation of thyroid hormone mediated signaling pathway; IEA:Ensembl. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:BHF-UCL. DR GO; GO:0009409; P:response to cold; IEA:Ensembl. DR GO; GO:0048384; P:retinoic acid receptor signaling pathway; IBA:GO_Central. DR GO; GO:0030878; P:thyroid gland development; IEA:Ensembl. DR GO; GO:0002154; P:thyroid hormone mediated signaling pathway; IBA:GO_Central. DR GO; GO:0006366; P:transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0060509; P:type I pneumocyte differentiation; IEA:Ensembl. DR CDD; cd06961; NR_DBD_TR; 1. DR CDD; cd06935; NR_LBD_TR; 1. DR Gene3D; 3.30.50.10; Erythroid Transcription Factor GATA-1, subunit A; 1. DR Gene3D; 1.10.565.10; Retinoid X Receptor; 1. DR InterPro; IPR035500; NHR-like_dom_sf. DR InterPro; IPR000536; Nucl_hrmn_rcpt_lig-bd. DR InterPro; IPR001723; Nuclear_hrmn_rcpt. DR InterPro; IPR001728; ThyrH_rcpt. DR InterPro; IPR001628; Znf_hrmn_rcpt. DR InterPro; IPR013088; Znf_NHR/GATA. DR PANTHER; PTHR24082; NUCLEAR HORMONE RECEPTOR; 1. DR PANTHER; PTHR24082:SF42; THYROID HORMONE RECEPTOR ALPHA; 1. DR Pfam; PF00104; Hormone_recep; 1. DR Pfam; PF00105; zf-C4; 1. DR PRINTS; PR00398; STRDHORMONER. DR PRINTS; PR00047; STROIDFINGER. DR PRINTS; PR00546; THYROIDHORMR. DR SMART; SM00430; HOLI; 1. DR SMART; SM00399; ZnF_C4; 1. DR SUPFAM; SSF57716; Glucocorticoid receptor-like (DNA-binding domain); 1. DR SUPFAM; SSF48508; Nuclear receptor ligand-binding domain; 1. DR PROSITE; PS51843; NR_LBD; 1. DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1. DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1. DR Genevisible; P10827; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Congenital hypothyroidism; Cytoplasm; KW Disease variant; DNA-binding; Metal-binding; Nucleus; Receptor; KW Reference proteome; Transcription; Transcription regulation; Zinc; KW Zinc-finger. FT CHAIN 1..490 FT /note="Thyroid hormone receptor alpha" FT /id="PRO_0000053424" FT DOMAIN 163..407 FT /note="NR LBD" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01189" FT DNA_BIND 53..127 FT /note="Nuclear receptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407" FT ZN_FING 53..73 FT /note="NR C4-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407" FT ZN_FING 91..115 FT /note="NR C4-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00407" FT REGION 1..52 FT /note="Modulating" FT REGION 1..32 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 457..490 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1..30 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 467..481 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 53 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P10828" FT BINDING 56 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P10828" FT BINDING 70 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P10828" FT BINDING 73 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P10828" FT BINDING 91 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P10828" FT BINDING 97 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P10828" FT BINDING 107 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P10828" FT BINDING 110 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P10828" FT BINDING 228 FT /ligand="3,3',5-triiodo-L-thyronine" FT /ligand_id="ChEBI:CHEBI:533015" FT /evidence="ECO:0000269|PubMed:16781732, FT ECO:0007744|PDB:2H77, ECO:0007744|PDB:2H79" FT BINDING 277 FT /ligand="3,3',5-triiodo-L-thyronine" FT /ligand_id="ChEBI:CHEBI:533015" FT /evidence="ECO:0000269|PubMed:16781732, FT ECO:0007744|PDB:2H79" FT VAR_SEQ 371..490 FT /note="EREVQSSILYKGAAAEGRPGGSLGVHPEGQQLLGMHVVQGPQVRQLEQQLGE FT AGSLQGPVLQHQSPKSPQQRLLELLHRSGILHARAVCGEDDSSEADSPSSSEEEPEVCE FT DLAGNAASP -> VTDLRMIGACHASRFLHMKVECPTELFPPLFLEVFEDQEV (in FT isoform Alpha-1)" FT /evidence="ECO:0000303|PubMed:1850510, FT ECO:0000303|PubMed:2539258" FT /id="VSP_003621" FT VAR_SEQ 371..412 FT /note="Missing (in isoform Alpha-4)" FT /evidence="ECO:0000303|Ref.10" FT /id="VSP_003623" FT VAR_SEQ 371..409 FT /note="Missing (in isoform Alpha-3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_003622" FT VARIANT 263 FT /note="A -> V (in CHNG6; no effect on T3 binding; no effect FT on thyroid hormone-dependent transcriptional activation; FT dbSNP:rs1555545033)" FT /evidence="ECO:0000269|PubMed:24969835" FT /id="VAR_074559" FT VARIANT 359 FT /note="N -> Y (in CHNG6; atypical phenotype; weak reduction FT in transcriptional activation)" FT /evidence="ECO:0000269|PubMed:26037512" FT /id="VAR_074560" FT MUTAGEN 277 FT /note="S->N: No effect on thyroid hormone binding." FT /evidence="ECO:0000269|PubMed:14673100, FT ECO:0000269|PubMed:19926848" FT CONFLICT 37 FT /note="T -> S (in Ref. 4; CAA68539)" FT /evidence="ECO:0000305" FT CONFLICT 119 FT /note="G -> A (in Ref. 4; CAA68539)" FT /evidence="ECO:0000305" FT CONFLICT 285 FT /note="E -> A (in Ref. 1; CAB57886/CAA38899)" FT /evidence="ECO:0000305" FT HELIX 148..151 FT /evidence="ECO:0007829|PDB:3ILZ" FT TURN 152..154 FT /evidence="ECO:0007829|PDB:3ILZ" FT HELIX 162..176 FT /evidence="ECO:0007829|PDB:3ILZ" FT TURN 180..184 FT /evidence="ECO:0007829|PDB:2H79" FT TURN 186..188 FT /evidence="ECO:0007829|PDB:3ILZ" FT STRAND 189..191 FT /evidence="ECO:0007829|PDB:3ILZ" FT STRAND 196..198 FT /evidence="ECO:0007829|PDB:2H79" FT HELIX 212..234 FT /evidence="ECO:0007829|PDB:3ILZ" FT HELIX 237..240 FT /evidence="ECO:0007829|PDB:3ILZ" FT HELIX 244..264 FT /evidence="ECO:0007829|PDB:3ILZ" FT TURN 269..272 FT /evidence="ECO:0007829|PDB:3ILZ" FT STRAND 273..276 FT /evidence="ECO:0007829|PDB:3ILZ" FT TURN 277..279 FT /evidence="ECO:0007829|PDB:3ILZ" FT STRAND 280..282 FT /evidence="ECO:0007829|PDB:3ILZ" FT HELIX 284..289 FT /evidence="ECO:0007829|PDB:3ILZ" FT TURN 290..293 FT /evidence="ECO:0007829|PDB:3ILZ" FT HELIX 294..306 FT /evidence="ECO:0007829|PDB:3ILZ" FT HELIX 307..309 FT /evidence="ECO:0007829|PDB:3ILZ" FT HELIX 313..324 FT /evidence="ECO:0007829|PDB:3ILZ" FT STRAND 329..331 FT /evidence="ECO:0007829|PDB:3ILZ" FT HELIX 335..356 FT /evidence="ECO:0007829|PDB:3ILZ" FT HELIX 363..370 FT /evidence="ECO:0007829|PDB:3ILZ" FT VARIANT P10827-2:263 FT /note="A -> V (in CHNG6, reduces T3 binding, impairs FT thyroid hormone-dependent transcriptional activation, no FT effect on DNA-binding) (Ref.24)" FT /evidence="ECO:0000269|PubMed:24969835" FT /id="VAR_082873" FT VARIANT P10827-2:359 FT /note="N -> Y (in CHNG6, decreases transcriptional FT activity, decreases T3 binding) (Ref.25)" FT /evidence="ECO:0000269|PubMed:26037512" FT /id="VAR_082874" FT VARIANT P10827-2:398 FT /note="P -> R (in CHNG6) (Ref.26)" FT /evidence="ECO:0000269|PubMed:25670821" FT /id="VAR_082875" FT VARIANT P10827-2:403 FT /note="E -> Q (in CHNG6) (Ref.26)" FT /evidence="ECO:0000305" FT /id="VAR_082876" SQ SEQUENCE 490 AA; 54816 MW; C87C7D2F67B1AE49 CRC64; MEQKPSKVEC GSDPEENSAR SPDGKRKRKN GQCSLKTSMS GYIPSYLDKD EQCVVCGDKA TGYHYRCITC EGCKGFFRRT IQKNLHPTYS CKYDSCCVID KITRNQCQLC RFKKCIAVGM AMDLVLDDSK RVAKRKLIEQ NRERRRKEEM IRSLQQRPEP TPEEWDLIHI ATEAHRSTNA QGSHWKQRRK FLPDDIGQSP IVSMPDGDKV DLEAFSEFTK IITPAITRVV DFAKKLPMFS ELPCEDQIIL LKGCCMEIMS LRAAVRYDPE SDTLTLSGEM AVKREQLKNG GLGVVSDAIF ELGKSLSAFN LDDTEVALLQ AVLLMSTDRS GLLCVDKIEK SQEAYLLAFE HYVNHRKHNI PHFWPKLLMK EREVQSSILY KGAAAEGRPG GSLGVHPEGQ QLLGMHVVQG PQVRQLEQQL GEAGSLQGPV LQHQSPKSPQ QRLLELLHRS GILHARAVCG EDDSSEADSP SSSEEEPEVC EDLAGNAASP //