THA_HUMAN
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 03-AUG-2022, entry version 246.
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; 97.
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; P10827; -.
DR PeptideAtlas; P10827; -.
DR PRIDE; 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; 662 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 CTD; 7067; -.
DR DisGeNET; 7067; -.
DR GeneCards; THRA; -.
DR HGNC; HGNC:11796; THRA.
DR HPA; ENSG00000126351; Tissue enhanced (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; IMCLRIA; -.
DR OrthoDB; 1112927at2759; -.
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 1106 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 202 other tissues.
DR ExpressionAtlas; P10827; baseline and differential.
DR Genevisible; P10827; HS.
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; IC: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:0044877; F:protein-containing complex binding; IEA:Ensembl.
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: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:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
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: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 Gene3D; 1.10.565.10; -; 1.
DR Gene3D; 3.30.50.10; -; 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 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; SSF48508; SSF48508; 1.
DR PROSITE; PS51843; NR_LBD; 1.
DR PROSITE; PS00031; NUCLEAR_REC_DBD_1; 1.
DR PROSITE; PS51030; NUCLEAR_REC_DBD_2; 1.
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
