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Protein

Thyrotropin receptor

Gene

TSHR

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Receptor for thyrothropin. Plays a central role in controlling thyroid cell metabolism. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Also acts as a receptor for thyrostimulin (GPA2+GPB5).1 Publication

GO - Molecular functioni

  • G-protein coupled peptide receptor activity Source: GO_Central
  • thyroid-stimulating hormone receptor activity Source: ProtInc

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

G-protein coupled receptor, Receptor, Transducer

Enzyme and pathway databases

ReactomeiR-HSA-375281. Hormone ligand-binding receptors.
R-HSA-418555. G alpha (s) signalling events.
SignaLinkiP16473.
SIGNORiP16473.

Names & Taxonomyi

Protein namesi
Recommended name:
Thyrotropin receptor
Alternative name(s):
Thyroid-stimulating hormone receptor
Short name:
TSH-R
Gene namesi
Name:TSHR
Synonyms:LGR3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 14

Organism-specific databases

HGNCiHGNC:12373. TSHR.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini21 – 413393ExtracellularSequence analysisAdd
BLAST
Transmembranei414 – 44128Helical; Name=1Sequence analysisAdd
BLAST
Topological domaini442 – 4509CytoplasmicSequence analysis
Transmembranei451 – 47323Helical; Name=2Sequence analysisAdd
BLAST
Topological domaini474 – 49421ExtracellularSequence analysisAdd
BLAST
Transmembranei495 – 51723Helical; Name=3Sequence analysisAdd
BLAST
Topological domaini518 – 53720CytoplasmicSequence analysisAdd
BLAST
Transmembranei538 – 56023Helical; Name=4Sequence analysisAdd
BLAST
Topological domaini561 – 58020ExtracellularSequence analysisAdd
BLAST
Transmembranei581 – 60222Helical; Name=5Sequence analysisAdd
BLAST
Topological domaini603 – 62523CytoplasmicSequence analysisAdd
BLAST
Transmembranei626 – 64924Helical; Name=6Sequence analysisAdd
BLAST
Topological domaini650 – 66011ExtracellularSequence analysisAdd
BLAST
Transmembranei661 – 68222Helical; Name=7Sequence analysisAdd
BLAST
Topological domaini683 – 76482CytoplasmicSequence analysisAdd
BLAST

GO - Cellular componenti

  • integral component of plasma membrane Source: ProtInc
  • plasma membrane Source: Reactome
  • receptor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Defects in TSHR are found in patients affected by hyperthyroidism with different etiologies. Somatic, constitutively activating TSHR mutations and/or constitutively activating G(s)alpha mutations have been identified in toxic thyroid nodules (TTNs) that are the predominant cause of hyperthyroidism in iodine deficient areas. These mutations lead to TSH independent activation of the cAMP cascade resulting in thyroid growth and hormone production. TSHR mutations are found in autonomously functioning thyroid nodules (AFTN), toxic multinodular goiter (TMNG) and hyperfunctioning thyroid adenomas (HTA). TMNG encompasses a spectrum of different clinical entities, ranging from a single hyperfunctioning nodule within an enlarged thyroid, to multiple hyperfunctioning areas scattered throughout the gland. HTA are discrete encapsulated neoplasms characterized by TSH-independent autonomous growth, hypersecretion of thyroid hormones, and TSH suppression. Defects in TSHR are also a cause of thyroid neoplasms (papillary and follicular cancers).

Autoantibodies against TSHR are directly responsible for the pathogenesis and hyperthyroidism of Graves disease. Antibody interaction with TSHR results in an uncontrolled receptor stimulation.

Hypothyroidism, congenital, non-goitrous, 1 (CHNG1)12 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA non-autoimmune condition characterized by resistance to thyroid-stimulating hormone (TSH) leading to increased levels of plasma TSH and low levels of thyroid hormone. It presents variable severity depending on the completeness of the defect. Most patients are euthyroid and asymptomatic, with a normal sized thyroid gland. Only a subset of patients develop hypothyroidism and present a hypoplastic thyroid gland.
See also OMIM:275200
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti41 – 411C → S in CHNG1. 2 Publications
VAR_011519
Natural varianti109 – 1091R → Q in CHNG1. 1 Publication
VAR_011520
Natural varianti162 – 1621P → A in CHNG1. 5 Publications
Corresponds to variant rs121908863 [ dbSNP | Ensembl ].
VAR_011521
Natural varianti167 – 1671I → N in CHNG1. 1 Publication
VAR_011522
Natural varianti252 – 2521L → P in CHNG1; displays a low expression at the cell surface and a reduced response to bovine TSH in terms of cAMP production. 1 Publication
VAR_021495
Natural varianti310 – 3101R → C in CHNG1. 1 Publication
VAR_011524
Natural varianti390 – 3901C → W in CHNG1; persistent hypothyroidism and defective thyroid development; habolishes high affinity hormone binding. 2 Publications
VAR_011525
Natural varianti410 – 4101D → N in CHNG1; lack of adenylate cyclase activation. 1 Publication
VAR_011526
Natural varianti432 – 4321N → D in CHNG1; unknown pathological significance; abolishes cell membrane location; abolishes adenylate cyclase-activating G-protein coupled receptor signaling pathway; abolishes phospholipase C-activating G-protein coupled receptor signaling pathway. 1 Publication
VAR_075585
Natural varianti449 – 4491P → L in CHNG1; no effect on cell membrane location; increases cell surface expression; upon TSH stimulation decreases more phospholipase C-activating G-protein coupled receptor signaling pathway than adenylate cyclase-activating G-protein coupled receptor signaling pathway. 1 Publication
VAR_075586
Natural varianti450 – 4501R → H in CHNG1. 1 Publication
VAR_011528
Natural varianti467 – 4671L → P in CHNG1. 1 Publication
VAR_017295
Natural varianti477 – 4771T → I in CHNG1; severe hypothyroidism. 1 Publication
VAR_017296
Natural varianti498 – 4981G → S in CHNG1. 1 Publication
VAR_011533
Natural varianti525 – 5251F → L in CHNG1; impairs adenylate cyclase activation. 1 Publication
VAR_011537
Natural varianti553 – 5531A → T in CHNG1; severe hypothyroidism. 2 Publications
VAR_011538
Natural varianti600 – 6001C → R in CHNG1. 1 Publication
VAR_017297
Familial gestational hyperthyroidism (HTFG)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA condition characterized by abnormally high levels of serum thyroid hormones occurring during early pregnancy.
See also OMIM:603373
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti183 – 1831K → R in HTFG; enhances receptor response to chorionic gonadotropin. 1 Publication
VAR_003566
Hyperthyroidism, non-autoimmune (HTNA)16 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA condition characterized by abnormally high levels of serum thyroid hormones, thyroid hyperplasia, goiter and lack of anti-thyroid antibodies. Typical features of Graves disease such as exophthalmia, myxedema, antibodies anti-TSH receptor and lymphocytic infiltration of the thyroid gland are absent.
See also OMIM:609152
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti281 – 2811S → N in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas. 5 Publications
VAR_003570
Natural varianti431 – 4311G → S in HTNA; gain of function; constitutive activation of the G(s)/adenylyl cyclase system. 2 Publications
VAR_011527
Natural varianti453 – 4531M → T in HTNA; sporadic; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas. 4 Publications
VAR_011529
Natural varianti463 – 4631M → V in HTNA; gain of function. 1 Publication
VAR_011530
Natural varianti486 – 4861I → F in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas; also in hyperfunctioning follicular carcinoma. 4 Publications
VAR_011531
Natural varianti486 – 4861I → M in HTNA; found in hyperfunctioning thyroid adenomas. 3 Publications
VAR_011532
Natural varianti505 – 5051S → N in HTNA; found in toxic thyroid nodules. 3 Publications
VAR_003571
Natural varianti505 – 5051S → R in HTNA; gain of function. 1 Publication
VAR_011534
Natural varianti509 – 5091V → A in HTNA; gain of function. 1 Publication
VAR_011535
Natural varianti568 – 5681I → T in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas. 3 Publications
VAR_011539
Natural varianti597 – 5971V → F in HTNA; 11-fold increase in specific constitutive activity associated with reduction in receptor protein expression. 1 Publication
VAR_021499
Natural varianti629 – 6291L → F in HTNA; also in hyperfunctioning thyroid adenomas and non-adenomatous nodules. 3 Publications
VAR_003575
Natural varianti631 – 6311F → L in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas. 3 Publications
VAR_011545
Natural varianti632 – 6321T → A in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning non-adenomatous nodules. 3 Publications
VAR_011546
Natural varianti632 – 6321T → I in HTNA; gain of function; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas. 7 Publications
VAR_011547
Natural varianti633 – 6331D → E in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas. 4 Publications
VAR_011549
Natural varianti639 – 6391P → S in HTNA; gain of function. 1 Publication
VAR_011552
Natural varianti647 – 6471A → V in HTNA; found in non-adenomatous hyperfunctioning nodules. 1 Publication
VAR_011553
Natural varianti650 – 6501N → Y in HTNA; gain of function. 1 Publication
VAR_011554
Natural varianti670 – 6701N → S in HTNA; gain of function. 1 Publication
VAR_011556
Natural varianti672 – 6721C → Y in HTNA; gain of function. 1 Publication
VAR_011557

Keywords - Diseasei

Congenital hypothyroidism, Disease mutation

Organism-specific databases

MalaCardsiTSHR.
MIMi275200. phenotype.
603372. gene+phenotype.
603373. phenotype.
609152. phenotype.
Orphaneti95713. Athyreosis.
99819. Familial gestational hyperthyroidism.
424. Familial hyperthyroidism due to mutations in TSH receptor.
90673. Hypothyroidism due to TSH receptor mutations.
95720. Thyroid hypoplasia.
PharmGKBiPA37042.

Chemistry

ChEMBLiCHEMBL1963.
DrugBankiDB00024. Thyrotropin Alfa.

Polymorphism and mutation databases

BioMutaiTSHR.
DMDMi62298994.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2020Add
BLAST
Chaini21 – 764744Thyrotropin receptorPRO_0000012786Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi31 ↔ 41
Glycosylationi77 – 771N-linked (GlcNAc...)2 Publications
Glycosylationi99 – 991N-linked (GlcNAc...)1 Publication
Glycosylationi113 – 1131N-linked (GlcNAc...)2 Publications
Glycosylationi177 – 1771N-linked (GlcNAc...)1 Publication
Glycosylationi198 – 1981N-linked (GlcNAc...)2 Publications
Glycosylationi302 – 3021N-linked (GlcNAc...)1 Publication
Disulfide bondi494 ↔ 569PROSITE-ProRule annotation

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

EPDiP16473.
PaxDbiP16473.
PeptideAtlasiP16473.
PRIDEiP16473.

PTM databases

iPTMnetiP16473.
PhosphoSiteiP16473.
SwissPalmiP16473.

Expressioni

Tissue specificityi

Expressed in the thyroid.1 Publication

Gene expression databases

BgeeiENSG00000165409.
CleanExiHS_TSHR.
ExpressionAtlasiP16473. baseline and differential.
GenevisibleiP16473. HS.

Organism-specific databases

HPAiCAB000473.
HPA026680.

Interactioni

Subunit structurei

Interacts (via the PDZ-binding motif) with SCRIB; regulates TSHR trafficking and function.3 Publications

Protein-protein interaction databases

BioGridi113104. 29 interactions.
STRINGi9606.ENSP00000298171.

Chemistry

BindingDBiP16473.

Structurei

Secondary structure

1
764
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi26 – 283Combined sources
Beta strandi30 – 334Combined sources
Turni35 – 373Combined sources
Beta strandi38 – 414Combined sources
Beta strandi56 – 616Combined sources
Beta strandi65 – 673Combined sources
Turni69 – 746Combined sources
Beta strandi80 – 845Combined sources
Turni94 – 963Combined sources
Beta strandi97 – 993Combined sources
Beta strandi105 – 1117Combined sources
Beta strandi121 – 1233Combined sources
Beta strandi130 – 1367Combined sources
Beta strandi152 – 1609Combined sources
Turni169 – 1746Combined sources
Beta strandi175 – 1839Combined sources
Beta strandi190 – 1923Combined sources
Turni194 – 1996Combined sources
Beta strandi201 – 2066Combined sources
Turni218 – 2236Combined sources
Beta strandi229 – 2324Combined sources
Beta strandi250 – 2534Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1XUMmodel-A54-236[»]
2XWTX-ray1.90C22-260[»]
3G04X-ray2.55C22-260[»]
ProteinModelPortaliP16473.
SMRiP16473. Positions 24-257, 411-686.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP16473.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Repeati100 – 12425LRR 1Add
BLAST
Repeati125 – 15026LRR 2Add
BLAST
Repeati152 – 17423LRR 3Add
BLAST
Repeati176 – 19924LRR 4Add
BLAST
Repeati200 – 22324LRR 5Add
BLAST
Repeati227 – 24822LRR 6Add
BLAST
Repeati250 – 27122LRR 7Add
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi762 – 7643PDZ-binding

Sequence similaritiesi

Belongs to the G-protein coupled receptor 1 family. FSH/LSH/TSH subfamily.PROSITE-ProRule annotation
Contains 7 LRR (leucine-rich) repeats.Curated

Keywords - Domaini

Leucine-rich repeat, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2087. Eukaryota.
ENOG410XR1T. LUCA.
GeneTreeiENSGT00760000119088.
HOVERGENiHBG052887.
InParanoidiP16473.
KOiK04249.
PhylomeDBiP16473.

Family and domain databases

Gene3Di3.80.10.10. 1 hit.
InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR002131. Gphrmn_rcpt_fam.
IPR032675. L_dom-like.
IPR026906. LRR_5.
IPR002274. TSH_rcpt.
[Graphical view]
PANTHERiPTHR24372. PTHR24372. 1 hit.
PTHR24372:SF0. PTHR24372:SF0. 1 hit.
PfamiPF00001. 7tm_1. 1 hit.
PF13306. LRR_5. 2 hits.
[Graphical view]
PRINTSiPR00373. GLYCHORMONER.
PR00237. GPCRRHODOPSN.
PR01145. TSHRECEPTOR.
SUPFAMiSSF52058. SSF52058. 1 hit.
PROSITEiPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Additional isoforms seem to exist.
Isoform Long (identifier: P16473-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MRPADLLQLV LLLDLPRDLG GMGCSSPPCE CHQEEDFRVT CKDIQRIPSL
60 70 80 90 100
PPSTQTLKLI ETHLRTIPSH AFSNLPNISR IYVSIDVTLQ QLESHSFYNL
110 120 130 140 150
SKVTHIEIRN TRNLTYIDPD ALKELPLLKF LGIFNTGLKM FPDLTKVYST
160 170 180 190 200
DIFFILEITD NPYMTSIPVN AFQGLCNETL TLKLYNNGFT SVQGYAFNGT
210 220 230 240 250
KLDAVYLNKN KYLTVIDKDA FGGVYSGPSL LDVSQTSVTA LPSKGLEHLK
260 270 280 290 300
ELIARNTWTL KKLPLSLSFL HLTRADLSYP SHCCAFKNQK KIRGILESLM
310 320 330 340 350
CNESSMQSLR QRKSVNALNS PLHQEYEENL GDSIVGYKEK SKFQDTHNNA
360 370 380 390 400
HYYVFFEEQE DEIIGFGQEL KNPQEETLQA FDSHYDYTIC GDSEDMVCTP
410 420 430 440 450
KSDEFNPCED IMGYKFLRIV VWFVSLLALL GNVFVLLILL TSHYKLNVPR
460 470 480 490 500
FLMCNLAFAD FCMGMYLLLI ASVDLYTHSE YYNHAIDWQT GPGCNTAGFF
510 520 530 540 550
TVFASELSVY TLTVITLERW YAITFAMRLD RKIRLRHACA IMVGGWVCCF
560 570 580 590 600
LLALLPLVGI SSYAKVSICL PMDTETPLAL AYIVFVLTLN IVAFVIVCCC
610 620 630 640 650
YVKIYITVRN PQYNPGDKDT KIAKRMAVLI FTDFICMAPI SFYALSAILN
660 670 680 690 700
KPLITVSNSK ILLVLFYPLN SCANPFLYAI FTKAFQRDVF ILLSKFGICK
710 720 730 740 750
RQAQAYRGQR VPPKNSTDIQ VQKVTHDMRQ GLHNMEDVYE LIENSHLTPK
760
KQGQISEEYM QTVL
Length:764
Mass (Da):86,830
Last modified:March 29, 2005 - v2
Checksum:iD2EE9CEBFD64A65F
GO
Isoform Short (identifier: P16473-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     232-253: DVSQTSVTALPSKGLEHLKELI → LPLGRKSLSFETQKAPRSSMPS
     254-764: Missing.

Show »
Length:253
Mass (Da):28,427
Checksum:i69E12F0A7D8B5FD0
GO
Isoform 3 (identifier: P16473-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     232-274: DVSQTSVTAL...LSLSFLHLTR → VENVAVSGKG...QKAPRSSMPS
     275-764: Missing.

Note: No experimental confirmation available.Curated
Show »
Length:274
Mass (Da):30,800
Checksum:iA8A8DBB061774F5C
GO

Sequence cautioni

The sequence AAA70232 differs from that shown. Reason: Frameshift at positions 130, 135 and 612. Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti87 – 871V → L no nucleotide entry (PubMed:2610690).Curated
Sequence conflicti196 – 1983AFN → DFF in AAA70232 (PubMed:2293030).Curated
Sequence conflicti257 – 2571T → S in AAA70232 (PubMed:2293030).Curated
Sequence conflicti264 – 2641P → A in AAA70232 (PubMed:2293030).Curated
Sequence conflicti306 – 3083MQS → IET in AAA70232 (PubMed:2293030).Curated
Sequence conflicti528 – 5281R → A in AAA70232 (PubMed:2293030).Curated
Sequence conflicti601 – 6011Y → H in AAA36783 (PubMed:2558651).Curated
Sequence conflicti635 – 6351I → T in AAA70232 (PubMed:2293030).Curated
Sequence conflicti645 – 6451L → V in AAA70232 (PubMed:2293030).Curated
Sequence conflicti669 – 6691L → I in AAA70232 (PubMed:2293030).Curated
Sequence conflicti744 – 7441N → K in AAA61236 (PubMed:2302212).Curated
Isoform Short (identifier: P16473-2)
Sequence conflicti239 – 2391L → F in AAB24246 (PubMed:1445355).Curated
Sequence conflicti248 – 2481R → S in AAB23390 (PubMed:1530609).Curated
Sequence conflicti248 – 2481R → S in AAH09237 (PubMed:15489334).Curated
Sequence conflicti248 – 2481R → S in AAI20974 (PubMed:15489334).Curated
Sequence conflicti251 – 2511M → T in AAB23390 (PubMed:1530609).Curated
Isoform 3 (identifier: P16473-3)
Sequence conflicti269 – 2691R → S in AAI27629 (PubMed:15489334).Curated

Polymorphismi

The Asp727Glu polymorphism is associated with Graves disease in a Russian population. The Glu727 allele and the heterozygous Asp727Glu genotype are related to higher risk of the disease. The Asp727Glu polymorphism significantly ameliorates G(s)alpha protein activation in the presence of the gain-of-function mutation Ala593Asn although it is functionally inert in the context of the wild-type TSHR.1 Publication

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti34 – 341E → K.
Corresponds to variant rs45499704 [ dbSNP | Ensembl ].
VAR_055925
Natural varianti36 – 361D → H in a patient with Graves disease. 5 Publications
Corresponds to variant rs61747482 [ dbSNP | Ensembl ].
VAR_003564
Natural varianti41 – 411C → S in CHNG1. 2 Publications
VAR_011519
Natural varianti52 – 521P → T Does not contribute to the genetic susceptibility to Graves disease. 7 Publications
Corresponds to variant rs2234919 [ dbSNP | Ensembl ].
VAR_003565
Natural varianti109 – 1091R → Q in CHNG1. 1 Publication
VAR_011520
Natural varianti162 – 1621P → A in CHNG1. 5 Publications
Corresponds to variant rs121908863 [ dbSNP | Ensembl ].
VAR_011521
Natural varianti167 – 1671I → N in CHNG1. 1 Publication
VAR_011522
Natural varianti183 – 1831K → R in HTFG; enhances receptor response to chorionic gonadotropin. 1 Publication
VAR_003566
Natural varianti197 – 1971F → I in papillary cancer. 1 Publication
VAR_003567
Natural varianti219 – 2191D → E in papillary cancer. 1 Publication
VAR_003568
Natural varianti252 – 2521L → P in CHNG1; displays a low expression at the cell surface and a reduced response to bovine TSH in terms of cAMP production. 1 Publication
VAR_021495
Natural varianti281 – 2811S → I in hyperthyroidism; congenital; due to a toxic adenoma. 1 Publication
VAR_003569
Natural varianti281 – 2811S → N in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas. 5 Publications
VAR_003570
Natural varianti281 – 2811S → T in hyperthyroidism; associated with hyperfunctioning thyroid adenomas. 1 Publication
VAR_011523
Natural varianti310 – 3101R → C in CHNG1. 1 Publication
VAR_011524
Natural varianti390 – 3901C → W in CHNG1; persistent hypothyroidism and defective thyroid development; habolishes high affinity hormone binding. 2 Publications
VAR_011525
Natural varianti410 – 4101D → N in CHNG1; lack of adenylate cyclase activation. 1 Publication
VAR_011526
Natural varianti425 – 4251S → I Found in toxic thyroid nodules; 8 to 9 times higher levels of basal cAMP than wild-type TSHR and similar response to maximal TSH stimulation. 1 Publication
VAR_021496
Natural varianti431 – 4311G → S in HTNA; gain of function; constitutive activation of the G(s)/adenylyl cyclase system. 2 Publications
VAR_011527
Natural varianti432 – 4321N → D in CHNG1; unknown pathological significance; abolishes cell membrane location; abolishes adenylate cyclase-activating G-protein coupled receptor signaling pathway; abolishes phospholipase C-activating G-protein coupled receptor signaling pathway. 1 Publication
VAR_075585
Natural varianti449 – 4491P → L in CHNG1; no effect on cell membrane location; increases cell surface expression; upon TSH stimulation decreases more phospholipase C-activating G-protein coupled receptor signaling pathway than adenylate cyclase-activating G-protein coupled receptor signaling pathway. 1 Publication
VAR_075586
Natural varianti450 – 4501R → H in CHNG1. 1 Publication
VAR_011528
Natural varianti453 – 4531M → T in HTNA; sporadic; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas. 4 Publications
VAR_011529
Natural varianti463 – 4631M → V in HTNA; gain of function. 1 Publication
VAR_011530
Natural varianti467 – 4671L → P in CHNG1. 1 Publication
VAR_017295
Natural varianti477 – 4771T → I in CHNG1; severe hypothyroidism. 1 Publication
VAR_017296
Natural varianti486 – 4861I → F in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas; also in hyperfunctioning follicular carcinoma. 4 Publications
VAR_011531
Natural varianti486 – 4861I → M in HTNA; found in hyperfunctioning thyroid adenomas. 3 Publications
VAR_011532
Natural varianti498 – 4981G → S in CHNG1. 1 Publication
VAR_011533
Natural varianti505 – 5051S → N in HTNA; found in toxic thyroid nodules. 3 Publications
VAR_003571
Natural varianti505 – 5051S → R in HTNA; gain of function. 1 Publication
VAR_011534
Natural varianti509 – 5091V → A in HTNA; gain of function. 1 Publication
VAR_011535
Natural varianti512 – 5121L → Q Found in toxic thyroid nodules; 5 times higher levels of basal cAMP than wild-type TSHR and slightly less response to maximal TSH stimulation. 1 Publication
VAR_021497
Natural varianti512 – 5121L → R in hyperthyroidism; associated with autonomously functioning thyroid nodules; 3.3-fold increase in basal cAMP level. 3 Publications
VAR_011536
Natural varianti525 – 5251F → L in CHNG1; impairs adenylate cyclase activation. 1 Publication
VAR_011537
Natural varianti528 – 5281R → H.1 Publication
VAR_003572
Natural varianti553 – 5531A → T in CHNG1; severe hypothyroidism. 2 Publications
VAR_011538
Natural varianti568 – 5681I → T in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas. 3 Publications
VAR_011539
Natural varianti593 – 5931A → N in toxic thyroid adenoma; requires 2 nucleotide substitutions; somatic mutation; N-593 and N-593/E-727 constitutively activate the cAMP cascade; double mutant's specific constitutive activity is 2.3-fold lower than the N-593 mutant. 1 Publication
VAR_021498
Natural varianti597 – 5971V → F in HTNA; 11-fold increase in specific constitutive activity associated with reduction in receptor protein expression. 1 Publication
VAR_021499
Natural varianti597 – 5971V → L in hyperthyroidism; congenital with severe thyrotoxicosis. 1 Publication
VAR_011540
Natural varianti600 – 6001C → R in CHNG1. 1 Publication
VAR_017297
Natural varianti606 – 6061I → M.1 Publication
VAR_011541
Natural varianti619 – 6191D → G in hyperthyroidism; found in toxic thyroid nodules; associated with hyperfunctioning thyroid adenomas. 3 Publications
VAR_003573
Natural varianti623 – 6231A → I in hyperthyroidism; associated with hyperfunctioning thyroid adenomas; gain of function; requires 2 nucleotide substitutions. 2 Publications
VAR_003574
Natural varianti623 – 6231A → V in hyperthyroidism; found in toxic thyroid nodules; associated with hyperfunctioning thyroid adenomas; gain of function. 2 Publications
VAR_011542
Natural varianti629 – 6291L → F in HTNA; also in hyperfunctioning thyroid adenomas and non-adenomatous nodules. 3 Publications
VAR_003575
Natural varianti630 – 6301I → L in hyperthyroidism; associated with hyperfunctioning thyroid adenomas. 1 Publication
VAR_011543
Natural varianti631 – 6311F → C in hyperthyroidism; associated with hyperfunctioning thyroid adenomas. 1 Publication
VAR_011544
Natural varianti631 – 6311F → L in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas. 3 Publications
VAR_011545
Natural varianti632 – 6321T → A in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning non-adenomatous nodules. 3 Publications
VAR_011546
Natural varianti632 – 6321T → I in HTNA; gain of function; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas. 7 Publications
VAR_011547
Natural varianti633 – 6331D → A in hyperthyroidism; associated with hyperfunctioning thyroid adenomas. 1 Publication
VAR_011548
Natural varianti633 – 6331D → E in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas. 4 Publications
VAR_011549
Natural varianti633 – 6331D → H in hyperthyroidism; found in toxic thyroid nodules; associated with hyperfunctioning thyroid adenomas; also in hyperfunctioning insular carcinoma; with severe thyrotoxicosis; gain of function. 3 Publications
Corresponds to variant rs28937584 [ dbSNP | Ensembl ].
VAR_011550
Natural varianti633 – 6331D → Y in hyperthyroidism; found in toxic thyroid nodules; associated with hyperfunctioning thyroid adenomas. 3 Publications
VAR_011551
Natural varianti639 – 6391P → A Found in toxic thyroid nodules. 1 Publication
VAR_021500
Natural varianti639 – 6391P → S in HTNA; gain of function. 1 Publication
VAR_011552
Natural varianti647 – 6471A → V in HTNA; found in non-adenomatous hyperfunctioning nodules. 1 Publication
VAR_011553
Natural varianti650 – 6501N → Y in HTNA; gain of function. 1 Publication
VAR_011554
Natural varianti656 – 6561V → F Found in toxic thyroid nodules. 1 Publication
VAR_021501
Natural varianti658 – 6614Missing in hyperthyroidism; associated with hyperfunctioning thyroid adenomas. 1 Publication
VAR_011555
Natural varianti670 – 6701N → S in HTNA; gain of function. 1 Publication
VAR_011556
Natural varianti672 – 6721C → Y in HTNA; gain of function. 1 Publication
VAR_011557
Natural varianti677 – 6771L → V in thyroid carcinoma; with thyrotoxicosis; gain of function. 1 Publication
VAR_011558
Natural varianti703 – 7031A → G.1 Publication
VAR_011559
Natural varianti715 – 7151N → D in papillary cancer. 1 Publication
VAR_003576
Natural varianti720 – 7201Q → E.1 Publication
VAR_011560
Natural varianti723 – 7231K → M in papillary cancer. 1 Publication
VAR_003577
Natural varianti727 – 7271D → E May be a predisposing factor in toxic multinodular goiter pathogenesis; activation of the cAMP cascade does not differ from the wild-type. 7 Publications
Corresponds to variant rs1991517 [ dbSNP | Ensembl ].
VAR_003578

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei232 – 27443DVSQT…LHLTR → VENVAVSGKGFCKSLFSWLY RLPLGRKSLSFETQKAPRSS MPS in isoform 3. 1 PublicationVSP_044643Add
BLAST
Alternative sequencei232 – 25322DVSQT…LKELI → LPLGRKSLSFETQKAPRSSM PS in isoform Short. 3 PublicationsVSP_001981Add
BLAST
Alternative sequencei254 – 764511Missing in isoform Short. 3 PublicationsVSP_001982Add
BLAST
Alternative sequencei275 – 764490Missing in isoform 3. 1 PublicationVSP_044644Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M31774 mRNA. Translation: AAA36783.1.
M32215 mRNA. Translation: AAA61236.1.
M73747 mRNA. Translation: AAA70232.1. Frameshift.
S45272 mRNA. Translation: AAB23390.2.
S49816 mRNA. Translation: AAB24246.1.
AY429111 mRNA. Translation: AAR07906.1.
AC007262 Genomic DNA. Translation: AAD31568.1.
AC010072 Genomic DNA. Translation: AAF09032.1.
AC010582 Genomic DNA. Translation: AAF26775.1.
AL136040 Genomic DNA. No translation available.
BC009237 mRNA. Translation: AAH09237.1.
BC024205 mRNA. Translation: AAH24205.1.
BC063613 mRNA. Translation: AAH63613.1.
BC108653 mRNA. Translation: AAI08654.1.
BC120973 mRNA. Translation: AAI20974.1.
BC127628 mRNA. Translation: AAI27629.1.
BC141970 mRNA. Translation: AAI41971.1.
CCDSiCCDS32131.1. [P16473-2]
CCDS55935.1. [P16473-3]
CCDS9872.1. [P16473-1]
PIRiA33789. QRHURH.
JC1319.
T01787.
RefSeqiNP_000360.2. NM_000369.2.
NP_001018046.1. NM_001018036.2. [P16473-2]
NP_001136098.1. NM_001142626.2. [P16473-3]
XP_005268096.1. XM_005268039.1. [P16473-2]
XP_006720308.1. XM_006720245.1. [P16473-3]
UniGeneiHs.160411.

Genome annotation databases

EnsembliENST00000342443; ENSP00000340113; ENSG00000165409. [P16473-2]
ENST00000554435; ENSP00000450549; ENSG00000165409. [P16473-3]
GeneIDi7253.
KEGGihsa:7253.
UCSCiuc001xvc.4. human. [P16473-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

TSH receptor database
SHMPD

The Singapore human mutation and polymorphism database

Wikipedia

TSH receptor entry

Sequence-structure-function-analysis of glycoprotein hormone receptors
Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M31774 mRNA. Translation: AAA36783.1.
M32215 mRNA. Translation: AAA61236.1.
M73747 mRNA. Translation: AAA70232.1. Frameshift.
S45272 mRNA. Translation: AAB23390.2.
S49816 mRNA. Translation: AAB24246.1.
AY429111 mRNA. Translation: AAR07906.1.
AC007262 Genomic DNA. Translation: AAD31568.1.
AC010072 Genomic DNA. Translation: AAF09032.1.
AC010582 Genomic DNA. Translation: AAF26775.1.
AL136040 Genomic DNA. No translation available.
BC009237 mRNA. Translation: AAH09237.1.
BC024205 mRNA. Translation: AAH24205.1.
BC063613 mRNA. Translation: AAH63613.1.
BC108653 mRNA. Translation: AAI08654.1.
BC120973 mRNA. Translation: AAI20974.1.
BC127628 mRNA. Translation: AAI27629.1.
BC141970 mRNA. Translation: AAI41971.1.
CCDSiCCDS32131.1. [P16473-2]
CCDS55935.1. [P16473-3]
CCDS9872.1. [P16473-1]
PIRiA33789. QRHURH.
JC1319.
T01787.
RefSeqiNP_000360.2. NM_000369.2.
NP_001018046.1. NM_001018036.2. [P16473-2]
NP_001136098.1. NM_001142626.2. [P16473-3]
XP_005268096.1. XM_005268039.1. [P16473-2]
XP_006720308.1. XM_006720245.1. [P16473-3]
UniGeneiHs.160411.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1XUMmodel-A54-236[»]
2XWTX-ray1.90C22-260[»]
3G04X-ray2.55C22-260[»]
ProteinModelPortaliP16473.
SMRiP16473. Positions 24-257, 411-686.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi113104. 29 interactions.
STRINGi9606.ENSP00000298171.

Chemistry

BindingDBiP16473.
ChEMBLiCHEMBL1963.
DrugBankiDB00024. Thyrotropin Alfa.

Protein family/group databases

GPCRDBiSearch...

PTM databases

iPTMnetiP16473.
PhosphoSiteiP16473.
SwissPalmiP16473.

Polymorphism and mutation databases

BioMutaiTSHR.
DMDMi62298994.

Proteomic databases

EPDiP16473.
PaxDbiP16473.
PeptideAtlasiP16473.
PRIDEiP16473.

Protocols and materials databases

DNASUi7253.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000342443; ENSP00000340113; ENSG00000165409. [P16473-2]
ENST00000554435; ENSP00000450549; ENSG00000165409. [P16473-3]
GeneIDi7253.
KEGGihsa:7253.
UCSCiuc001xvc.4. human. [P16473-1]

Organism-specific databases

CTDi7253.
GeneCardsiTSHR.
H-InvDBHIX0021925.
HGNCiHGNC:12373. TSHR.
HPAiCAB000473.
HPA026680.
MalaCardsiTSHR.
MIMi275200. phenotype.
603372. gene+phenotype.
603373. phenotype.
609152. phenotype.
neXtProtiNX_P16473.
Orphaneti95713. Athyreosis.
99819. Familial gestational hyperthyroidism.
424. Familial hyperthyroidism due to mutations in TSH receptor.
90673. Hypothyroidism due to TSH receptor mutations.
95720. Thyroid hypoplasia.
PharmGKBiPA37042.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2087. Eukaryota.
ENOG410XR1T. LUCA.
GeneTreeiENSGT00760000119088.
HOVERGENiHBG052887.
InParanoidiP16473.
KOiK04249.
PhylomeDBiP16473.

Enzyme and pathway databases

ReactomeiR-HSA-375281. Hormone ligand-binding receptors.
R-HSA-418555. G alpha (s) signalling events.
SignaLinkiP16473.
SIGNORiP16473.

Miscellaneous databases

EvolutionaryTraceiP16473.
GeneWikiiThyrotropin_receptor.
GenomeRNAii7253.
PROiP16473.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000165409.
CleanExiHS_TSHR.
ExpressionAtlasiP16473. baseline and differential.
GenevisibleiP16473. HS.

Family and domain databases

Gene3Di3.80.10.10. 1 hit.
InterProiIPR000276. GPCR_Rhodpsn.
IPR017452. GPCR_Rhodpsn_7TM.
IPR002131. Gphrmn_rcpt_fam.
IPR032675. L_dom-like.
IPR026906. LRR_5.
IPR002274. TSH_rcpt.
[Graphical view]
PANTHERiPTHR24372. PTHR24372. 1 hit.
PTHR24372:SF0. PTHR24372:SF0. 1 hit.
PfamiPF00001. 7tm_1. 1 hit.
PF13306. LRR_5. 2 hits.
[Graphical view]
PRINTSiPR00373. GLYCHORMONER.
PR00237. GPCRRHODOPSN.
PR01145. TSHRECEPTOR.
SUPFAMiSSF52058. SSF52058. 1 hit.
PROSITEiPS00237. G_PROTEIN_RECEP_F1_1. 1 hit.
PS50262. G_PROTEIN_RECEP_F1_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTSHR_HUMAN
AccessioniPrimary (citable) accession number: P16473
Secondary accession number(s): A0PJU7
, F5GYU5, G3V2A9, Q16503, Q8TB90, Q96GT6, Q9P1V4, Q9ULA3, Q9UPH3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 1, 1990
Last sequence update: March 29, 2005
Last modified: September 7, 2016
This is version 201 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  2. Human chromosome 14
    Human chromosome 14: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.