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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

BioCyciZFISH:ENSG00000165409-MONOMER.
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)DescriptionActionsGraphical viewLength
Topological domaini21 – 413ExtracellularSequence analysisAdd BLAST393
Transmembranei414 – 441Helical; Name=1Sequence analysisAdd BLAST28
Topological domaini442 – 450CytoplasmicSequence analysis9
Transmembranei451 – 473Helical; Name=2Sequence analysisAdd BLAST23
Topological domaini474 – 494ExtracellularSequence analysisAdd BLAST21
Transmembranei495 – 517Helical; Name=3Sequence analysisAdd BLAST23
Topological domaini518 – 537CytoplasmicSequence analysisAdd BLAST20
Transmembranei538 – 560Helical; Name=4Sequence analysisAdd BLAST23
Topological domaini561 – 580ExtracellularSequence analysisAdd BLAST20
Transmembranei581 – 602Helical; Name=5Sequence analysisAdd BLAST22
Topological domaini603 – 625CytoplasmicSequence analysisAdd BLAST23
Transmembranei626 – 649Helical; Name=6Sequence analysisAdd BLAST24
Topological domaini650 – 660ExtracellularSequence analysisAdd BLAST11
Transmembranei661 – 682Helical; Name=7Sequence analysisAdd BLAST22
Topological domaini683 – 764CytoplasmicSequence analysisAdd BLAST82

GO - Cellular componenti

  • cell surface Source: UniProtKB
  • 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)DescriptionActionsGraphical viewLength
Natural variantiVAR_01151941C → S in CHNG1. 2 Publications1
Natural variantiVAR_011520109R → Q in CHNG1. 1 Publication1
Natural variantiVAR_011521162P → A in CHNG1. 5 PublicationsCorresponds to variant rs121908863dbSNPEnsembl.1
Natural variantiVAR_011522167I → N in CHNG1. 1 Publication1
Natural variantiVAR_021495252L → P in CHNG1; displays a low expression at the cell surface and a reduced response to bovine TSH in terms of cAMP production. 1 Publication1
Natural variantiVAR_011524310R → C in CHNG1. 1 Publication1
Natural variantiVAR_011525390C → W in CHNG1; persistent hypothyroidism and defective thyroid development; habolishes high affinity hormone binding. 2 Publications1
Natural variantiVAR_011526410D → N in CHNG1; lack of adenylate cyclase activation. 1 Publication1
Natural variantiVAR_075585432N → 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 Publication1
Natural variantiVAR_075586449P → 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 Publication1
Natural variantiVAR_011528450R → H in CHNG1. 1 Publication1
Natural variantiVAR_017295467L → P in CHNG1. 1 Publication1
Natural variantiVAR_017296477T → I in CHNG1; severe hypothyroidism. 1 Publication1
Natural variantiVAR_011533498G → S in CHNG1. 1 Publication1
Natural variantiVAR_011537525F → L in CHNG1; impairs adenylate cyclase activation. 1 Publication1
Natural variantiVAR_011538553A → T in CHNG1; severe hypothyroidism. 2 Publications1
Natural variantiVAR_017297600C → R in CHNG1. 1 Publication1
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)DescriptionActionsGraphical viewLength
Natural variantiVAR_003566183K → R in HTFG; enhances receptor response to chorionic gonadotropin. 1 Publication1
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)DescriptionActionsGraphical viewLength
Natural variantiVAR_003570281S → N in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas. 5 Publications1
Natural variantiVAR_011527431G → S in HTNA; gain of function; constitutive activation of the G(s)/adenylyl cyclase system. 2 Publications1
Natural variantiVAR_011529453M → T in HTNA; sporadic; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas. 4 Publications1
Natural variantiVAR_011530463M → V in HTNA; gain of function. 1 Publication1
Natural variantiVAR_011531486I → F in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas; also in hyperfunctioning follicular carcinoma. 4 Publications1
Natural variantiVAR_011532486I → M in HTNA; found in hyperfunctioning thyroid adenomas. 3 Publications1
Natural variantiVAR_003571505S → N in HTNA; found in toxic thyroid nodules. 3 Publications1
Natural variantiVAR_011534505S → R in HTNA; gain of function. 1 Publication1
Natural variantiVAR_011535509V → A in HTNA; gain of function. 1 Publication1
Natural variantiVAR_011539568I → T in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas. 3 Publications1
Natural variantiVAR_021499597V → F in HTNA; 11-fold increase in specific constitutive activity associated with reduction in receptor protein expression. 1 Publication1
Natural variantiVAR_003575629L → F in HTNA; also in hyperfunctioning thyroid adenomas and non-adenomatous nodules. 3 Publications1
Natural variantiVAR_011545631F → L in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas. 3 Publications1
Natural variantiVAR_011546632T → A in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning non-adenomatous nodules. 3 Publications1
Natural variantiVAR_011547632T → I in HTNA; gain of function; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas. 7 Publications1
Natural variantiVAR_011549633D → E in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas. 4 Publications1
Natural variantiVAR_011552639P → S in HTNA; gain of function. 1 Publication1
Natural variantiVAR_011553647A → V in HTNA; found in non-adenomatous hyperfunctioning nodules. 1 Publication1
Natural variantiVAR_011554650N → Y in HTNA; gain of function. 1 Publication1
Natural variantiVAR_011556670N → S in HTNA; gain of function. 1 Publication1
Natural variantiVAR_011557672C → Y in HTNA; gain of function. 1 Publication1

Keywords - Diseasei

Congenital hypothyroidism, Disease mutation

Organism-specific databases

DisGeNETi7253.
MalaCardsiTSHR.
MIMi275200. phenotype.
603372. gene+phenotype.
603373. phenotype.
609152. phenotype.
OpenTargetsiENSG00000165409.
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 databases

ChEMBLiCHEMBL1963.
DrugBankiDB00024. Thyrotropin Alfa.
GuidetoPHARMACOLOGYi255.

Polymorphism and mutation databases

BioMutaiTSHR.
DMDMi62298994.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 20Add BLAST20
ChainiPRO_000001278621 – 764Thyrotropin receptorAdd BLAST744

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi31 ↔ 41
Glycosylationi77N-linked (GlcNAc...)2 Publications1
Glycosylationi99N-linked (GlcNAc...)1 Publication1
Glycosylationi113N-linked (GlcNAc...)2 Publications1
Glycosylationi177N-linked (GlcNAc...)1 Publication1
Glycosylationi198N-linked (GlcNAc...)2 Publications1
Glycosylationi302N-linked (GlcNAc...)1 Publication1
Disulfide bondi494 ↔ 569PROSITE-ProRule annotation

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

EPDiP16473.
PaxDbiP16473.
PeptideAtlasiP16473.
PRIDEiP16473.

PTM databases

iPTMnetiP16473.
PhosphoSitePlusiP16473.
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 interactors.
STRINGi9606.ENSP00000298171.

Chemistry databases

BindingDBiP16473.

Structurei

Secondary structure

1764
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi26 – 28Combined sources3
Beta strandi30 – 33Combined sources4
Turni35 – 37Combined sources3
Beta strandi38 – 41Combined sources4
Beta strandi56 – 61Combined sources6
Beta strandi65 – 67Combined sources3
Turni69 – 74Combined sources6
Beta strandi80 – 84Combined sources5
Turni94 – 96Combined sources3
Beta strandi97 – 99Combined sources3
Beta strandi105 – 111Combined sources7
Beta strandi121 – 123Combined sources3
Beta strandi130 – 136Combined sources7
Beta strandi152 – 160Combined sources9
Turni169 – 174Combined sources6
Beta strandi175 – 183Combined sources9
Beta strandi190 – 192Combined sources3
Turni194 – 199Combined sources6
Beta strandi201 – 206Combined sources6
Turni218 – 223Combined sources6
Beta strandi229 – 232Combined sources4
Beta strandi250 – 253Combined sources4

3D structure databases

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

Miscellaneous databases

EvolutionaryTraceiP16473.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati100 – 124LRR 1Add BLAST25
Repeati125 – 150LRR 2Add BLAST26
Repeati152 – 174LRR 3Add BLAST23
Repeati176 – 199LRR 4Add BLAST24
Repeati200 – 223LRR 5Add BLAST24
Repeati227 – 248LRR 6Add BLAST22
Repeati250 – 271LRR 7Add BLAST22

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi762 – 764PDZ-binding3

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)DescriptionActionsGraphical viewLength
Sequence conflicti87V → L no nucleotide entry (PubMed:2610690).Curated1
Sequence conflicti196 – 198AFN → DFF in AAA70232 (PubMed:2293030).Curated3
Sequence conflicti257T → S in AAA70232 (PubMed:2293030).Curated1
Sequence conflicti264P → A in AAA70232 (PubMed:2293030).Curated1
Sequence conflicti306 – 308MQS → IET in AAA70232 (PubMed:2293030).Curated3
Sequence conflicti528R → A in AAA70232 (PubMed:2293030).Curated1
Sequence conflicti601Y → H in AAA36783 (PubMed:2558651).Curated1
Sequence conflicti635I → T in AAA70232 (PubMed:2293030).Curated1
Sequence conflicti645L → V in AAA70232 (PubMed:2293030).Curated1
Sequence conflicti669L → I in AAA70232 (PubMed:2293030).Curated1
Sequence conflicti744N → K in AAA61236 (PubMed:2302212).Curated1
Isoform Short (identifier: P16473-2)
Sequence conflicti239L → F in AAB24246 (PubMed:1445355).Curated1
Sequence conflicti248R → S in AAB23390 (PubMed:1530609).Curated1
Sequence conflicti248R → S in AAH09237 (PubMed:15489334).Curated1
Sequence conflicti248R → S in AAI20974 (PubMed:15489334).Curated1
Sequence conflicti251M → T in AAB23390 (PubMed:1530609).Curated1
Isoform 3 (identifier: P16473-3)
Sequence conflicti269R → S in AAI27629 (PubMed:15489334).Curated1

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)DescriptionActionsGraphical viewLength
Natural variantiVAR_05592534E → K.Corresponds to variant rs45499704dbSNPEnsembl.1
Natural variantiVAR_00356436D → H in a patient with Graves disease. 5 PublicationsCorresponds to variant rs61747482dbSNPEnsembl.1
Natural variantiVAR_01151941C → S in CHNG1. 2 Publications1
Natural variantiVAR_00356552P → T Does not contribute to the genetic susceptibility to Graves disease. 7 PublicationsCorresponds to variant rs2234919dbSNPEnsembl.1
Natural variantiVAR_011520109R → Q in CHNG1. 1 Publication1
Natural variantiVAR_011521162P → A in CHNG1. 5 PublicationsCorresponds to variant rs121908863dbSNPEnsembl.1
Natural variantiVAR_011522167I → N in CHNG1. 1 Publication1
Natural variantiVAR_003566183K → R in HTFG; enhances receptor response to chorionic gonadotropin. 1 Publication1
Natural variantiVAR_003567197F → I in papillary cancer. 1 Publication1
Natural variantiVAR_003568219D → E in papillary cancer. 1 Publication1
Natural variantiVAR_021495252L → P in CHNG1; displays a low expression at the cell surface and a reduced response to bovine TSH in terms of cAMP production. 1 Publication1
Natural variantiVAR_003569281S → I in hyperthyroidism; congenital; due to a toxic adenoma. 1 Publication1
Natural variantiVAR_003570281S → N in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas. 5 Publications1
Natural variantiVAR_011523281S → T in hyperthyroidism; associated with hyperfunctioning thyroid adenomas. 1 Publication1
Natural variantiVAR_011524310R → C in CHNG1. 1 Publication1
Natural variantiVAR_011525390C → W in CHNG1; persistent hypothyroidism and defective thyroid development; habolishes high affinity hormone binding. 2 Publications1
Natural variantiVAR_011526410D → N in CHNG1; lack of adenylate cyclase activation. 1 Publication1
Natural variantiVAR_021496425S → 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 Publication1
Natural variantiVAR_011527431G → S in HTNA; gain of function; constitutive activation of the G(s)/adenylyl cyclase system. 2 Publications1
Natural variantiVAR_075585432N → 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 Publication1
Natural variantiVAR_075586449P → 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 Publication1
Natural variantiVAR_011528450R → H in CHNG1. 1 Publication1
Natural variantiVAR_011529453M → T in HTNA; sporadic; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas. 4 Publications1
Natural variantiVAR_011530463M → V in HTNA; gain of function. 1 Publication1
Natural variantiVAR_017295467L → P in CHNG1. 1 Publication1
Natural variantiVAR_017296477T → I in CHNG1; severe hypothyroidism. 1 Publication1
Natural variantiVAR_011531486I → F in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas; also in hyperfunctioning follicular carcinoma. 4 Publications1
Natural variantiVAR_011532486I → M in HTNA; found in hyperfunctioning thyroid adenomas. 3 Publications1
Natural variantiVAR_011533498G → S in CHNG1. 1 Publication1
Natural variantiVAR_003571505S → N in HTNA; found in toxic thyroid nodules. 3 Publications1
Natural variantiVAR_011534505S → R in HTNA; gain of function. 1 Publication1
Natural variantiVAR_011535509V → A in HTNA; gain of function. 1 Publication1
Natural variantiVAR_021497512L → 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 Publication1
Natural variantiVAR_011536512L → R in hyperthyroidism; associated with autonomously functioning thyroid nodules; 3.3-fold increase in basal cAMP level. 3 Publications1
Natural variantiVAR_011537525F → L in CHNG1; impairs adenylate cyclase activation. 1 Publication1
Natural variantiVAR_003572528R → H.1 Publication1
Natural variantiVAR_011538553A → T in CHNG1; severe hypothyroidism. 2 Publications1
Natural variantiVAR_011539568I → T in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas. 3 Publications1
Natural variantiVAR_021498593A → 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 Publication1
Natural variantiVAR_021499597V → F in HTNA; 11-fold increase in specific constitutive activity associated with reduction in receptor protein expression. 1 Publication1
Natural variantiVAR_011540597V → L in hyperthyroidism; congenital with severe thyrotoxicosis. 1 Publication1
Natural variantiVAR_017297600C → R in CHNG1. 1 Publication1
Natural variantiVAR_011541606I → M.1 Publication1
Natural variantiVAR_003573619D → G in hyperthyroidism; found in toxic thyroid nodules; associated with hyperfunctioning thyroid adenomas. 3 Publications1
Natural variantiVAR_003574623A → I in hyperthyroidism; associated with hyperfunctioning thyroid adenomas; gain of function; requires 2 nucleotide substitutions. 2 Publications1
Natural variantiVAR_011542623A → V in hyperthyroidism; found in toxic thyroid nodules; associated with hyperfunctioning thyroid adenomas; gain of function. 2 Publications1
Natural variantiVAR_003575629L → F in HTNA; also in hyperfunctioning thyroid adenomas and non-adenomatous nodules. 3 Publications1
Natural variantiVAR_011543630I → L in hyperthyroidism; associated with hyperfunctioning thyroid adenomas. 1 Publication1
Natural variantiVAR_011544631F → C in hyperthyroidism; associated with hyperfunctioning thyroid adenomas. 1 Publication1
Natural variantiVAR_011545631F → L in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning thyroid adenomas. 3 Publications1
Natural variantiVAR_011546632T → A in HTNA; gain of function; found in toxic thyroid nodules and hyperfunctioning non-adenomatous nodules. 3 Publications1
Natural variantiVAR_011547632T → I in HTNA; gain of function; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas. 7 Publications1
Natural variantiVAR_011548633D → A in hyperthyroidism; associated with hyperfunctioning thyroid adenomas. 1 Publication1
Natural variantiVAR_011549633D → E in HTNA; found in thyroid toxic nodules and hyperfunctioning thyroid adenomas. 4 Publications1
Natural variantiVAR_011550633D → 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 PublicationsCorresponds to variant rs28937584dbSNPEnsembl.1
Natural variantiVAR_011551633D → Y in hyperthyroidism; found in toxic thyroid nodules; associated with hyperfunctioning thyroid adenomas. 3 Publications1
Natural variantiVAR_021500639P → A Found in toxic thyroid nodules. 1 Publication1
Natural variantiVAR_011552639P → S in HTNA; gain of function. 1 Publication1
Natural variantiVAR_011553647A → V in HTNA; found in non-adenomatous hyperfunctioning nodules. 1 Publication1
Natural variantiVAR_011554650N → Y in HTNA; gain of function. 1 Publication1
Natural variantiVAR_021501656V → F Found in toxic thyroid nodules. 1 Publication1
Natural variantiVAR_011555658 – 661Missing in hyperthyroidism; associated with hyperfunctioning thyroid adenomas. 1 Publication4
Natural variantiVAR_011556670N → S in HTNA; gain of function. 1 Publication1
Natural variantiVAR_011557672C → Y in HTNA; gain of function. 1 Publication1
Natural variantiVAR_011558677L → V in thyroid carcinoma; with thyrotoxicosis; gain of function. 1 Publication1
Natural variantiVAR_011559703A → G.1 Publication1
Natural variantiVAR_003576715N → D in papillary cancer. 1 Publication1
Natural variantiVAR_011560720Q → E.1 Publication1
Natural variantiVAR_003577723K → M in papillary cancer. 1 Publication1
Natural variantiVAR_003578727D → E May be a predisposing factor in toxic multinodular goiter pathogenesis; activation of the cAMP cascade does not differ from the wild-type. 7 PublicationsCorresponds to variant rs1991517dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_044643232 – 274DVSQT…LHLTR → VENVAVSGKGFCKSLFSWLY RLPLGRKSLSFETQKAPRSS MPS in isoform 3. 1 PublicationAdd BLAST43
Alternative sequenceiVSP_001981232 – 253DVSQT…LKELI → LPLGRKSLSFETQKAPRSSM PS in isoform Short. 3 PublicationsAdd BLAST22
Alternative sequenceiVSP_001982254 – 764Missing in isoform Short. 3 PublicationsAdd BLAST511
Alternative sequenceiVSP_044644275 – 764Missing in isoform 3. 1 PublicationAdd BLAST490

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
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1XUMmodel-A54-236[»]
2XWTX-ray1.90C22-260[»]
3G04X-ray2.55C22-260[»]
ProteinModelPortaliP16473.
SMRiP16473.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi113104. 29 interactors.
STRINGi9606.ENSP00000298171.

Chemistry databases

BindingDBiP16473.
ChEMBLiCHEMBL1963.
DrugBankiDB00024. Thyrotropin Alfa.
GuidetoPHARMACOLOGYi255.

Protein family/group databases

GPCRDBiSearch...

PTM databases

iPTMnetiP16473.
PhosphoSitePlusiP16473.
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.
DisGeNETi7253.
GeneCardsiTSHR.
H-InvDBHIX0021925.
HGNCiHGNC:12373. TSHR.
HPAiCAB000473.
HPA026680.
MalaCardsiTSHR.
MIMi275200. phenotype.
603372. gene+phenotype.
603373. phenotype.
609152. phenotype.
neXtProtiNX_P16473.
OpenTargetsiENSG00000165409.
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

BioCyciZFISH:ENSG00000165409-MONOMER.
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: November 2, 2016
This is version 203 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.