{"results":[{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"P16473","secondaryAccessions":["A0A0A0MTJ0","A0PJU7","F5GYU5","G3V2A9","Q16503","Q8TB90","Q96GT6","Q9P1V4","Q9ULA3","Q9UPH3"],"uniProtkbId":"TSHR_HUMAN","entryAudit":{"firstPublicDate":"1990-08-01","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2024-10-02","entryVersion":264,"sequenceVersion":3},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"value":"Thyrotropin receptor"}},"alternativeNames":[{"fullName":{"value":"Thyroid-stimulating hormone receptor"},"shortNames":[{"value":"TSH-R"}]}],"flag":"Precursor"},"genes":[{"geneName":{"value":"TSHR"},"synonyms":[{"value":"LGR3"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"P21463"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11847099"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12045258"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27638195"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35940204"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35940205"}],"value":"Receptor for the thyroid-stimulating hormone (TSH) or thyrotropin (PubMed:11847099, PubMed:12045258). Also acts as a receptor for the heterodimeric glycoprotein hormone (GPHA2:GPHB5) or thyrostimulin (PubMed:12045258). TSHR is coupled to G(s) proteins and mediates the activation of adenylate cyclase (PubMed:11847099, PubMed:35940205, PubMed:35940204). This leads to the generation of cyclic adenosine monophosphate (cAMP), which in turn activates protein kinase A (PKA). PKA subsequently phosphorylates downstream targets involved in thyroid hormone biosynthesis and secretion, including thyroid peroxidase (TPO) and the sodium/iodide symporter (NIS) (PubMed:27638195). Additionally, plays a central role in controlling thyroid cell metabolism (By similarity)"}],"commentType":"FUNCTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12045258"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15775968"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35940204"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"35940205"}],"value":"Interacts with heterodimer GPHA2:GPHB5; this interaction stimulates cAMP production (PubMed:12045258). Interacts (via the PDZ-binding motif) with SCRIB; regulates TSHR trafficking and function (PubMed:15775968). Interacts with GNAS (PubMed:35940205, PubMed:35940204)"}],"commentType":"SUBUNIT"},{"commentType":"INTERACTION","interactions":[{"interactantOne":{"uniProtKBAccession":"P16473","intActId":"EBI-13939599"},"interactantTwo":{"uniProtKBAccession":"P30542","geneName":"ADORA1","intActId":"EBI-2903663"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P16473","intActId":"EBI-13939599"},"interactantTwo":{"uniProtKBAccession":"Q9NPA3","geneName":"MID1IP1","intActId":"EBI-750096"},"numberOfExperiments":2,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P16473","intActId":"EBI-13939599"},"interactantTwo":{"uniProtKBAccession":"Q14160","geneName":"SCRIB","intActId":"EBI-357345"},"numberOfExperiments":3,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P16473","intActId":"EBI-13939599"},"interactantTwo":{"uniProtKBAccession":"Q13485","geneName":"SMAD4","intActId":"EBI-347263"},"numberOfExperiments":6,"organismDiffer":false},{"interactantOne":{"uniProtKBAccession":"P16473","intActId":"EBI-13939599"},"interactantTwo":{"uniProtKBAccession":"P21579","geneName":"SYT1","intActId":"EBI-524909"},"numberOfExperiments":2,"organismDiffer":false}]},{"commentType":"SUBCELLULAR LOCATION","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11847099"}],"value":"Cell membrane","id":"SL-0039"},"topology":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Multi-pass membrane protein","id":"SL-9909"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11847099"}],"value":"Basolateral cell membrane","id":"SL-0026"},"topology":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Multi-pass membrane protein","id":"SL-9909"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"Long"},"isoformIds":["P16473-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"Short"},"isoformIds":["P16473-2"],"sequenceIds":["VSP_001981","VSP_001982"],"isoformSequenceStatus":"Described"},{"name":{"value":"3"},"isoformIds":["P16473-3"],"sequenceIds":["VSP_044643","VSP_044644"],"isoformSequenceStatus":"Described"}],"note":{"texts":[{"value":"Additional isoforms seem to exist."}]}},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11847099"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"2610690"}],"value":"Expressed in thyroide cells (at protein level) (PubMed:11847099). Expressed in the thyroid (PubMed:2610690)"}],"commentType":"TISSUE SPECIFICITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11847099"}],"value":"Glycosylated"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11847099"}],"value":"Sulfated. Sulfation on Tyr-385 plays a role in thyrotropin receptor binding and activation"}],"commentType":"PTM"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11887032"}],"value":"Polymorphism at position 727 could be associated with Graves disease"}],"commentType":"POLYMORPHISM"},{"commentType":"DISEASE","note":{"texts":[{"value":"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)"}]}},{"commentType":"DISEASE","note":{"texts":[{"value":"Autoantibodies against TSHR are directly responsible for the pathogenesis and hyperthyroidism of Graves disease. Antibody interaction with TSHR results in an uncontrolled receptor stimulation"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Hypothyroidism, congenital, non-goitrous, 1","diseaseAccession":"DI-00362","acronym":"CHNG1","description":"A 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.","diseaseCrossReference":{"database":"MIM","id":"275200"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"10720030"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11095460"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"11442002"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"12050212"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"14725684"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"15531543"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"25978107"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"7528344"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8954020"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9100579"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9185526"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9329388"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Familial gestational hyperthyroidism","diseaseAccession":"DI-02821","acronym":"HTFG","description":"A condition characterized by abnormally high levels of serum thyroid hormones occurring during early pregnancy.","diseaseCrossReference":{"database":"MIM","id":"603373"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"9854118"}]},"note":{"texts":[{"value":"The disease is caused by variants affecting the gene represented in this entry"}]}},{"commentType":"DISEASE","disease":{"diseaseId":"Hyperthyroidism, non-autoimmune","diseaseAccession":"DI-02059","acronym":"HTNA","description":"A condition characterized by abnormally high levels of serum thyroid hormones, thyroid hyperplasia, goiter and lack of anti-thyroid antibodies. 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