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P06213

- INSR_HUMAN

UniProt

P06213 - INSR_HUMAN

Protein

Insulin receptor

Gene

INSR

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 206 (01 Oct 2014)
      Sequence version 4 (05 Oct 2010)
      Previous versions | rss
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    Functioni

    Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.7 Publications

    Catalytic activityi

    ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.8 PublicationsPROSITE-ProRule annotation

    Enzyme regulationi

    Activated in response to insulin. Autophosphorylation activates the kinase activity. PTPN1, PTPRE and PTPRF dephosphorylate important tyrosine residues, thereby reducing INSR activity. Inhibited by ENPP1. GRB10 and GRB14 inhibit the catalytic activity of the INSR, they block access of substrates to the activated receptor. SOCS1 and SOCS3 act as negative regulators of INSR activity, they bind to the activated INRS and interfere with the phosphorylation of INSR substrates.5 Publications

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei66 – 661Insulin-bindingCurated
    Binding sitei1033 – 10331ATP1 PublicationPROSITE-ProRule annotation
    Binding sitei1057 – 10571ATP1 PublicationPROSITE-ProRule annotation
    Active sitei1159 – 11591Proton donor/acceptor1 Publication
    Binding sitei1177 – 11771ATP1 PublicationPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi1104 – 11107ATP1 PublicationPROSITE-ProRule annotation
    Nucleotide bindingi1163 – 11642ATP1 PublicationPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: BHF-UCL
    2. GTP binding Source: BHF-UCL
    3. insulin-activated receptor activity Source: UniProtKB
    4. insulin binding Source: UniProtKB
    5. insulin-like growth factor I binding Source: BHF-UCL
    6. insulin-like growth factor II binding Source: BHF-UCL
    7. insulin-like growth factor receptor binding Source: BHF-UCL
    8. insulin receptor substrate binding Source: UniProtKB
    9. phosphatidylinositol 3-kinase binding Source: UniProtKB
    10. protein binding Source: BHF-UCL
    11. protein tyrosine kinase activity Source: UniProtKB
    12. PTB domain binding Source: UniProtKB
    13. receptor signaling protein tyrosine kinase activity Source: BHF-UCL

    GO - Biological processi

    1. activation of MAPK activity Source: BHF-UCL
    2. activation of protein kinase activity Source: BHF-UCL
    3. activation of protein kinase B activity Source: BHF-UCL
    4. carbohydrate metabolic process Source: UniProtKB-KW
    5. cellular response to growth factor stimulus Source: Ensembl
    6. cellular response to insulin stimulus Source: BHF-UCL
    7. exocrine pancreas development Source: Ensembl
    8. glucose homeostasis Source: BHF-UCL
    9. G-protein coupled receptor signaling pathway Source: BHF-UCL
    10. heart morphogenesis Source: BHF-UCL
    11. insulin receptor signaling pathway Source: UniProtKB
    12. male sex determination Source: Ensembl
    13. peptidyl-tyrosine phosphorylation Source: BHF-UCL
    14. positive regulation of cell migration Source: BHF-UCL
    15. positive regulation of cell proliferation Source: BHF-UCL
    16. positive regulation of developmental growth Source: BHF-UCL
    17. positive regulation of DNA replication Source: BHF-UCL
    18. positive regulation of glucose import Source: BHF-UCL
    19. positive regulation of glycogen biosynthetic process Source: BHF-UCL
    20. positive regulation of glycolytic process Source: BHF-UCL
    21. positive regulation of MAPK cascade Source: BHF-UCL
    22. positive regulation of mitosis Source: BHF-UCL
    23. positive regulation of nitric oxide biosynthetic process Source: BHF-UCL
    24. positive regulation of protein kinase B signaling Source: BHF-UCL
    25. positive regulation of protein phosphorylation Source: BHF-UCL
    26. positive regulation of respiratory burst Source: BHF-UCL
    27. protein autophosphorylation Source: UniProtKB
    28. protein heterotetramerization Source: UniProtKB
    29. regulation of embryonic development Source: BHF-UCL
    30. regulation of transcription, DNA-templated Source: BHF-UCL
    31. signal transduction by phosphorylation Source: GOC
    32. transformation of host cell by virus Source: BHF-UCL

    Keywords - Molecular functioni

    Kinase, Receptor, Transferase, Tyrosine-protein kinase

    Keywords - Biological processi

    Carbohydrate metabolism

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.10.1. 2681.
    ReactomeiREACT_1109. Insulin receptor recycling.
    REACT_1661. SHC activation.
    REACT_498. Signaling by Insulin receptor.
    REACT_508. Signal attenuation.
    REACT_570. IRS activation.
    SABIO-RKP06213.
    SignaLinkiP06213.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Insulin receptor (EC:2.7.10.1)
    Short name:
    IR
    Alternative name(s):
    CD_antigen: CD220
    Cleaved into the following 2 chains:
    Gene namesi
    Name:INSR
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 19

    Organism-specific databases

    HGNCiHGNC:6091. INSR.

    Subcellular locationi

    GO - Cellular componenti

    1. caveola Source: BHF-UCL
    2. endosome membrane Source: Reactome
    3. extracellular vesicular exosome Source: UniProt
    4. insulin receptor complex Source: BHF-UCL
    5. integral component of plasma membrane Source: BHF-UCL
    6. membrane Source: BHF-UCL
    7. plasma membrane Source: BHF-UCL
    8. receptor complex Source: MGI

    Keywords - Cellular componenti

    Cell membrane, Membrane

    Pathology & Biotechi

    Involvement in diseasei

    Rabson-Mendenhall syndrome (RMS) [MIM:262190]: Severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive.5 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti42 – 421N → K in RMS; impairs transport to the plasma membrane and reduces the affinity to bind insulin. 1 Publication
    VAR_004079
    Natural varianti236 – 2361H → R in LEPRCH; Winnipeg; in one patient with in RMS heterozygous compound with S-386; may impair receptor processing. 2 Publications
    VAR_004084
    Natural varianti350 – 3501S → L in RMS and LEPRCH. 2 Publications
    VAR_015914
    Natural varianti386 – 3861G → S in RMS; may impair receptor processing. 1 Publication
    VAR_031520
    Natural varianti997 – 9971P → T in RMS; reduces insulin binding. 1 Publication
    VAR_015921
    Natural varianti1143 – 11431I → T in RMS; reduces insulin binding. 2 Publications
    VAR_015926
    Natural varianti1158 – 11581R → W in RMS; abolishes insulin binding. 2 Publications
    VAR_015928
    Natural varianti1201 – 12011R → W in LEPRCH and RMS; reduces insulin binding possibly due to reduced receptor levels on the cell surface. 2 Publications
    VAR_015930
    Leprechaunism (LEPRCH) [MIM:246200]: Represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive.15 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti55 – 551V → A in LEPRCH; Verona-1. 1 Publication
    VAR_004080
    Natural varianti58 – 581G → R in LEPRCH; Helmond; inhibits processing and transport. 1 Publication
    Corresponds to variant rs52836744 [ dbSNP | Ensembl ].
    VAR_004081
    Natural varianti113 – 1131R → P in LEPRCH; Atlanta-1; abolishes insulin binding. 1 Publication
    VAR_004082
    Natural varianti119 – 1191A → V in LEPRCH; markedly impairs insulin binding.
    VAR_015909
    Natural varianti120 – 1201L → Q in LEPRCH; inhibits receptor processing. 1 Publication
    VAR_031518
    Natural varianti146 – 1461I → M in LEPRCH; mild. 2 Publications
    VAR_015539
    Natural varianti236 – 2361H → R in LEPRCH; Winnipeg; in one patient with in RMS heterozygous compound with S-386; may impair receptor processing. 2 Publications
    VAR_004084
    Natural varianti260 – 2601L → P in LEPRCH; Geldeimalsen. 1 Publication
    VAR_004085
    Natural varianti301 – 3011C → Y in LEPRCH. 1 Publication
    VAR_015912
    Natural varianti308 – 3081Missing in LEPRCH; abolishes insulin binding. 2 Publications
    VAR_015913
    Natural varianti350 – 3501S → L in RMS and LEPRCH. 2 Publications
    VAR_015914
    Natural varianti362 – 3621Missing in LEPRCH. 1 Publication
    VAR_015541
    Natural varianti393 – 3931G → R in LEPRCH; Verona-1. 1 Publication
    VAR_004086
    Natural varianti439 – 4391W → S in LEPRCH; impairs transport of the receptor to the cell surface. 1 Publication
    VAR_015542
    Natural varianti458 – 4581N → D in LEPRCH; partially inhibits receptor processing and autophosphorylation; strongly impairs ERK phosphorylation; induces wild-type levels of IRS-1 phosphorylation. 1 Publication
    VAR_031521
    Natural varianti487 – 4871K → E in LEPRCH; ARK-1. 1 Publication
    Corresponds to variant rs28933083 [ dbSNP | Ensembl ].
    VAR_004088
    Natural varianti925 – 9251I → T in LEPRCH; abolishes insulin binding.
    VAR_015918
    Natural varianti926 – 9261R → W in LEPRCH; markedly impairs insulin binding.
    VAR_015919
    Natural varianti937 – 9371T → M in LEPRCH; impaired receptor processing.
    VAR_015920
    Natural varianti1119 – 11191R → W in LEPRCH. 2 Publications
    VAR_015925
    Natural varianti1201 – 12011R → W in LEPRCH and RMS; reduces insulin binding possibly due to reduced receptor levels on the cell surface. 2 Publications
    VAR_015930
    Natural varianti1206 – 12061E → K in LEPRCH. 1 Publication
    VAR_015932
    Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.3 Publications
    Note: The gene represented in this entry may be involved in disease pathogenesis.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti858 – 8581T → A in NIDDM. 1 Publication
    Corresponds to variant rs182552223 [ dbSNP | Ensembl ].
    VAR_015917
    Natural varianti1095 – 10951K → E in a NIDDM subject. 1 Publication
    VAR_015924
    Natural varianti1158 – 11581R → Q in NIDDM. 1 Publication
    VAR_015927
    Natural varianti1191 – 11911R → Q in NIDDM. 1 Publication
    VAR_004098
    Familial hyperinsulinemic hypoglycemia 5 (HHF5) [MIM:609968]: Familial hyperinsulinemic hypoglycemia [MIM:256450], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels.1 Publication
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti1201 – 12011R → Q in HHF5 and IRAN type A; interferes with kinase activation by insulin. 2 Publications
    Corresponds to variant rs28933086 [ dbSNP | Ensembl ].
    VAR_015929
    Insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:610549]: Characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor.16 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti86 – 861D → G in IRAN type A. 1 Publication
    VAR_015907
    Natural varianti89 – 891L → P in IRAN type A. 1 Publication
    VAR_015908
    Natural varianti167 – 1671V → L in IRAN type A. 1 Publication
    VAR_015910
    Natural varianti279 – 2791R → C in IRAN type A; inhibits receptor internalization. 1 Publication
    VAR_015540
    Natural varianti279 – 2791R → H in IRAN type A; interferes with receptor processing. 1 Publication
    VAR_031519
    Natural varianti280 – 2801C → Y in IRAN type A. 1 Publication
    VAR_015911
    Natural varianti409 – 4091F → V in IRAN type A. 1 Publication
    VAR_004087
    Natural varianti489 – 4891N → S in IRAN type A. 1 Publication
    Corresponds to variant rs28933085 [ dbSNP | Ensembl ].
    VAR_004089
    Natural varianti762 – 7621R → S in IRAN type A. 1 Publication
    VAR_004090
    Natural varianti1020 – 10201R → Q in IRAN type A. 1 Publication
    VAR_004092
    Natural varianti1035 – 10351G → V in IRAN type A. 1 Publication
    VAR_004093
    Natural varianti1055 – 10551A → V in IRAN type A. 1 Publication
    VAR_015923
    Natural varianti1075 – 10751A → D in IRAN type A. 1 Publication
    VAR_004094
    Natural varianti1161 – 11611A → T in IRAN type A. 1 Publication
    Corresponds to variant rs28933084 [ dbSNP | Ensembl ].
    VAR_004095
    Natural varianti1162 – 11621A → E in IRAN type A; impairs proteolytic processing.
    VAR_004096
    Natural varianti1201 – 12011R → Q in HHF5 and IRAN type A; interferes with kinase activation by insulin. 2 Publications
    Corresponds to variant rs28933086 [ dbSNP | Ensembl ].
    VAR_015929
    Natural varianti1205 – 12051P → L in IRAN type A; moderate. 2 Publications
    VAR_004099
    Natural varianti1206 – 12061E → D in IRAN type A; accelerates degradation of the protein and impairs kinase activity.
    VAR_015931
    Natural varianti1220 – 12201W → L in IRAN type A; accelerates degradation of the protein and impairs kinase activity. 1 Publication
    Corresponds to variant rs52800171 [ dbSNP | Ensembl ].
    VAR_004100
    Natural varianti1227 – 12271W → S in IRAN type A. 1 Publication
    VAR_004101
    Natural varianti1378 – 13781R → Q in IRAN type A. 1 Publication
    Corresponds to variant rs52826008 [ dbSNP | Ensembl ].
    VAR_015934

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi991 – 9911L → A: Reduces interaction with IRS1 but has no effect on interaction with SHC1. 1 Publication
    Mutagenesisi992 – 9921Y → A: Reduces interaction with IRS1 but has no effect on interaction with SHC1. 1 Publication
    Mutagenesisi996 – 9972NP → AA: Abolishes interaction with IRS1. Severely disrupts, but does not abolish interaction with SHC1. 2 Publications
    Mutagenesisi996 – 9961N → A: Abolishes interaction with IRS1 and significantly reduces interaction with SHC1. Has no effect on interaction with PIK3R1. 2 Publications
    Mutagenesisi997 – 9971P → A: Abolishes interaction with IRS1 and significantly reduces interaction with SHC1. Has no effect on interaction with PIK3R1. 2 Publications
    Mutagenesisi998 – 9981E → A: Does not affect interaction with IRS1, SHC1 or PIK3R1. 1 Publication
    Mutagenesisi999 – 9991Y → E: Abolishes interaction with IRS1 and SHC1. 4 Publications
    Mutagenesisi999 – 9991Y → F: Has no effect on insulin-stimulated autophosphorylation, but inhibits the biological activity of the receptor. Abolishes interaction with IRS1 and almost completely prevents interaction with SHC1. Has no effect on interaction with PIK3R1. Abolishes interaction with STAT5B. 4 Publications
    Mutagenesisi1000 – 10001L → A or R: Severely reduces interaction with SHC1. Has no effect on interaction with IRS1. 1 Publication
    Mutagenesisi1002 – 10021A → D: Reduces interaction with IRS1 but has no effect on interaction with SHC1. 1 Publication
    Mutagenesisi1011 – 10111Y → A: Increases kinase activity. 1 Publication
    Mutagenesisi1057 – 10571K → A: Abolishes the kinase activity and abolishes interaction with IRS1, SHC1, GRB7 and PIK3R1. 3 Publications
    Mutagenesisi1057 – 10571K → M or R: Abolishes the kinase activity. 3 Publications
    Mutagenesisi1159 – 11591D → N: Loss of kinase activity. 1 Publication
    Mutagenesisi1163 – 11631R → Q: Loss of kinase activity. 1 Publication
    Mutagenesisi1189 – 11891Y → F: Reduced interaction with GRB7. 1 Publication
    Mutagenesisi1190 – 11901Y → F: Strongly reduced interaction with GRB7. 1 Publication

    Keywords - Diseasei

    Diabetes mellitus, Disease mutation

    Organism-specific databases

    MIMi125853. phenotype.
    246200. phenotype.
    262190. phenotype.
    609968. phenotype.
    610549. phenotype.
    Orphaneti263458. Hyperinsulinism due to INSR deficiency.
    2297. Insulin-resistance syndrome type A.
    508. Leprechaunism.
    769. Rabson-Mendenhall syndrome.
    PharmGKBiPA202.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 27273 PublicationsAdd
    BLAST
    Chaini28 – 758731Insulin receptor subunit alphaPRO_0000016687Add
    BLAST
    Chaini763 – 1382620Insulin receptor subunit betaPRO_0000016689Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi35 ↔ 53
    Glycosylationi43 – 431N-linked (GlcNAc...)3 Publications
    Glycosylationi52 – 521N-linked (GlcNAc...)2 Publications
    Glycosylationi105 – 1051N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi138 – 1381N-linked (GlcNAc...)2 Publications
    Disulfide bondi153 ↔ 182
    Disulfide bondi186 ↔ 209
    Disulfide bondi196 ↔ 215
    Disulfide bondi219 ↔ 228
    Disulfide bondi223 ↔ 234
    Disulfide bondi235 ↔ 243
    Disulfide bondi239 ↔ 252
    Glycosylationi242 – 2421N-linked (GlcNAc...)3 Publications
    Disulfide bondi255 ↔ 264
    Disulfide bondi268 ↔ 280
    Glycosylationi282 – 2821N-linked (GlcNAc...)2 Publications
    Disulfide bondi286 ↔ 311
    Disulfide bondi293 ↔ 301
    Disulfide bondi315 ↔ 328
    Glycosylationi322 – 3221N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi331 ↔ 335
    Disulfide bondi339 ↔ 360
    Glycosylationi364 – 3641N-linked (GlcNAc...)1 Publication
    Modified residuei400 – 4001Phosphoserine1 Publication
    Modified residuei401 – 4011Phosphotyrosine1 Publication
    Modified residuei407 – 4071Phosphoserine1 Publication
    Glycosylationi424 – 4241N-linked (GlcNAc...)1 Publication
    Glycosylationi445 – 4451N-linked (GlcNAc...)2 Publications
    Disulfide bondi462 ↔ 4951 Publication
    Glycosylationi541 – 5411N-linked (GlcNAc...)2 Publications
    Disulfide bondi551 – 551Interchain1 Publication
    Glycosylationi633 – 6331N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi651 – 6511N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi674 ↔ 899
    Glycosylationi698 – 6981N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi769 – 7691N-linked (GlcNAc...)1 Publication
    Glycosylationi782 – 7821N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi825 ↔ 834
    Glycosylationi920 – 9201N-linked (GlcNAc...)1 Publication
    Glycosylationi933 – 9331N-linked (GlcNAc...)Sequence Analysis
    Modified residuei992 – 9921Phosphotyrosine; by autocatalysisCurated
    Modified residuei999 – 9991Phosphotyrosine; by autocatalysis1 Publication
    Modified residuei1011 – 10111Phosphotyrosine; by autocatalysisCurated
    Modified residuei1185 – 11851Phosphotyrosine; by autocatalysis7 Publications
    Modified residuei1189 – 11891Phosphotyrosine; by autocatalysis7 Publications
    Modified residuei1190 – 11901Phosphotyrosine; by autocatalysis7 Publications
    Modified residuei1355 – 13551Phosphotyrosine; by autocatalysis1 Publication
    Modified residuei1361 – 13611Phosphotyrosine; by autocatalysis1 Publication

    Post-translational modificationi

    After being transported from the endoplasmic reticulum to the Golgi apparatus, the single glycosylated precursor is further glycosylated and then cleaved, followed by its transport to the plasma membrane.6 Publications
    Autophosphorylated on tyrosine residues in response to insulin. Phosphorylation of Tyr-999 is required for binding to IRS1, SHC1 and STAT5B. Dephosphorylated by PTPRE at Tyr-999, Tyr-1185, Tyr-1189 and Tyr-1190. Dephosphorylated by PTPRF and PTPN1. Dephosphorylated by PTPN2; down-regulates insulin-induced signaling.10 Publications

    Keywords - PTMi

    Cleavage on pair of basic residues, Disulfide bond, Glycoprotein, Phosphoprotein

    Proteomic databases

    MaxQBiP06213.
    PaxDbiP06213.
    PRIDEiP06213.

    PTM databases

    PhosphoSiteiP06213.

    Expressioni

    Tissue specificityi

    Isoform Long and isoform Short are predominantly expressed in tissue targets of insulin metabolic effects: liver, adipose tissue and skeletal muscle but are also expressed in the peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta vascular endothelium, fibroblasts, monocytes, granulocytes, erythrocytes and skin. Isoform Short is preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas.4 Publications

    Gene expression databases

    ArrayExpressiP06213.
    BgeeiP06213.
    CleanExiHS_INSR.
    GenevestigatoriP06213.

    Organism-specific databases

    HPAiHPA036302.

    Interactioni

    Subunit structurei

    Tetramer of 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains carry the insulin-binding regions, while the beta chains carry the kinase domain. Forms a hybrid receptor with IGF1R, the hybrid is a tetramer consisting of 1 alpha chain and 1 beta chain of INSR and 1 alpha chain and 1 beta chain of IGF1R. Interacts with SORBS1 but dissociates from it following insulin stimulation. Binds SH2B2. Activated form of INSR interacts (via Tyr-999) with the PTB/PID domains of IRS1 and SHC1. The sequences surrounding the phosphorylated NPXY motif contribute differentially to either IRS1 or SHC1 recognition. Interacts (via tyrosines in the C-terminus) with IRS2 (via PTB domain and 591-786 AA); the 591-786 would be the primary anchor of IRS2 to INSR while the PTB domain would have a stabilizing action on the interaction with INSR. Interacts with the SH2 domains of the 85 kDa regulatory subunit of PI3K (PIK3R1) in vitro, when autophosphorylated on tyrosine residues. Interacts with SOCS7. Interacts (via the phosphorylated Tyr-999), with SOCS3. Interacts (via the phosphorylated Tyr-1185, Tyr-1189, Tyr-1190) with SOCS1. Interacts with CAV2 (tyrosine-phosphorylated form); the interaction is increased with 'Tyr-27'phosphorylation of CAV2 By similarity. Interacts with ARRB2 By similarity. Interacts with GRB10; this interaction blocks the association between IRS1/IRS2 and INSR, significantly reduces insulin-stimulated tyrosine phosphorylation of IRS1 and IRS2 and thus decreases insulin signaling. Interacts with GRB7. Interacts with PDPK1. Interacts (via Tyr-1190) with GRB14 (via BPS domain); this interaction protects the tyrosines in the activation loop from dephosphorylation, but promotes dephosphorylation of Tyr-999, this results in decreased interaction with, and phosphorylation of, IRS1. Interacts (via subunit alpha) with ENPP1 (via 485-599 AA); this interaction blocks autophosphorylation. Interacts with PTPRE; this interaction is dependent of Tyr-1185, Tyr-1189 and Tyr-1190 of the INSR. Interacts with STAT5B (via SH2 domain). Interacts with PTPRF.By similarity26 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    AGAP2Q994902EBI-475899,EBI-2361824
    ENPP1P224132EBI-475899,EBI-3197846
    GRB10Q133223EBI-475899,EBI-80275
    IGF1P050194EBI-475899,EBI-7902275
    INSP013175EBI-475899,EBI-3989070From a different organism.
    IRS1P355683EBI-475899,EBI-517592
    Irs1P355705EBI-475899,EBI-520230From a different organism.
    PIK3R1P279863EBI-475899,EBI-79464
    PLCG1P191749EBI-475899,EBI-79387
    PTPN1P1803133EBI-475899,EBI-968788
    PTPN11Q061242EBI-475899,EBI-297779
    SH2B1Q9NRF26EBI-475899,EBI-310491
    SHC1P293532EBI-475899,EBI-78835

    Protein-protein interaction databases

    BioGridi109854. 58 interactions.
    DIPiDIP-480N.
    IntActiP06213. 43 interactions.
    MINTiMINT-1516246.
    STRINGi9606.ENSP00000303830.

    Structurei

    Secondary structure

    1
    1382
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi33 – 4210
    Helixi45 – 506
    Beta strandi53 – 6513
    Helixi70 – 723
    Turni73 – 753
    Beta strandi83 – 864
    Beta strandi88 – 936
    Turni100 – 1023
    Beta strandi118 – 1247
    Beta strandi141 – 1499
    Helixi160 – 1623
    Beta strandi171 – 1755
    Helixi176 – 1783
    Turni187 – 1926
    Beta strandi199 – 2013
    Beta strandi204 – 2063
    Beta strandi209 – 2113
    Helixi221 – 2233
    Beta strandi243 – 2475
    Beta strandi251 – 26010
    Beta strandi263 – 2675
    Beta strandi273 – 2753
    Turni276 – 2783
    Beta strandi279 – 2813
    Helixi283 – 29513
    Beta strandi298 – 3003
    Beta strandi305 – 3073
    Beta strandi310 – 3145
    Beta strandi319 – 3213
    Beta strandi327 – 3304
    Beta strandi332 – 3343
    Beta strandi338 – 34811
    Helixi351 – 3555
    Turni356 – 3594
    Beta strandi361 – 3699
    Helixi377 – 3859
    Beta strandi390 – 3934
    Beta strandi395 – 3995
    Beta strandi404 – 4063
    Turni422 – 4243
    Beta strandi425 – 4306
    Turni441 – 4433
    Beta strandi452 – 4587
    Helixi463 – 47210
    Turni476 – 4783
    Turni481 – 4833
    Beta strandi486 – 4905
    Helixi941 – 9466
    Helixi953 – 97927
    Helixi1009 – 10113
    Helixi1014 – 10163
    Helixi1020 – 10223
    Beta strandi1023 – 10319
    Beta strandi1033 – 104311
    Beta strandi1046 – 10483
    Beta strandi1050 – 10578
    Helixi1065 – 107814
    Beta strandi1089 – 10935
    Beta strandi1095 – 10984
    Beta strandi1100 – 11045
    Helixi1111 – 11177
    Beta strandi1119 – 11213
    Helixi1133 – 115220
    Beta strandi1154 – 11563
    Helixi1162 – 11643
    Beta strandi1165 – 11673
    Beta strandi1173 – 11753
    Beta strandi1181 – 11833
    Turni1185 – 11873
    Beta strandi1190 – 11923
    Beta strandi1194 – 11985
    Helixi1200 – 12023
    Helixi1205 – 12106
    Helixi1215 – 123016
    Turni1236 – 12394
    Helixi1242 – 12509
    Helixi1263 – 127210
    Helixi1277 – 12793
    Helixi1283 – 12908
    Helixi1291 – 12933
    Helixi1298 – 13014
    Turni1303 – 13053
    Helixi1307 – 13093

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1GAGX-ray2.70A1005-1310[»]
    1I44X-ray2.40A1005-1310[»]
    1IR3X-ray1.90A1005-1310[»]
    1IRKX-ray2.10A1005-1310[»]
    1P14X-ray1.90A1005-1310[»]
    1RQQX-ray2.60A/B1005-1310[»]
    2AUHX-ray3.20A1005-1310[»]
    2B4SX-ray2.30B/D1005-1310[»]
    2DTGX-ray3.80E28-955[»]
    2HR7X-ray2.32A/B28-512[»]
    2MFRNMR-A940-988[»]
    2Z8CX-ray3.25A1008-1310[»]
    3BU3X-ray1.65A1005-1310[»]
    3BU5X-ray2.10A1005-1310[»]
    3BU6X-ray1.95A1005-1310[»]
    3EKKX-ray2.10A1005-1310[»]
    3EKNX-ray2.20A1005-1310[»]
    3ETAX-ray2.60A/B1017-1322[»]
    3LOHX-ray3.80E28-956[»]
    3W11X-ray3.90E28-337[»]
    F731-744[»]
    3W12X-ray4.30E28-337[»]
    F731-744[»]
    3W13X-ray4.30E28-337[»]
    F724-744[»]
    3W14X-ray4.40E/F28-746[»]
    4IBMX-ray1.80A/B1005-1310[»]
    ProteinModelPortaliP06213.
    SMRiP06213. Positions 31-988, 1009-1339.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP06213.

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini28 – 758731ExtracellularCuratedAdd
    BLAST
    Topological domaini763 – 956194ExtracellularCuratedAdd
    BLAST
    Topological domaini980 – 1382403CytoplasmicCuratedAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei957 – 97923HelicalSequence AnalysisAdd
    BLAST

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini624 – 726103Fibronectin type-III 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini757 – 84286Fibronectin type-III 2PROSITE-ProRule annotationAdd
    BLAST
    Domaini853 – 94795Fibronectin type-III 3PROSITE-ProRule annotationAdd
    BLAST
    Domaini1023 – 1298276Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni733 – 7419Insulin-binding
    Regioni999 – 9991Important for interaction with IRS1, SHC1 and STAT5B
    Regioni1361 – 13644PIK3R1-binding

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi28 – 174147Leu-richAdd
    BLAST
    Compositional biasi182 – 339158Cys-richAdd
    BLAST

    Domaini

    The tetrameric insulin receptor binds insulin via non-identical regions from two alpha chains, primarily via the C-terminal region of the first INSR alpha chain. Residues from the leucine-rich N-terminus of the other INSR alpha chain also contribute to this insulin binding site. A secondary insulin-binding site is formed by residues at the junction of fibronectin type-III domain 1 and 2.3 Publications

    Sequence similaritiesi

    Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.PROSITE-ProRule annotation
    Contains 3 fibronectin type-III domains.PROSITE-ProRule annotation
    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Keywords - Domaini

    Repeat, Signal, Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiCOG0515.
    HOGENOMiHOG000038045.
    HOVERGENiHBG006134.
    InParanoidiP06213.
    KOiK04527.
    OMAiCPERVTD.
    OrthoDBiEOG73RB9N.
    PhylomeDBiP06213.
    TreeFamiTF351636.

    Family and domain databases

    Gene3Di2.60.40.10. 4 hits.
    3.80.20.20. 2 hits.
    InterProiIPR000494. EGF_rcpt_L.
    IPR003961. Fibronectin_type3.
    IPR006211. Furin-like_Cys-rich_dom.
    IPR006212. Furin_repeat.
    IPR009030. Growth_fac_rcpt_N_dom.
    IPR013783. Ig-like_fold.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
    IPR008266. Tyr_kinase_AS.
    IPR020635. Tyr_kinase_cat_dom.
    IPR016246. Tyr_kinase_insulin-like_rcpt.
    IPR002011. Tyr_kinase_rcpt_2_CS.
    [Graphical view]
    PfamiPF00041. fn3. 1 hit.
    PF00757. Furin-like. 1 hit.
    PF07714. Pkinase_Tyr. 1 hit.
    PF01030. Recep_L_domain. 2 hits.
    [Graphical view]
    PIRSFiPIRSF000620. Insulin_receptor. 1 hit.
    PRINTSiPR00109. TYRKINASE.
    SMARTiSM00060. FN3. 3 hits.
    SM00261. FU. 2 hits.
    SM00219. TyrKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF49265. SSF49265. 4 hits.
    SSF56112. SSF56112. 1 hit.
    SSF57184. SSF57184. 1 hit.
    PROSITEiPS50853. FN3. 2 hits.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00109. PROTEIN_KINASE_TYR. 1 hit.
    PS00239. RECEPTOR_TYR_KIN_II. 1 hit.
    [Graphical view]

    Sequences (2)i

    Sequence statusi: Complete.

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

    This entry describes 2 isoformsi produced by alternative splicing. Align

    Isoform Long (identifier: P06213-1) [UniParc]FASTAAdd to Basket

    Also known as: HIR-B

    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

    MATGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL     50
    ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLLL FRVYGLESLK 100
    DLFPNLTVIR GSRLFFNYAL VIFEMVHLKE LGLYNLMNIT RGSVRIEKNN 150
    ELCYLATIDW SRILDSVEDN YIVLNKDDNE ECGDICPGTA KGKTNCPATV 200
    INGQFVERCW THSHCQKVCP TICKSHGCTA EGLCCHSECL GNCSQPDDPT 250
    KCVACRNFYL DGRCVETCPP PYYHFQDWRC VNFSFCQDLH HKCKNSRRQG 300
    CHQYVIHNNK CIPECPSGYT MNSSNLLCTP CLGPCPKVCH LLEGEKTIDS 350
    VTSAQELRGC TVINGSLIIN IRGGNNLAAE LEANLGLIEE ISGYLKIRRS 400
    YALVSLSFFR KLRLIRGETL EIGNYSFYAL DNQNLRQLWD WSKHNLTITQ 450
    GKLFFHYNPK LCLSEIHKME EVSGTKGRQE RNDIALKTNG DQASCENELL 500
    KFSYIRTSFD KILLRWEPYW PPDFRDLLGF MLFYKEAPYQ NVTEFDGQDA 550
    CGSNSWTVVD IDPPLRSNDP KSQNHPGWLM RGLKPWTQYA IFVKTLVTFS 600
    DERRTYGAKS DIIYVQTDAT NPSVPLDPIS VSNSSSQIIL KWKPPSDPNG 650
    NITHYLVFWE RQAEDSELFE LDYCLKGLKL PSRTWSPPFE SEDSQKHNQS 700
    EYEDSAGECC SCPKTDSQIL KELEESSFRK TFEDYLHNVV FVPRKTSSGT 750
    GAEDPRPSRK RRSLGDVGNV TVAVPTVAAF PNTSSTSVPT SPEEHRPFEK 800
    VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAYV SARTMPEAKA 850
    DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYRR YGDEELHLCV 900
    SRKHFALERG CRLRGLSPGN YSVRIRATSL AGNGSWTEPT YFYVTDYLDV 950
    PSNIAKIIIG PLIFVFLFSV VIGSIYLFLR KRQPDGPLGP LYASSNPEYL 1000
    SASDVFPCSV YVPDEWEVSR EKITLLRELG QGSFGMVYEG NARDIIKGEA 1050
    ETRVAVKTVN ESASLRERIE FLNEASVMKG FTCHHVVRLL GVVSKGQPTL 1100
    VVMELMAHGD LKSYLRSLRP EAENNPGRPP PTLQEMIQMA AEIADGMAYL 1150
    NAKKFVHRDL AARNCMVAHD FTVKIGDFGM TRDIYETDYY RKGGKGLLPV 1200
    RWMAPESLKD GVFTTSSDMW SFGVVLWEIT SLAEQPYQGL SNEQVLKFVM 1250
    DGGYLDQPDN CPERVTDLMR MCWQFNPKMR PTFLEIVNLL KDDLHPSFPE 1300
    VSFFHSEENK APESEELEME FEDMENVPLD RSSHCQREEA GGRDGGSSLG 1350
    FKRSYEEHIP YTHMNGGKKN GRILTLPRSN PS 1382
    Length:1,382
    Mass (Da):156,333
    Last modified:October 5, 2010 - v4
    Checksum:i709A955660739066
    GO
    Isoform Short (identifier: P06213-2) [UniParc]FASTAAdd to Basket

    Also known as: HIR-A

    The sequence of this isoform differs from the canonical sequence as follows:
         745-756: Missing.

    Show »
    Length:1,370
    Mass (Da):155,146
    Checksum:iA396F39279C2764D
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti601 – 6011D → N AA sequence (PubMed:3447155)Curated
    Sequence conflicti830 – 8301P → E AA sequence (PubMed:3447155)Curated
    Sequence conflicti1278 – 12781K → N in CAA26096. (PubMed:2983222)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti2 – 21A → G.8 Publications
    Corresponds to variant rs7508518 [ dbSNP | Ensembl ].
    VAR_058395
    Natural varianti42 – 421N → K in RMS; impairs transport to the plasma membrane and reduces the affinity to bind insulin. 1 Publication
    VAR_004079
    Natural varianti55 – 551V → A in LEPRCH; Verona-1. 1 Publication
    VAR_004080
    Natural varianti58 – 581G → R in LEPRCH; Helmond; inhibits processing and transport. 1 Publication
    Corresponds to variant rs52836744 [ dbSNP | Ensembl ].
    VAR_004081
    Natural varianti86 – 861D → G in IRAN type A. 1 Publication
    VAR_015907
    Natural varianti89 – 891L → P in IRAN type A. 1 Publication
    VAR_015908
    Natural varianti113 – 1131R → P in LEPRCH; Atlanta-1; abolishes insulin binding. 1 Publication
    VAR_004082
    Natural varianti119 – 1191A → V in LEPRCH; markedly impairs insulin binding.
    VAR_015909
    Natural varianti120 – 1201L → Q in LEPRCH; inhibits receptor processing. 1 Publication
    VAR_031518
    Natural varianti146 – 1461I → M in LEPRCH; mild. 2 Publications
    VAR_015539
    Natural varianti167 – 1671V → L in IRAN type A. 1 Publication
    VAR_015910
    Natural varianti171 – 1711Y → H.1 Publication
    Corresponds to variant rs1051692 [ dbSNP | Ensembl ].
    VAR_058396
    Natural varianti220 – 2201P → L in Ins resistance; severe. 1 Publication
    VAR_004083
    Natural varianti228 – 2281C → R in a gastric adenocarcinoma sample; somatic mutation. 1 Publication
    VAR_041429
    Natural varianti236 – 2361H → R in LEPRCH; Winnipeg; in one patient with in RMS heterozygous compound with S-386; may impair receptor processing. 2 Publications
    VAR_004084
    Natural varianti260 – 2601L → P in LEPRCH; Geldeimalsen. 1 Publication
    VAR_004085
    Natural varianti279 – 2791R → C in IRAN type A; inhibits receptor internalization. 1 Publication
    VAR_015540
    Natural varianti279 – 2791R → H in IRAN type A; interferes with receptor processing. 1 Publication
    VAR_031519
    Natural varianti280 – 2801C → Y in IRAN type A. 1 Publication
    VAR_015911
    Natural varianti301 – 3011C → Y in LEPRCH. 1 Publication
    VAR_015912
    Natural varianti308 – 3081Missing in LEPRCH; abolishes insulin binding. 2 Publications
    VAR_015913
    Natural varianti350 – 3501S → L in RMS and LEPRCH. 2 Publications
    VAR_015914
    Natural varianti362 – 3621Missing in LEPRCH. 1 Publication
    VAR_015541
    Natural varianti386 – 3861G → S in RMS; may impair receptor processing. 1 Publication
    VAR_031520
    Natural varianti393 – 3931G → R in LEPRCH; Verona-1. 1 Publication
    VAR_004086
    Natural varianti409 – 4091F → V in IRAN type A. 1 Publication
    VAR_004087
    Natural varianti439 – 4391W → S in LEPRCH; impairs transport of the receptor to the cell surface. 1 Publication
    VAR_015542
    Natural varianti448 – 4481I → T.1 Publication
    Corresponds to variant rs1051691 [ dbSNP | Ensembl ].
    VAR_015915
    Natural varianti458 – 4581N → D in LEPRCH; partially inhibits receptor processing and autophosphorylation; strongly impairs ERK phosphorylation; induces wild-type levels of IRS-1 phosphorylation. 1 Publication
    VAR_031521
    Natural varianti487 – 4871K → E in LEPRCH; ARK-1. 1 Publication
    Corresponds to variant rs28933083 [ dbSNP | Ensembl ].
    VAR_004088
    Natural varianti489 – 4891N → S in IRAN type A. 1 Publication
    Corresponds to variant rs28933085 [ dbSNP | Ensembl ].
    VAR_004089
    Natural varianti492 – 4921Q → K.1 Publication
    Corresponds to variant rs1131851 [ dbSNP | Ensembl ].
    VAR_015916
    Natural varianti695 – 6951Q → R.1 Publication
    Corresponds to variant rs55906835 [ dbSNP | Ensembl ].
    VAR_041430
    Natural varianti762 – 7621R → S in IRAN type A. 1 Publication
    VAR_004090
    Natural varianti811 – 8111G → S.1 Publication