ID LEPR_HUMAN Reviewed; 1165 AA. AC P48357; Q13592; Q13593; Q13594; Q92919; Q92920; Q92921; DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot. DT 17-OCT-2006, sequence version 2. DT 27-MAR-2024, entry version 231. DE RecName: Full=Leptin receptor; DE Short=LEP-R; DE AltName: Full=HuB219; DE AltName: Full=OB receptor; DE Short=OB-R; DE AltName: CD_antigen=CD295; DE Flags: Precursor; GN Name=LEPR; Synonyms=DB, OBR; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS B AND E). RC TISSUE=Brain; RX PubMed=8548812; DOI=10.1016/0092-8674(95)90151-5; RA Tartaglia L.A., Dembski M., Weng X., Deng N., Culpepper J., Devos R., RA Richards G.J., Campfield L.A., Clark F.T., Deeds J., Muir C., Sanker S., RA Moriarty A., Moore K.J., Smutko J.S., Mays G.G., Woolf E.A., Monroe C.A., RA Tepper R.I.; RT "Identification and expression cloning of a leptin receptor, OB-R."; RL Cell 83:1263-1271(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A; B AND C), AND FUNCTION. RC TISSUE=Fetal liver; RX PubMed=8805376; DOI=10.1016/s0960-9822(02)70684-2; RA Bennett B.D., Solar G.P., Yuan J.Q., Mathias J., Thomas G.R., Matthews W.; RT "A role for leptin and its cognate receptor in hematopoiesis."; RL Curr. Biol. 6:1170-1180(1996). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A; C AND D), AND VARIANTS ARG-109 AND RP ARG-223. RC TISSUE=Fetal liver; RX PubMed=8616721; DOI=10.1038/nm0596-585; RA Cioffi J.A., Shafer A.W., Zupancic T.J., Smith-Gbur J., Mikhail A., RA Platika D., Snodgrass H.R.; RT "Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis RT and reproduction."; RL Nat. Med. 2:585-589(1996). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM B), AND VARIANTS ARG-109 AND RP ARG-223. RX PubMed=9158141; DOI=10.1093/hmg/6.5.675; RA Thompson D.B., Ravussin E., Bennett P.H., Bogardus C.; RT "Structure and sequence variation at the human leptin receptor gene in lean RT and obese Pima Indians."; RL Hum. Mol. Genet. 6:675-679(1997). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A). RX PubMed=9061609; DOI=10.1677/jme.0.0180077; RA Luoh S.-M., Di Marco F., Levin N., Armanini M., Xie M.H., Nelson C., RA Bennett G.L., Williams M., Spencer S.A., Gurney A., de Sauvage F.J.; RT "Cloning and characterization of a human leptin receptor using a RT biologically active leptin immunoadhesin."; RL J. Mol. Endocrinol. 18:77-85(1997). RN [6] RP INVOLVEMENT IN LEPRD, AND FUNCTION. RX PubMed=9537324; DOI=10.1038/32911; RA Clement K., Vaisse C., Lahlou N., Cabrol S., Pelloux V., Cassuto D., RA Gourmelen M., Dina C., Chambaz J., Lacorte J.M., Basdevant A., RA Bougneres P., Lebouc Y., Froguel P., Guy-Grand B.; RT "A mutation in the human leptin receptor gene causes obesity and pituitary RT dysfunction."; RL Nature 392:398-401(1998). RN [7] RP ALTERNATIVE SPLICING DUE TO AN ENDOGENOUS RETROVIRUS. RX PubMed=9929394; DOI=10.1007/pl00013153; RA Kapitonov V.V., Jurka J.; RT "The long terminal repeat of an endogenous retrovirus induces alternative RT splicing and encodes an additional carboxy-terminal sequence in the human RT leptin receptor."; RL J. Mol. Evol. 48:248-251(1999). RN [8] RP INTERACTION WITH PTPN11, AND MUTAGENESIS OF TYR-986; 1078-TYR-TYR-1079 AND RP TYR-1141. RX PubMed=9600917; DOI=10.1073/pnas.95.11.6061; RA Carpenter L.R., Farruggella T.J., Symes A., Karow M.L., Yancopoulos G.D., RA Stahl N.; RT "Enhancing leptin response by preventing SH2-containing phosphatase 2 RT interaction with Ob receptor."; RL Proc. Natl. Acad. Sci. U.S.A. 95:6061-6066(1998). RN [9] RP GLYCOSYLATION AT ASN-23; ASN-41; ASN-56; ASN-73; ASN-81; ASN-98; ASN-187; RP ASN-206; ASN-276; ASN-347; ASN-397; ASN-516; ASN-624; ASN-659; ASN-688; RP ASN-697; ASN-728 AND ASN-750, DISULFIDE BONDS, AND PARTIAL PROTEIN RP SEQUENCE. RX PubMed=9786864; DOI=10.1074/jbc.273.44.28691; RA Haniu M., Arakawa T., Bures E.J., Young Y., Hui J.O., Rohde M.F., RA Welcher A.A., Horan T.; RT "Human leptin receptor. Determination of disulfide structure and N- RT glycosylation sites of the extracellular domain."; RL J. Biol. Chem. 273:28691-28699(1998). RN [10] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=10896907; DOI=10.1136/gut.47.2.178; RA Sobhani I., Bado A., Vissuzaine C., Buyse M., Kermorgant S., Laigneau J.P., RA Attoub S., Lehy T., Henin D., Mignon M., Lewin M.J.; RT "Leptin secretion and leptin receptor in the human stomach."; RL Gut 47:178-183(2000). RN [11] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=12504075; DOI=10.1016/s0006-291x(02)02838-3; RA Zhao Y., Sun R., You L., Gao C., Tian Z.; RT "Expression of leptin receptors and response to leptin stimulation of human RT natural killer cell lines."; RL Biochem. Biophys. Res. Commun. 300:247-252(2003). RN [12] RP TISSUE SPECIFICITY. RX PubMed=16052473; DOI=10.1002/jcb.20521; RA Solberg R., Aas V., Thoresen G.H., Kase E.T., Drevon C.A., Rustan A.C., RA Reseland J.E.; RT "Leptin expression in human primary skeletal muscle cells is reduced during RT differentiation."; RL J. Cell. Biochem. 96:89-96(2005). RN [13] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-276 AND ASN-516. RC TISSUE=Plasma; RX PubMed=16335952; DOI=10.1021/pr0502065; RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., RA Smith R.D.; RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, RT hydrazide chemistry, and mass spectrometry."; RL J. Proteome Res. 4:2070-2080(2005). RN [14] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-276 AND ASN-397. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [15] RP REVIEW ON FUNCTION, AND SUBUNIT. RX PubMed=25232147; DOI=10.1530/joe-14-0404; RA Allison M.B., Myers M.G. Jr.; RT "20 years of leptin: connecting leptin signaling to biological function."; RL J. Endocrinol. 223:T25-T35(2014). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-882, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [17] RP FUNCTION. RX PubMed=25060689; DOI=10.1016/j.metabol.2014.06.010; RA Cassano S., Pucino V., La Rocca C., Procaccini C., De Rosa V., Marone G., RA Matarese G.; RT "Leptin modulates autophagy in human CD4+CD25- conventional T cells."; RL Metabolism 63:1272-1279(2014). RN [18] RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 428-633 IN COMPLEX WITH ANTIBODY, RP LEPTIN-BINDING REGION, DISULFIDE BONDS, AND FUNCTION. RX PubMed=22405007; DOI=10.1016/j.str.2012.01.019; RA Carpenter B., Hemsworth G.R., Wu Z., Maamra M., Strasburger C.J., RA Ross R.J., Artymiuk P.J.; RT "Structure of the human obesity receptor leptin-binding domain reveals the RT mechanism of leptin antagonism by a monoclonal antibody."; RL Structure 20:487-497(2012). RN [19] RP VARIANT ARG-223. RX PubMed=8666155; DOI=10.2337/diab.45.7.992; RA Considine R.V., Considine E.L., Williams C.J., Hyde T.M., Caro J.F.; RT "The hypothalamic leptin receptor in humans: identification of incidental RT sequence polymorphisms and absence of the db/db mouse and fa/fa rat RT mutations."; RL Diabetes 45:992-994(1996). RN [20] RP VARIANTS ARG-109; ARG-204; ARG-223 AND ASN-656. RX PubMed=9144432; DOI=10.1006/bbrc.1997.6430; RA Echwald S.M., Soerensen T.D., Soerensen T.I., Tybjaerg-Hansen A., RA Andersen T., Chung W.K., Leibel R.L., Pedersen O.; RT "Amino acid variants in the human leptin receptor: lack of association to RT juvenile onset obesity."; RL Biochem. Biophys. Res. Commun. 233:248-252(1997). RN [21] RP VARIANTS ARG-109; ARG-223 AND ASN-656. RX PubMed=9287054; DOI=10.2337/diab.46.9.1509; RA Chung W.K., Power-Kehoe L., Chua M., Chu F., Aronne L., Huma Z., RA Sothern M., Udall J.N., Kahle B., Leibel R.L.; RT "Exonic and intronic sequence variation in the human leptin receptor gene RT (LEPR)."; RL Diabetes 46:1509-1511(1997). RN [22] RP VARIANTS ARG-109; ARG-223 AND ASN-656. RX PubMed=9175732; DOI=10.1093/hmg/6.6.869; RA Gotoda T., Manning B.S., Goldstone A.P., Imrie H., Evans A.L., RA Strosberg A.D., McKeigue P.M., Scott J., Aitman T.J.; RT "Leptin receptor gene variation and obesity: lack of association in a white RT British male population."; RL Hum. Mol. Genet. 6:869-876(1997). RN [23] RP VARIANTS ARG-109; ARG-223; ASN-656 AND THR-675. RX PubMed=9860295; DOI=10.1007/s004390050867; RA Roth H., Korn T., Rosenkranz K., Hinney A., Ziegler A., Kunz J., RA Siegfried W., Mayer H., Hebebrand J., Grzeschik K.-H.; RT "Transmission disequilibrium and sequence variants at the leptin receptor RT gene in extremely obese German children and adolescents."; RL Hum. Genet. 103:540-546(1998). RN [24] RP VARIANTS [LARGE SCALE ANALYSIS] ARG-109 AND ARG-223. RX PubMed=18987736; DOI=10.1038/nature07485; RA Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K., RA Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L., RA Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A., RA Abbott S., Locke D., Hillier L.W., Miner T., Fulton L., Magrini V., RA Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R., RA Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E., RA Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J., Heath S., RA Shannon W.D., Nagarajan R., Walter M.J., Link D.C., Graubert T.A., RA DiPersio J.F., Wilson R.K.; RT "DNA sequencing of a cytogenetically normal acute myeloid leukaemia RT genome."; RL Nature 456:66-72(2008). RN [25] RP VARIANTS LEPRD HIS-422; GLY-604 AND PRO-786. RX PubMed=25751111; DOI=10.1210/jc.2015-1036; RA Huvenne H., Le Beyec J., Pepin D., Alili R., Kherchiche P.P., Jeannic E., RA Frelut M.L., Lacorte J.M., Nicolino M., Viard A., Laville M., Ledoux S., RA Tounian P., Poitou C., Dubern B., Clement K.; RT "Seven novel deleterious LEPR mutations found in early-onset obesity: a RT DeltaExon6-8 shared by subjects from Reunion Island, France, suggests a RT founder effect."; RL J. Clin. Endocrinol. Metab. 100:E757-E766(2015). CC -!- FUNCTION: Receptor for hormone LEP/leptin (Probable) (PubMed:22405007). CC On ligand binding, mediates LEP central and peripheral effects through CC the activation of different signaling pathways such as JAK2/STAT3 and CC MAPK cascade/FOS. In the hypothalamus, LEP acts as an appetite- CC regulating factor that induces a decrease in food intake and an CC increase in energy consumption by inducing anorexinogenic factors and CC suppressing orexigenic neuropeptides, also regulates bone mass and CC secretion of hypothalamo-pituitary-adrenal hormones (By similarity) CC (PubMed:9537324). In the periphery, increases basal metabolism, CC influences reproductive function, regulates pancreatic beta-cell CC function and insulin secretion, is pro-angiogenic and affects innate CC and adaptive immunity (PubMed:25060689, PubMed:12504075, CC PubMed:8805376). Control of energy homeostasis and melanocortin CC production (stimulation of POMC and full repression of AgRP CC transcription) is mediated by STAT3 signaling, whereas distinct signals CC regulate NPY and the control of fertility, growth and glucose CC homeostasis. Involved in the regulation of counter-regulatory response CC to hypoglycemia by inhibiting neurons of the parabrachial nucleus. Has CC a specific effect on T lymphocyte responses, differentially regulating CC the proliferation of naive and memory T -ells. Leptin increases Th1 and CC suppresses Th2 cytokine production (By similarity). CC {ECO:0000250|UniProtKB:P48356, ECO:0000269|PubMed:12504075, CC ECO:0000269|PubMed:22405007, ECO:0000269|PubMed:25060689, CC ECO:0000269|PubMed:8805376, ECO:0000269|PubMed:9537324, CC ECO:0000305|PubMed:25232147}. CC -!- FUNCTION: [Isoform A]: May transport LEP across the blood-brain CC barrier. Binds LEP and mediates LEP endocytosis. Does not induce CC phosphorylation of and activate STAT3. {ECO:0000250|UniProtKB:P48356}. CC -!- FUNCTION: [Isoform E]: Antagonizes Isoform A and isoform B-mediated LEP CC binding and endocytosis. {ECO:0000250|UniProtKB:P48356}. CC -!- SUBUNIT: Present as a mixture of monomers and dimers (Probable). The CC phosphorylated receptor binds a number of SH2 domain-containing CC proteins such as JAK2, STAT3, PTPN11, and SOCS3 (By similarity) CC (PubMed:9600917). Interaction with SOCS3 inhibits JAK/STAT signaling CC and MAPK cascade (By similarity). {ECO:0000250|UniProtKB:P48356, CC ECO:0000269|PubMed:9600917, ECO:0000305|PubMed:25232147}. CC -!- INTERACTION: CC P48357; P62993: GRB2; NbExp=3; IntAct=EBI-518596, EBI-401755; CC P48357; O15243: LEPROT; NbExp=2; IntAct=EBI-518596, EBI-15672507; CC P48357-1; P48357-1: LEPR; NbExp=3; IntAct=EBI-7886250, EBI-7886250; CC P48357-2; P48357-1: LEPR; NbExp=4; IntAct=EBI-7886387, EBI-7886250; CC P48357-3; P48357-1: LEPR; NbExp=4; IntAct=EBI-7886448, EBI-7886250; CC P48357-3; P48357-3: LEPR; NbExp=3; IntAct=EBI-7886448, EBI-7886448; CC P48357-3; P0CG48: UBC; NbExp=2; IntAct=EBI-7886448, EBI-3390054; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:19159218}; CC Single-pass type I membrane protein {ECO:0000305}. Basolateral cell CC membrane {ECO:0000269|PubMed:19159218}. CC -!- SUBCELLULAR LOCATION: [Isoform E]: Secreted CC {ECO:0000250|UniProtKB:P48356}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=5; CC Name=B; Synonyms=13.2, OBRb; CC IsoId=P48357-1; Sequence=Displayed; CC Name=A; Synonyms=6.4, HuB219.3; CC IsoId=P48357-2; Sequence=VSP_001689, VSP_001690; CC Name=C; Synonyms=12.1, OBRa; CC IsoId=P48357-3; Sequence=VSP_001691, VSP_001692; CC Name=D; Synonyms=HuB219.2; CC IsoId=P48357-4; Sequence=VSP_001693, VSP_001694; CC Name=E; CC IsoId=P48357-5; Sequence=VSP_001688; CC -!- TISSUE SPECIFICITY: Isoform A is expressed in fetal liver and in CC hematopoietic tissues and choroid plexus. In adults highest expression CC in heart, liver, small intestine, prostate and ovary. Low level in lung CC and kidney. Isoform B is highly expressed in hypothalamus, but also in CC skeletal muscle. Detected in fundic and antral epithelial cells of the CC gastric mucosa (PubMed:19159218). Isoform B and isoform A are expressed CC by NK cells (at protein level) (PubMed:12504075). CC {ECO:0000269|PubMed:12504075, ECO:0000269|PubMed:16052473, CC ECO:0000269|PubMed:19159218}. CC -!- DOMAIN: The cytoplasmic domain may be essential for intracellular CC signal transduction by activation of JAK tyrosine kinase and STATs. CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein CC folding and thereby efficient intracellular transport and cell-surface CC receptor binding. CC -!- DOMAIN: The box 1 motif is required for JAK interaction and/or CC activation. CC -!- PTM: On ligand binding, phosphorylated on two conserved C-terminal CC tyrosine residues (isoform B only) by JAK2. Tyr-986 is required for CC complete binding and activation of PTPN11, ERK/FOS activation,for CC interaction with SOCS3 and SOCS3 mediated inhibition of leptin CC signaling. Phosphorylation on Tyr-1141 is required for STAT3 CC binding/activation. Phosphorylation of Tyr-1079 has a more accessory CC role. {ECO:0000250|UniProtKB:P48356}. CC -!- DISEASE: Leptin receptor deficiency (LEPRD) [MIM:614963]: A rare CC disease characterized by normal levels of serum leptin, hyperphagia and CC severe obesity from an early age. Additional features include CC alterations in immune function, and delayed puberty due to CC hypogonadotropic hypogonadism. {ECO:0000269|PubMed:25751111, CC ECO:0000269|PubMed:9537324}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 2 CC subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U43168; AAA93015.1; -; mRNA. DR EMBL; U66495; AAB07495.1; -; mRNA. DR EMBL; U66496; AAB07496.1; -; mRNA. DR EMBL; U66497; AAB07497.1; -; mRNA. DR EMBL; U52912; AAC50509.1; -; mRNA. DR EMBL; U52913; AAC50510.1; -; mRNA. DR EMBL; U52914; AAC50511.1; -; mRNA. DR EMBL; U59263; AAB09673.1; -; Genomic_DNA. DR EMBL; U59248; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U59249; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U59250; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U59252; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U59253; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U59254; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U59255; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U59256; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U59257; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U59258; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U59259; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U59260; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U59261; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U59262; AAB09673.1; JOINED; Genomic_DNA. DR EMBL; U50748; AAC23650.1; -; mRNA. DR CCDS; CCDS30740.1; -. [P48357-2] DR CCDS; CCDS30741.1; -. [P48357-3] DR CCDS; CCDS55604.1; -. [P48357-4] DR CCDS; CCDS631.1; -. [P48357-1] DR RefSeq; NP_001003679.1; NM_001003679.3. [P48357-2] DR RefSeq; NP_001003680.1; NM_001003680.3. [P48357-3] DR RefSeq; NP_001185616.1; NM_001198687.1. [P48357-3] DR RefSeq; NP_001185617.1; NM_001198688.1. [P48357-4] DR RefSeq; NP_001185618.1; NM_001198689.1. [P48357-2] DR RefSeq; NP_002294.2; NM_002303.5. [P48357-1] DR PDB; 3V6O; X-ray; 1.95 A; A/B=428-633. DR PDB; 6E2P; X-ray; 2.83 A; C/D=863-933. DR PDB; 7Z3Q; X-ray; 3.62 A; B/D/F=428-635. DR PDB; 8AVE; EM; 5.62 A; B/D=22-839. DR PDB; 8AVF; EM; 6.45 A; B/D/F=22-839. DR PDB; 8AVO; EM; 6.84 A; B/D/F=22-839. DR PDBsum; 3V6O; -. DR PDBsum; 6E2P; -. DR PDBsum; 7Z3Q; -. DR PDBsum; 8AVE; -. DR PDBsum; 8AVF; -. DR PDBsum; 8AVO; -. DR AlphaFoldDB; P48357; -. DR EMDB; EMD-15680; -. DR EMDB; EMD-15681; -. DR EMDB; EMD-15683; -. DR SMR; P48357; -. DR BioGRID; 110144; 31. DR CORUM; P48357; -. DR DIP; DIP-6117N; -. DR IntAct; P48357; 18. DR MINT; P48357; -. DR STRING; 9606.ENSP00000330393; -. DR ChEMBL; CHEMBL5913; -. DR DrugBank; DB05098; Leptin. DR DrugBank; DB09046; Metreleptin. DR DrugCentral; P48357; -. DR GlyConnect; 1954; 17 N-Linked glycans (8 sites). DR GlyCosmos; P48357; 19 sites, 17 glycans. DR GlyGen; P48357; 19 sites, 17 N-linked glycans (8 sites). DR iPTMnet; P48357; -. DR PhosphoSitePlus; P48357; -. DR BioMuta; LEPR; -. DR DMDM; 116242617; -. DR EPD; P48357; -. DR jPOST; P48357; -. DR MassIVE; P48357; -. DR MaxQB; P48357; -. DR PaxDb; 9606-ENSP00000330393; -. DR PeptideAtlas; P48357; -. DR ProteomicsDB; 55876; -. [P48357-1] DR ProteomicsDB; 55877; -. [P48357-2] DR ProteomicsDB; 55878; -. [P48357-3] DR ProteomicsDB; 55879; -. [P48357-4] DR ProteomicsDB; 55880; -. [P48357-5] DR Pumba; P48357; -. DR ABCD; P48357; 1 sequenced antibody. DR Antibodypedia; 33374; 1098 antibodies from 44 providers. DR DNASU; 3953; -. DR Ensembl; ENST00000344610.12; ENSP00000340884.8; ENSG00000116678.20. [P48357-4] DR Ensembl; ENST00000349533.11; ENSP00000330393.7; ENSG00000116678.20. [P48357-1] DR Ensembl; ENST00000371058.1; ENSP00000360097.1; ENSG00000116678.20. [P48357-4] DR Ensembl; ENST00000371059.7; ENSP00000360098.3; ENSG00000116678.20. [P48357-3] DR Ensembl; ENST00000371060.7; ENSP00000360099.3; ENSG00000116678.20. [P48357-2] DR Ensembl; ENST00000616738.4; ENSP00000483390.1; ENSG00000116678.20. [P48357-2] DR GeneID; 3953; -. DR KEGG; hsa:3953; -. DR MANE-Select; ENST00000349533.11; ENSP00000330393.7; NM_002303.6; NP_002294.2. DR UCSC; uc001dcg.4; human. [P48357-1] DR AGR; HGNC:6554; -. DR CTD; 3953; -. DR DisGeNET; 3953; -. DR GeneCards; LEPR; -. DR HGNC; HGNC:6554; LEPR. DR HPA; ENSG00000116678; Tissue enriched (liver). DR MalaCards; LEPR; -. DR MIM; 601007; gene. DR MIM; 614963; phenotype. DR neXtProt; NX_P48357; -. DR OpenTargets; ENSG00000116678; -. DR Orphanet; 179494; Obesity due to leptin receptor gene deficiency. DR PharmGKB; PA229; -. DR VEuPathDB; HostDB:ENSG00000116678; -. DR eggNOG; ENOG502RK5B; Eukaryota. DR GeneTree; ENSGT00730000111209; -. DR HOGENOM; CLU_008491_0_0_1; -. DR InParanoid; P48357; -. DR OMA; FPPHCLF; -. DR OrthoDB; 5344962at2759; -. DR PhylomeDB; P48357; -. DR TreeFam; TF106501; -. DR PathwayCommons; P48357; -. DR Reactome; R-HSA-2586552; Signaling by Leptin. [P48357-1] DR SignaLink; P48357; -. DR SIGNOR; P48357; -. DR BioGRID-ORCS; 3953; 13 hits in 1155 CRISPR screens. DR ChiTaRS; LEPR; human. DR GeneWiki; Leptin_receptor; -. DR GenomeRNAi; 3953; -. DR Pharos; P48357; Tclin. DR PRO; PR:P48357; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; P48357; Protein. DR Bgee; ENSG00000116678; Expressed in trabecular bone tissue and 198 other cell types or tissues. DR GO; GO:0016323; C:basolateral plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0043235; C:receptor complex; IDA:MGI. DR GO; GO:0019955; F:cytokine binding; IBA:GO_Central. DR GO; GO:0004896; F:cytokine receptor activity; IBA:GO_Central. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0038021; F:leptin receptor activity; IDA:ARUK-UCL. DR GO; GO:0004888; F:transmembrane signaling receptor activity; TAS:ProtInc. DR GO; GO:0001525; P:angiogenesis; IMP:UniProtKB. DR GO; GO:0098868; P:bone growth; ISS:UniProtKB. DR GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:ProtInc. DR GO; GO:0008203; P:cholesterol metabolic process; IEA:Ensembl. DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IBA:GO_Central. DR GO; GO:0097009; P:energy homeostasis; ISS:UniProtKB. DR GO; GO:0006112; P:energy reserve metabolic process; TAS:ProtInc. DR GO; GO:0014009; P:glial cell proliferation; IEA:Ensembl. DR GO; GO:0006094; P:gluconeogenesis; IEA:Ensembl. DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB. DR GO; GO:0005977; P:glycogen metabolic process; IEA:Ensembl. DR GO; GO:0033210; P:leptin-mediated signaling pathway; IDA:ARUK-UCL. DR GO; GO:0007275; P:multicellular organism development; TAS:ProtInc. DR GO; GO:0010507; P:negative regulation of autophagy; IDA:UniProtKB. DR GO; GO:0045721; P:negative regulation of gluconeogenesis; IEA:Ensembl. DR GO; GO:0006909; P:phagocytosis; IEA:Ensembl. DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:ARUK-UCL. DR GO; GO:0046850; P:regulation of bone remodeling; ISS:UniProtKB. DR GO; GO:0060259; P:regulation of feeding behavior; ISS:UniProtKB. DR GO; GO:0051049; P:regulation of transport; IDA:ARUK-UCL. DR GO; GO:0044321; P:response to leptin; ISS:UniProtKB. DR GO; GO:0019953; P:sexual reproduction; ISS:UniProtKB. DR GO; GO:0030217; P:T cell differentiation; ISS:UniProtKB. DR GO; GO:0150104; P:transport across blood-brain barrier; NAS:ARUK-UCL. DR CDD; cd00063; FN3; 3. DR Gene3D; 2.60.40.10; Immunoglobulins; 7. DR InterPro; IPR003961; FN3_dom. DR InterPro; IPR036116; FN3_sf. DR InterPro; IPR003529; Hematopoietin_rcpt_Gp130_CS. DR InterPro; IPR003531; Hempt_rcpt_S_F1_CS. DR InterPro; IPR007110; Ig-like_dom. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR010457; IgC2-like_lig-bd. DR InterPro; IPR041182; LEP-R_IGD. DR PANTHER; PTHR23036; CYTOKINE RECEPTOR; 1. DR PANTHER; PTHR23036:SF109; LEPTIN RECEPTOR; 1. DR Pfam; PF06328; Lep_receptor_Ig; 1. DR Pfam; PF18589; ObR_Ig; 2. DR SMART; SM00060; FN3; 4. DR SUPFAM; SSF49265; Fibronectin type III; 4. DR PROSITE; PS50853; FN3; 3. DR PROSITE; PS01353; HEMATOPO_REC_L_F2; 1. DR PROSITE; PS50835; IG_LIKE; 1. DR Genevisible; P48357; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; KW Direct protein sequencing; Disulfide bond; Glycoprotein; KW Immunoglobulin domain; Membrane; Obesity; Phosphoprotein; Receptor; KW Reference proteome; Repeat; Secreted; Signal; Transmembrane; KW Transmembrane helix. FT SIGNAL 1..21 FT CHAIN 22..1165 FT /note="Leptin receptor" FT /id="PRO_0000010904" FT TOPO_DOM 22..839 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 840..862 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 863..1165 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 239..333 FT /note="Fibronectin type-III 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 331..429 FT /note="Ig-like" FT DOMAIN 539..634 FT /note="Fibronectin type-III 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 639..732 FT /note="Fibronectin type-III 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 740..833 FT /note="Fibronectin type-III 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT REGION 467..484 FT /note="Leptin-binding" FT /evidence="ECO:0000305|PubMed:22405007" FT REGION 893..898 FT /note="Required for JAK2 activation" FT /evidence="ECO:0000250|UniProtKB:P48356" FT REGION 898..906 FT /note="Required for STAT3 phosphorylation" FT /evidence="ECO:0000250|UniProtKB:P48356" FT MOTIF 622..626 FT /note="WSXWS motif" FT MOTIF 871..879 FT /note="Box 1 motif" FT MOD_RES 882 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 986 FT /note="Phosphotyrosine; by JAK2" FT /evidence="ECO:0000250|UniProtKB:P48356" FT MOD_RES 1079 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P48356" FT MOD_RES 1141 FT /note="Phosphotyrosine; by JAK2" FT /evidence="ECO:0000250|UniProtKB:P48356" FT CARBOHYD 23 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 41 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 56 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 73 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 81 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 98 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 187 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 206 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 276 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16335952, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:9786864" FT CARBOHYD 347 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 397 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218, FT ECO:0000269|PubMed:9786864" FT CARBOHYD 516 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16335952, FT ECO:0000269|PubMed:9786864" FT CARBOHYD 624 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 659 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 688 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 697 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 728 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT CARBOHYD 750 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:9786864" FT DISULFID 37..90 FT /evidence="ECO:0000269|PubMed:22405007" FT DISULFID 89..99 FT /evidence="ECO:0000269|PubMed:22405007" FT DISULFID 131..142 FT /evidence="ECO:0000269|PubMed:22405007" FT DISULFID 186..196 FT /evidence="ECO:0000269|PubMed:22405007" FT DISULFID 188..193 FT /evidence="ECO:0000269|PubMed:22405007" FT DISULFID 352..412 FT /evidence="ECO:0000269|PubMed:22405007" FT DISULFID 413..418 FT /evidence="ECO:0000269|PubMed:22405007" FT DISULFID 436..447 FT /evidence="ECO:0000269|PubMed:22405007" FT DISULFID 473..528 FT /evidence="ECO:0000269|PubMed:22405007" FT DISULFID 488..498 FT /evidence="ECO:0000269|PubMed:22405007" FT VAR_SEQ 840..1165 FT /note="Missing (in isoform E)" FT /evidence="ECO:0000303|PubMed:8548812" FT /id="VSP_001688" FT VAR_SEQ 892..958 FT /note="PETFEHLFIKHTASVTCGPLLLEPETISEDISVDTSWKNKDEMMPTTVVSLL FT STTDLEKGSVCISDQ -> MLEGSMFVKSHHHSLISSTQGHKHCGRPQGPLHRKTRDLC FT SLVYLLTLPPLLSYDPAKSPSVRNTQE (in isoform C)" FT /evidence="ECO:0000303|PubMed:8616721, FT ECO:0000303|PubMed:8805376" FT /id="VSP_001691" FT VAR_SEQ 892..906 FT /note="PETFEHLFIKHTASV -> KMPGTKELLGGGWLT (in isoform D)" FT /evidence="ECO:0000303|PubMed:8616721" FT /id="VSP_001693" FT VAR_SEQ 892..896 FT /note="PETFE -> RTDIL (in isoform A)" FT /evidence="ECO:0000303|PubMed:8616721, FT ECO:0000303|PubMed:8805376, ECO:0000303|PubMed:9061609" FT /id="VSP_001689" FT VAR_SEQ 897..1165 FT /note="Missing (in isoform A)" FT /evidence="ECO:0000303|PubMed:8616721, FT ECO:0000303|PubMed:8805376, ECO:0000303|PubMed:9061609" FT /id="VSP_001690" FT VAR_SEQ 907..1165 FT /note="Missing (in isoform D)" FT /evidence="ECO:0000303|PubMed:8616721" FT /id="VSP_001694" FT VAR_SEQ 959..1165 FT /note="Missing (in isoform C)" FT /evidence="ECO:0000303|PubMed:8616721, FT ECO:0000303|PubMed:8805376" FT /id="VSP_001692" FT VARIANT 109 FT /note="K -> R (in dbSNP:rs1137100)" FT /evidence="ECO:0000269|PubMed:18987736, FT ECO:0000269|PubMed:8616721, ECO:0000269|PubMed:9144432, FT ECO:0000269|PubMed:9158141, ECO:0000269|PubMed:9175732, FT ECO:0000269|PubMed:9287054, ECO:0000269|PubMed:9860295" FT /id="VAR_002703" FT VARIANT 124 FT /note="D -> G (in dbSNP:rs35573508)" FT /id="VAR_049167" FT VARIANT 204 FT /note="K -> R (in dbSNP:rs146442768)" FT /evidence="ECO:0000269|PubMed:9144432" FT /id="VAR_002704" FT VARIANT 223 FT /note="Q -> R (in dbSNP:rs1137101)" FT /evidence="ECO:0000269|PubMed:18987736, FT ECO:0000269|PubMed:8616721, ECO:0000269|PubMed:8666155, FT ECO:0000269|PubMed:9144432, ECO:0000269|PubMed:9158141, FT ECO:0000269|PubMed:9175732, ECO:0000269|PubMed:9287054, FT ECO:0000269|PubMed:9860295" FT /id="VAR_002705" FT VARIANT 422 FT /note="Y -> H (in LEPRD; uncertain significance)" FT /evidence="ECO:0000269|PubMed:25751111" FT /id="VAR_075723" FT VARIANT 503 FT /note="I -> V (in dbSNP:rs13306526)" FT /id="VAR_028201" FT VARIANT 604 FT /note="C -> G (in LEPRD; uncertain significance)" FT /evidence="ECO:0000269|PubMed:25751111" FT /id="VAR_075724" FT VARIANT 656 FT /note="K -> N (in dbSNP:rs1805094)" FT /evidence="ECO:0000269|PubMed:9144432, FT ECO:0000269|PubMed:9175732, ECO:0000269|PubMed:9287054, FT ECO:0000269|PubMed:9860295" FT /id="VAR_002706" FT VARIANT 675 FT /note="S -> T (in dbSNP:rs373154589)" FT /evidence="ECO:0000269|PubMed:9860295" FT /id="VAR_002707" FT VARIANT 699 FT /note="T -> M (in dbSNP:rs34499590)" FT /id="VAR_049168" FT VARIANT 786 FT /note="L -> P (in LEPRD; uncertain significance; FT dbSNP:rs1303050393)" FT /evidence="ECO:0000269|PubMed:25751111" FT /id="VAR_075725" FT MUTAGEN 986 FT /note="Y->F: Greatly reduced PTPN11 binding; no PTPN11 FT phosphorylation; no effect on STAT3 phosphorylation." FT /evidence="ECO:0000269|PubMed:9600917" FT MUTAGEN 1078..1079 FT /note="YY->FF: No effect on PTPN11 nor STAT3 FT phosphorylation." FT /evidence="ECO:0000269|PubMed:9600917" FT MUTAGEN 1141 FT /note="Y->F: No effect on PTPN11 phosphorylation; no STAT3 FT phosphorylation." FT /evidence="ECO:0000269|PubMed:9600917" FT CONFLICT 85 FT /note="T -> A (in Ref. 3; AAC50509/AAC50510/AAC50511)" FT /evidence="ECO:0000305" FT CONFLICT 976 FT /note="D -> A (in Ref. 1; AAA93015 and 4; AAB09673)" FT /evidence="ECO:0000305" FT STRAND 435..438 FT /evidence="ECO:0007829|PDB:3V6O" FT STRAND 445..449 FT /evidence="ECO:0007829|PDB:3V6O" FT STRAND 461..468 FT /evidence="ECO:0007829|PDB:3V6O" FT STRAND 484..486 FT /evidence="ECO:0007829|PDB:3V6O" FT STRAND 488..490 FT /evidence="ECO:0007829|PDB:3V6O" FT STRAND 496..500 FT /evidence="ECO:0007829|PDB:3V6O" FT STRAND 509..517 FT /evidence="ECO:0007829|PDB:3V6O" FT STRAND 527..529 FT /evidence="ECO:0007829|PDB:3V6O" FT HELIX 531..534 FT /evidence="ECO:0007829|PDB:3V6O" FT STRAND 544..548 FT /evidence="ECO:0007829|PDB:3V6O" FT TURN 549..552 FT /evidence="ECO:0007829|PDB:3V6O" FT STRAND 553..557 FT /evidence="ECO:0007829|PDB:3V6O" FT STRAND 568..580 FT /evidence="ECO:0007829|PDB:3V6O" FT STRAND 584..588 FT /evidence="ECO:0007829|PDB:3V6O" FT STRAND 595..598 FT /evidence="ECO:0007829|PDB:3V6O" FT STRAND 607..615 FT /evidence="ECO:0007829|PDB:3V6O" FT HELIX 878..880 FT /evidence="ECO:0007829|PDB:6E2P" FT STRAND 881..883 FT /evidence="ECO:0007829|PDB:6E2P" SQ SEQUENCE 1165 AA; 132494 MW; CAA03BEAF2602D0A CRC64; MICQKFCVVL LHWEFIYVIT AFNLSYPITP WRFKLSCMPP NSTYDYFLLP AGLSKNTSNS NGHYETAVEP KFNSSGTHFS NLSKTTFHCC FRSEQDRNCS LCADNIEGKT FVSTVNSLVF QQIDANWNIQ CWLKGDLKLF ICYVESLFKN LFRNYNYKVH LLYVLPEVLE DSPLVPQKGS FQMVHCNCSV HECCECLVPV PTAKLNDTLL MCLKITSGGV IFQSPLMSVQ PINMVKPDPP LGLHMEITDD GNLKISWSSP PLVPFPLQYQ VKYSENSTTV IREADKIVSA TSLLVDSILP GSSYEVQVRG KRLDGPGIWS DWSTPRVFTT QDVIYFPPKI LTSVGSNVSF HCIYKKENKI VPSKEIVWWM NLAEKIPQSQ YDVVSDHVSK VTFFNLNETK PRGKFTYDAV YCCNEHECHH RYAELYVIDV NINISCETDG YLTKMTCRWS TSTIQSLAES TLQLRYHRSS LYCSDIPSIH PISEPKDCYL QSDGFYECIF QPIFLLSGYT MWIRINHSLG SLDSPPTCVL PDSVVKPLPP SSVKAEITIN IGLLKISWEK PVFPENNLQF QIRYGLSGKE VQWKMYEVYD AKSKSVSLPV PDLCAVYAVQ VRCKRLDGLG YWSNWSNPAY TVVMDIKVPM RGPEFWRIIN GDTMKKEKNV TLLWKPLMKN DSLCSVQRYV INHHTSCNGT WSEDVGNHTK FTFLWTEQAH TVTVLAINSI GASVANFNLT FSWPMSKVNI VQSLSAYPLN SSCVIVSWIL SPSDYKLMYF IIEWKNLNED GEIKWLRISS SVKKYYIHDH FIPIEKYQFS LYPIFMEGVG KPKIINSFTQ DDIEKHQSDA GLYVIVPVII SSSILLLGTL LISHQRMKKL FWEDVPNPKN CSWAQGLNFQ KPETFEHLFI KHTASVTCGP LLLEPETISE DISVDTSWKN KDEMMPTTVV SLLSTTDLEK GSVCISDQFN SVNFSEAEGT EVTYEDESQR QPFVKYATLI SNSKPSETGE EQGLINSSVT KCFSSKNSPL KDSFSNSSWE IEAQAFFILS DQHPNIISPH LTFSEGLDEL LKLEGNFPEE NNDKKSIYYL GVTSIKKRES GVLLTDKSRV SCPFPAPCLF TDIRVLQDSC SHFVENNINL GTSSKKTFAS YMPQFQTCST QTHKIMENKM CDLTV //