ID OREX_HUMAN Reviewed; 131 AA. AC O43612; DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-1998, sequence version 1. DT 13-FEB-2019, entry version 161. DE RecName: Full=Orexin; DE AltName: Full=Hypocretin; DE Short=Hcrt; DE Contains: DE RecName: Full=Orexin-A; DE AltName: Full=Hypocretin-1; DE Short=Hcrt1; DE Contains: DE RecName: Full=Orexin-B; DE AltName: Full=Hypocretin-2; DE Short=Hcrt2; DE Flags: Precursor; GN Name=HCRT; Synonyms=OX, PPORX, PPOX; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=9491897; DOI=10.1016/S0092-8674(00)80949-6; RA Sakurai T., Amemiya A., Ishii M., Matsuzaki I., Chemelli R.M., RA Tanaka H., Williams S.C., Richardson J.A., Kozlowski G.P., Wilson S., RA Arch J.R.S., Buckingham R.E., Haynes A.C., Carr S.A., Annan R.S., RA McNulty D.E., Liu W.-S., Terrett J.A., Elshourbagy N.A., Bergsma D.J., RA Yanagisawa M.; RT "Orexins and orexin receptors: a family of hypothalamic neuropeptides RT and G protein-coupled receptors that regulate feeding behavior."; RL Cell 92:573-585(1998). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=10364220; DOI=10.1074/jbc.274.25.17771; RA Sakurai T., Moriguchi T., Furuya K., Kajiwara N., Nakamura T., RA Yanagisawa M., Goto K.; RT "Structure and function of human prepro-orexin gene."; RL J. Biol. Chem. 274:17771-17776(1999). RN [3] RP STRUCTURE BY NMR OF 70-97. RX PubMed=10583376; DOI=10.1046/j.1432-1327.1999.00911.x; RA Lee J.-H., Bang E., Chae K.-J., Kim J.-Y., Lee D.W., Lee W.; RT "Solution structure of a new hypothalamic neuropeptide, human RT hypocretin-2/orexin-B."; RL Eur. J. Biochem. 266:831-839(1999). RN [4] RP REVIEW. RX PubMed=11340621; DOI=10.1002/bies.1058; RA Hungs M., Mignot E.; RT "Hypocretin/orexin, sleep and narcolepsy."; RL Bioessays 23:397-408(2001). RN [5] RP REVIEW. RX PubMed=11283317; DOI=10.1146/annurev.neuro.24.1.429; RA Willie J.T., Chemelli R.M., Sinton C.M., Yanagisawa M.; RT "To eat or to sleep? Orexin in the regulation of feeding and RT wakefulness."; RL Annu. Rev. Neurosci. 24:429-458(2001). RN [6] RP STRUCTURE BY NMR OF 34-66, AND DISULFIDE BONDS. RX PubMed=15479620; DOI=10.5483/BMBRep.2004.37.5.565; RA Kim H.Y., Hong E., Kim J.I., Lee W.; RT "Solution structure of human orexin-A: regulator of appetite and RT wakefulness."; RL J. Biochem. Mol. Biol. 37:565-573(2004). RN [7] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 1-12 IN COMPLEX OF RP HLA-DQA1/HLA-DQB1 HETERODIMER (HLA-DQ0602). RX PubMed=14769912; DOI=10.1073/pnas.0308458100; RA Siebold C., Hansen B.E., Wyer J.R., Harlos K., Esnouf R.E., RA Svejgaard A., Bell J.I., Strominger J.L., Jones E.Y., Fugger L.; RT "Crystal structure of HLA-DQ0602 that protects against type 1 diabetes RT and confers strong susceptibility to narcolepsy."; RL Proc. Natl. Acad. Sci. U.S.A. 101:1999-2004(2004). RN [8] RP STRUCTURE BY NMR OF 35-66, AND DISULFIDE BONDS. RX PubMed=16429482; DOI=10.1002/psc.747; RA Takai T., Takaya T., Nakano M., Akutsu H., Nakagawa A., Aimoto S., RA Nagai K., Ikegami T.; RT "Orexin-A is composed of a highly conserved C-terminal and a specific, RT hydrophilic N-terminal region, revealing the structural basis of RT specific recognition by the orexin-1 receptor."; RL J. Pept. Sci. 12:443-454(2006). RN [9] RP CHARACTERIZATION OF VARIANT NRCLP1 ARG-16, AND INVOLVEMENT IN NRCLP1. RX PubMed=10973318; DOI=10.1038/79690; RA Peyron C., Faraco J., Rogers W., Ripley B., Overeem S., Charnay Y., RA Nevsimalova S., Aldrich M., Reynolds D., Albin R., Li R., Hungs M., RA Pedrazzoli M., Padigaru M., Kucherlapati M., Fan J., Maki R., RA Lammers G.J., Bouras C., Kucherlapati R., Nishino S., Mignot E.; RT "A mutation in a case of early onset narcolepsy and a generalized RT absence of hypocretin peptides in human narcoleptic brains."; RL Nat. Med. 6:991-997(2000). CC -!- FUNCTION: Neuropeptides that play a significant role in the CC regulation of food intake and sleep-wakefulness, possibly by CC coordinating the complex behavioral and physiologic responses of CC these complementary homeostatic functions. A broader role in the CC homeostatic regulation of energy metabolism, autonomic function, CC hormonal balance and the regulation of body fluids, is also CC suggested. Orexin-A binds to both OX1R and OX2R with a high CC affinity, whereas orexin-B binds only to OX2R with a similar high CC affinity. CC -!- SUBCELLULAR LOCATION: Rough endoplasmic reticulum {ECO:0000250}. CC Cytoplasmic vesicle {ECO:0000250}. Cell junction, synapse CC {ECO:0000250}. Note=Associated with perikaryal rough endoplasmic CC reticulum as well as cytoplasmic large granular vesicles at CC synapses. {ECO:0000250}. CC -!- TISSUE SPECIFICITY: Abundantly expressed in subthalamic nucleus CC but undetectable in other brain regions tested (hypothalamus was CC not tested) and in heart, placenta, lung, liver, skeletal muscle, CC kidney and pancreas. CC -!- PTM: Specific enzymatic cleavages at paired basic residues yield CC the different active peptides. CC -!- DISEASE: Narcolepsy 1 (NRCLP1) [MIM:161400]: Neurological CC disabling sleep disorder, characterized by excessive daytime CC sleepiness, sleep fragmentation, symptoms of abnormal rapid-eye- CC movement (REM) sleep, cataplexy, hypnagogic hallucinations, and CC sleep paralysis. Cataplexy is a sudden loss of muscle tone CC triggered by emotions, which is the most valuable clinical feature CC used to diagnose narcolepsy. Human narcolepsy is primarily a CC sporadically occurring disorder but familial clustering has been CC observed. {ECO:0000269|PubMed:10973318}. Note=The disease is CC caused by mutations affecting the gene represented in this entry. CC Human narcolepsy is associated with a deficient orexin system. CC Orexins are absent and/or greatly diminished in the brain and CC cerebrospinal fluid (CSF) of most narcoleptic patients. CC -!- SIMILARITY: Belongs to the orexin family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Qui dort dine - Issue CC 15 of October 2001; CC URL="https://web.expasy.org/spotlight/back_issues/015"; 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; AF041240; AAC39600.1; -; mRNA. DR EMBL; AF118885; AAD24459.1; -; Genomic_DNA. DR CCDS; CCDS11421.1; -. DR RefSeq; NP_001515.1; NM_001524.1. DR UniGene; Hs.158348; -. DR PDB; 1CQ0; NMR; -; A=71-97. DR PDB; 1R02; NMR; -; A=34-66. DR PDB; 1UVQ; X-ray; 1.80 A; C=1-12. DR PDB; 1WSO; NMR; -; A=34-66. DR PDBsum; 1CQ0; -. DR PDBsum; 1R02; -. DR PDBsum; 1UVQ; -. DR PDBsum; 1WSO; -. DR ProteinModelPortal; O43612; -. DR SMR; O43612; -. DR IntAct; O43612; 1. DR STRING; 9606.ENSP00000293330; -. DR DrugBank; DB03088; Pyroglutamic Acid. DR BioMuta; HCRT; -. DR PaxDb; O43612; -. DR PeptideAtlas; O43612; -. DR PRIDE; O43612; -. DR ProteomicsDB; 49080; -. DR DNASU; 3060; -. DR Ensembl; ENST00000293330; ENSP00000293330; ENSG00000161610. DR GeneID; 3060; -. DR KEGG; hsa:3060; -. DR UCSC; uc002hzc.1; human. DR CTD; 3060; -. DR DisGeNET; 3060; -. DR EuPathDB; HostDB:ENSG00000161610.1; -. DR GeneCards; HCRT; -. DR HGNC; HGNC:4847; HCRT. DR HPA; CAB004758; -. DR MalaCards; HCRT; -. DR MIM; 161400; phenotype. DR MIM; 602358; gene. DR neXtProt; NX_O43612; -. DR OpenTargets; ENSG00000161610; -. DR Orphanet; 2073; Narcolepsy type 1. DR Orphanet; 83465; Narcolepsy type 2. DR PharmGKB; PA29221; -. DR eggNOG; ENOG410J4FI; Eukaryota. DR eggNOG; ENOG410Y5WS; LUCA. DR GeneTree; ENSGT00390000014272; -. DR HOGENOM; HOG000230990; -. DR HOVERGEN; HBG000256; -. DR InParanoid; O43612; -. DR KO; K05246; -. DR OMA; HPCPGRR; -. DR OrthoDB; 1094524at2759; -. DR PhylomeDB; O43612; -. DR TreeFam; TF330756; -. DR Reactome; R-HSA-389397; Orexin and neuropeptides FF and QRFP bind to their respective receptors. DR Reactome; R-HSA-416476; G alpha (q) signalling events. DR SIGNOR; O43612; -. DR EvolutionaryTrace; O43612; -. DR GenomeRNAi; 3060; -. DR PMAP-CutDB; O43612; -. DR PRO; PR:O43612; -. DR Proteomes; UP000005640; Chromosome 17. DR Bgee; ENSG00000161610; Expressed in 53 organ(s), highest expression level in hypothalamus. DR Genevisible; O43612; HS. DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl. DR GO; GO:0098794; C:postsynapse; IEA:GOC. DR GO; GO:0005791; C:rough endoplasmic reticulum; IEA:UniProtKB-SubCell. DR GO; GO:0030141; C:secretory granule; IEA:Ensembl. DR GO; GO:0008021; C:synaptic vesicle; TAS:ProtInc. DR GO; GO:0005184; F:neuropeptide hormone activity; IEA:Ensembl. DR GO; GO:0031771; F:type 1 hypocretin receptor binding; IEA:Ensembl. DR GO; GO:0031772; F:type 2 hypocretin receptor binding; IEA:Ensembl. DR GO; GO:0007268; P:chemical synaptic transmission; TAS:ProtInc. DR GO; GO:0042755; P:eating behavior; IEA:Ensembl. DR GO; GO:0060079; P:excitatory postsynaptic potential; IEA:Ensembl. DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; TAS:Reactome. DR GO; GO:0008156; P:negative regulation of DNA replication; IEA:Ensembl. DR GO; GO:0043267; P:negative regulation of potassium ion transport; IEA:Ensembl. DR GO; GO:0051970; P:negative regulation of transmission of nerve impulse; IEA:Ensembl. DR GO; GO:0007218; P:neuropeptide signaling pathway; IEA:UniProtKB-KW. DR GO; GO:0007200; P:phospholipase C-activating G protein-coupled receptor signaling pathway; IEA:Ensembl. DR GO; GO:0051928; P:positive regulation of calcium ion transport; IEA:Ensembl. DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab. DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; IEA:Ensembl. DR GO; GO:0051971; P:positive regulation of transmission of nerve impulse; IEA:Ensembl. DR GO; GO:0007205; P:protein kinase C-activating G protein-coupled receptor signaling pathway; IEA:Ensembl. DR GO; GO:0046928; P:regulation of neurotransmitter secretion; IEA:Ensembl. DR GO; GO:0001659; P:temperature homeostasis; IEA:Ensembl. DR InterPro; IPR001704; Orexin. DR PANTHER; PTHR15173; PTHR15173; 1. DR Pfam; PF02072; Orexin; 1. DR PIRSF; PIRSF037824; Orexin; 1. DR PRINTS; PR01091; OREXINPP. PE 1: Evidence at protein level; KW 3D-structure; Amidation; Cell junction; KW Cleavage on pair of basic residues; Complete proteome; KW Cytoplasmic vesicle; Disease mutation; Disulfide bond; KW Endoplasmic reticulum; Neuropeptide; Pyrrolidone carboxylic acid; KW Reference proteome; Signal; Synapse. FT SIGNAL 1 33 {ECO:0000250}. FT PEPTIDE 34 66 Orexin-A. FT /FTId=PRO_0000020261. FT PEPTIDE 70 97 Orexin-B. FT /FTId=PRO_0000020262. FT PROPEP 98 131 FT /FTId=PRO_0000020263. FT MOD_RES 34 34 Pyrrolidone carboxylic acid. FT {ECO:0000250|UniProtKB:O55232}. FT MOD_RES 66 66 Leucine amide. {ECO:0000250}. FT MOD_RES 97 97 Methionine amide. {ECO:0000250}. FT DISULFID 39 45 FT DISULFID 40 47 FT VARIANT 16 16 L -> R (in NRCLP1; early-onset; impaired FT trafficking and processing; FT dbSNP:rs104894574). FT {ECO:0000269|PubMed:10973318}. FT /FTId=VAR_011633. FT TURN 40 42 {ECO:0000244|PDB:1R02}. FT STRAND 43 45 {ECO:0000244|PDB:1R02}. FT HELIX 47 54 {ECO:0000244|PDB:1R02}. FT HELIX 58 64 {ECO:0000244|PDB:1R02}. FT HELIX 76 86 {ECO:0000244|PDB:1CQ0}. FT TURN 87 89 {ECO:0000244|PDB:1CQ0}. FT HELIX 91 95 {ECO:0000244|PDB:1CQ0}. SQ SEQUENCE 131 AA; 13363 MW; 139D9C33E39E4EF1 CRC64; MNLPSTKVSW AAVTLLLLLL LLPPALLSSG AAAQPLPDCC RQKTCSCRLY ELLHGAGNHA AGILTLGKRR SGPPGLQGRL QRLLQASGNH AAGILTMGRR AGAEPAPRPC LGRRCSAPAA ASVAPGGQSG I //