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   02-SEP-2026, entry version 197.
DE   RecName: Full=Hypocretin neuropeptide precursor {ECO:0000312|HGNC:HGNC:4847};
DE   AltName: Full=Hypocretin {ECO:0000303|PubMed:11340621};
DE            Short=Hcrt {ECO:0000303|PubMed:11340621};
DE   AltName: Full=Orexin precursor {ECO:0000303|PubMed:9491897};
DE   AltName: Full=Prepro-orexin {ECO:0000303|PubMed:9491897};
DE   AltName: Full=Preprohypocretin {ECO:0000250|UniProtKB:O55232};
DE   Contains:
DE     RecName: Full=Orexin-A {ECO:0000303|PubMed:9491897};
DE     AltName: Full=Hypocretin-1 {ECO:0000303|PubMed:10583376};
DE              Short=Hcrt1 {ECO:0000305};
DE   Contains:
DE     RecName: Full=Orexin-B {ECO:0000303|PubMed:9491897};
DE     AltName: Full=Hypocretin-2 {ECO:0000303|PubMed:10583376};
DE              Short=Hcrt2 {ECO:0000305};
DE   Flags: Precursor;
GN   Name=HCRT {ECO:0000312|HGNC:HGNC:4847}; Synonyms=OX, PPORX, PPOX;
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], AND TISSUE SPECIFICITY.
RX   PubMed=9491897; DOI=10.1016/s0092-8674(00)80949-6;
RA   Sakurai T., Amemiya A., Ishii M., Matsuzaki I., Chemelli R.M., Tanaka H.,
RA   Williams S.C., Richardson J.A., Kozlowski G.P., Wilson S., Arch J.R.S.,
RA   Buckingham R.E., Haynes A.C., Carr S.A., Annan R.S., McNulty D.E.,
RA   Liu W.-S., Terrett J.A., Elshourbagy N.A., Bergsma D.J., Yanagisawa M.;
RT   "Orexins and orexin receptors: a family of hypothalamic neuropeptides and G
RT   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 71-97.
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 hypocretin-
RT   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 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., Svejgaard A.,
RA   Bell J.I., Strominger J.L., Jones E.Y., Fugger L.;
RT   "Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and
RT   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 specific
RT   recognition by the orexin-1 receptor.";
RL   J. Pept. Sci. 12:443-454(2006).
RN   [9] {ECO:0007744|PDB:7L1U}
RP   STRUCTURE BY ELECTRON MICROSCOPY (3.20 ANGSTROMS) OF 70-97 IN COMPLEX WITH
RP   HCRTR2 3-389.
RX   PubMed=33547286; DOI=10.1038/s41467-021-21087-6;
RA   Hong C., Byrne N.J., Zamlynny B., Tummala S., Xiao L., Shipman J.M.,
RA   Partridge A.T., Minnick C., Breslin M.J., Rudd M.T., Stachel S.J.,
RA   Rada V.L., Kern J.C., Armacost K.A., Hollingsworth S.A., O'Brien J.A.,
RA   Hall D.L., McDonald T.P., Strickland C., Brooun A., Soisson S.M.,
RA   Hollenstein K.;
RT   "Structures of active-state orexin receptor 2 rationalize peptide and
RT   small-molecule agonist recognition and receptor activation.";
RL   Nat. Commun. 12:815-815(2021).
RN   [10]
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., Lammers G.J.,
RA   Bouras C., Kucherlapati R., Nishino S., Mignot E.;
RT   "A mutation in a case of early onset narcolepsy and a generalized absence
RT   of hypocretin peptides in human narcoleptic brains.";
RL   Nat. Med. 6:991-997(2000).
CC   -!- FUNCTION: Neuropeptides that play a significant role in the regulation
CC       of food intake and sleep-wakefulness, possibly by coordinating the
CC       complex behavioral and physiologic responses of these complementary
CC       homeostatic functions. A broader role in the homeostatic regulation of
CC       energy metabolism, autonomic function, hormonal balance and the
CC       regulation of body fluids, is also suggested.
CC       {ECO:0000250|UniProtKB:O55232}.
CC   -!- FUNCTION: [Orexin-A]: Binds to orexin receptors HCRTR1/OX1R and
CC       HCRTR2/OX2R with a high affinity (By similarity). Stimulates food
CC       intake (By similarity). Modulates pituitary luteinizing hormone
CC       secretion in an ovarian steroid-dependent manner (By similarity).
CC       {ECO:0000250|UniProtKB:O55232}.
CC   -!- FUNCTION: [Orexin-B]: Binds to orexin receptor HCRTR2/OX2R only (By
CC       similarity). Stimulates food intake (By similarity). Modulates
CC       pituitary luteinizing hormone secretion in an ovarian steroid-dependent
CC       manner (By similarity). {ECO:0000250|UniProtKB:O55232}.
CC   -!- SUBCELLULAR LOCATION: Rough endoplasmic reticulum
CC       {ECO:0000250|UniProtKB:O55232}. Cytoplasmic vesicle
CC       {ECO:0000250|UniProtKB:O55232}. Synapse {ECO:0000250|UniProtKB:O55232}.
CC       Note=Associated with perikaryal rough endoplasmic reticulum as well as
CC       cytoplasmic large granular vesicles at synapses.
CC       {ECO:0000250|UniProtKB:O55232}.
CC   -!- TISSUE SPECIFICITY: Abundantly expressed in subthalamic nucleus but
CC       undetectable in other brain regions tested (hypothalamus was not
CC       tested) and in heart, placenta, lung, liver, skeletal muscle, kidney
CC       and pancreas. {ECO:0000269|PubMed:9491897}.
CC   -!- PTM: Specific enzymatic cleavages at paired basic residues yield the
CC       different active peptides. {ECO:0000303|PubMed:9491897}.
CC   -!- DISEASE: Narcolepsy 1 (NRCLP1) [MIM:161400]: Neurological disabling
CC       sleep disorder, characterized by excessive daytime sleepiness, sleep
CC       fragmentation, symptoms of abnormal rapid-eye-movement (REM) sleep,
CC       cataplexy, hypnagogic hallucinations, and sleep paralysis. Cataplexy is
CC       a sudden loss of muscle tone triggered by emotions, which is the most
CC       valuable clinical feature used to diagnose narcolepsy. Human narcolepsy
CC       is primarily a sporadically occurring disorder but familial clustering
CC       has been observed. {ECO:0000269|PubMed:10973318}. Note=The disease is
CC       caused by variants affecting the gene represented in this entry. Human
CC       narcolepsy is associated with a deficient orexin system. Orexins are
CC       absent and/or greatly diminished in the brain and cerebrospinal fluid
CC       (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 15 of
CC       October 2001;
CC       URL="https://www.proteinspotlight.org/back_issues/015";
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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   PDB; 1CQ0; NMR; -; A=71-97.
DR   PDB; 1R02; NMR; -; A=34-66.
DR   PDB; 1UVQ; X-ray; 1.80 A; C=1-13.
DR   PDB; 1WSO; NMR; -; A=34-66.
DR   PDB; 7L1U; EM; 3.20 A; L=70-97.
DR   AlphaFoldDB; O43612; -.
DR   EMDB; EMD-23118; -.
DR   MDposit; O43612; -.
DR   SMR; O43612; -.
DR   BioGRID; 109310; 15.
DR   FunCoup; O43612; 372.
DR   IntAct; O43612; 3.
DR   NDEx; IQUERY-CP-HCRT; 1 NDEx IQuery Curated Pathway.
DR   STRING; 9606.ENSP00000293330; -.
DR   DrugBank; DB03088; Pidolic acid.
DR   iPTMnet; O43612; -.
DR   SwissPalm; O43612; -.
DR   BioMuta; HCRT; -.
DR   MassIVE; O43612; -.
DR   PaxDb; 9606-ENSP00000293330; -.
DR   PeptideAtlas; O43612; -.
DR   Antibodypedia; 3468; 351 antibodies from 35 providers.
DR   DNASU; 3060; -.
DR   Ensembl; ENST00000293330.1; ENSP00000293330.1; ENSG00000161610.1.
DR   GeneID; 3060; -.
DR   KEGG; hsa:3060; -.
DR   MANE-Select; ENST00000293330.1; ENSP00000293330.1; NM_001524.1; NP_001515.1.
DR   UCSC; uc002hzc.1; human.
DR   AGR; HGNC:4847; -.
DR   ClinPGx; PA29221; -.
DR   CTD; 3060; -.
DR   DisGeNET; 3060; -.
DR   GeneCards; HCRT; -.
DR   HGNC; HGNC:4847; HCRT.
DR   HPA; ENSG00000161610; Tissue enriched (brain).
DR   MalaCards; HCRT; -.
DR   MIM; 161400; phenotype.
DR   MIM; 602358; gene.
DR   OpenTargets; ENSG00000161610; -.
DR   Orphanet; 2073; Narcolepsy type 1.
DR   Orphanet; 83465; Narcolepsy type 2.
DR   VEuPathDB; HostDB:ENSG00000161610; -.
DR   eggNOG; ENOG502S83I; Eukaryota.
DR   GeneTree; ENSGT00390000014272; -.
DR   HOGENOM; CLU_149027_1_0_1; -.
DR   InParanoid; O43612; -.
DR   OMA; HPCPGRR; -.
DR   OrthoDB; 9379045at2759; -.
DR   PAN-GO; O43612; 10 GO annotations based on evolutionary models.
DR   PhylomeDB; O43612; -.
DR   PathwayCommons; O43612; -.
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   SignaLink; O43612; -.
DR   SIGNOR; O43612; -.
DR   Agora; ENSG00000161610; -.
DR   BioGRID-ORCS; 3060; 13 hits in 1144 CRISPR screens.
DR   EvolutionaryTrace; O43612; -.
DR   GenomeRNAi; 3060; -.
DR   Pharos; O43612; Tbio.
DR   PRO; PR:O43612; -.
DR   Proteomes; UP000005640; Chromosome 17.
DR   RNAct; O43612; protein.
DR   Bgee; ENSG00000161610; Expressed in hypothalamus and 71 other cell types or tissues.
DR   GO; GO:0031410; C:cytoplasmic vesicle; ISS:UniProtKB.
DR   GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR   GO; GO:0099013; C:neuronal dense core vesicle lumen; IEA:Ensembl.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IBA:GO_Central.
DR   GO; GO:0098794; C:postsynapse; IEA:GOC.
DR   GO; GO:0005791; C:rough endoplasmic reticulum; ISS:UniProtKB.
DR   GO; GO:0045202; C:synapse; ISS:UniProtKB.
DR   GO; GO:0008021; C:synaptic vesicle; TAS:ProtInc.
DR   GO; GO:0005184; F:neuropeptide hormone activity; IBA:GO_Central.
DR   GO; GO:0031771; F:type 1 orexin receptor binding; IBA:GO_Central.
DR   GO; GO:0031772; F:type 2 orexin receptor binding; IBA:GO_Central.
DR   GO; GO:0048149; P:behavioral response to ethanol; IEA:Ensembl.
DR   GO; GO:0007268; P:chemical synaptic transmission; TAS:ProtInc.
DR   GO; GO:0042756; P:drinking behavior; IEA:Ensembl.
DR   GO; GO:0042755; P:eating behavior; IBA:GO_Central.
DR   GO; GO:0060079; P:excitatory postsynaptic potential; IEA:Ensembl.
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:InterPro.
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; IBA:GO_Central.
DR   GO; GO:0046928; P:regulation of neurotransmitter secretion; IBA:GO_Central.
DR   GO; GO:1901652; P:response to peptide; IEA:Ensembl.
DR   GO; GO:0042594; P:response to starvation; IBA:GO_Central.
DR   GO; GO:0030431; P:sleep; IBA:GO_Central.
DR   GO; GO:0001659; P:temperature homeostasis; IBA:GO_Central.
DR   InterPro; IPR001704; Orexin.
DR   PANTHER; PTHR15173:SF2; HYPOCRETIN NEUROPEPTIDE PRECURSOR; 1.
DR   PANTHER; PTHR15173; OREXIN; 1.
DR   Pfam; PF02072; Orexin; 1.
DR   PIRSF; PIRSF037824; Orexin; 1.
DR   PRINTS; PR01091; OREXINPP.
DR   PDBsum; 1CQ0; -.
DR   PDBsum; 1R02; -.
DR   PDBsum; 1UVQ; -.
DR   PDBsum; 1WSO; -.
DR   PDBsum; 7L1U; -.
PE   1: Evidence at protein level;
KW   3D-structure; Amidation; Cleavage on pair of basic residues;
KW   Cytoplasmic vesicle; Disease variant; Disulfide bond;
KW   Endoplasmic reticulum; Neuropeptide; Proteomics identification;
KW   Pyrrolidone carboxylic acid; Reference proteome; Signal; Synapse.
FT   SIGNAL          1..33
FT                   /evidence="ECO:0000250|UniProtKB:O55232"
FT   PEPTIDE         34..66
FT                   /note="Orexin-A"
FT                   /evidence="ECO:0000250|UniProtKB:O55232"
FT                   /id="PRO_0000020261"
FT   PEPTIDE         70..97
FT                   /note="Orexin-B"
FT                   /evidence="ECO:0000250|UniProtKB:O55232"
FT                   /id="PRO_0000020262"
FT   PROPEP          98..131
FT                   /note="Removed in mature form"
FT                   /evidence="ECO:0000250|UniProtKB:O55232"
FT                   /id="PRO_0000020263"
FT   MOD_RES         34
FT                   /note="Pyrrolidone carboxylic acid"
FT                   /evidence="ECO:0000250|UniProtKB:O55232"
FT   MOD_RES         66
FT                   /note="Leucine amide"
FT                   /evidence="ECO:0000250|UniProtKB:O55232"
FT   MOD_RES         97
FT                   /note="Methionine amide"
FT                   /evidence="ECO:0000250|UniProtKB:O55232"
FT   DISULFID        39..45
FT                   /evidence="ECO:0000269|PubMed:15479620,
FT                   ECO:0000269|PubMed:16429482, ECO:0000312|PDB:1R02,
FT                   ECO:0000312|PDB:1WSO"
FT   DISULFID        40..47
FT                   /evidence="ECO:0000269|PubMed:15479620,
FT                   ECO:0000269|PubMed:16429482, ECO:0000312|PDB:1R02,
FT                   ECO:0000312|PDB:1WSO"
FT   VARIANT         16
FT                   /note="L -> R (in NRCLP1; early-onset; impaired trafficking
FT                   and processing; dbSNP:rs104894574)"
FT                   /evidence="ECO:0000269|PubMed:10973318"
FT                   /id="VAR_011633"
FT   HELIX           6..9
FT                   /evidence="ECO:0007829|PDB:1UVQ"
FT   HELIX           35..37
FT                   /evidence="ECO:0007829|PDB:1WSO"
FT   TURN            40..42
FT                   /evidence="ECO:0007829|PDB:1R02"
FT   STRAND          43..45
FT                   /evidence="ECO:0007829|PDB:1R02"
FT   HELIX           47..54
FT                   /evidence="ECO:0007829|PDB:1R02"
FT   HELIX           58..64
FT                   /evidence="ECO:0007829|PDB:1R02"
FT   HELIX           76..80
FT                   /evidence="ECO:0007829|PDB:1CQ0"
FT   HELIX           81..86
FT                   /evidence="ECO:0007829|PDB:1CQ0"
FT   TURN            87..89
FT                   /evidence="ECO:0007829|PDB:1CQ0"
FT   HELIX           94..96
FT                   /evidence="ECO:0007829|PDB:7L1U"
SQ   SEQUENCE   131 AA;  13363 MW;  139D9C33E39E4EF1 CRC64;
     MNLPSTKVSW AAVTLLLLLL LLPPALLSSG AAAQPLPDCC RQKTCSCRLY ELLHGAGNHA
     AGILTLGKRR SGPPGLQGRL QRLLQASGNH AAGILTMGRR AGAEPAPRPC LGRRCSAPAA
     ASVAPGGQSG I
//