OREX_HUMAN
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 03-AUG-2022, entry version 179.
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; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC 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., 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 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 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]
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. Orexin-A binds to both
CC OX1R and OX2R with a high affinity, whereas orexin-B binds only to OX2R
CC with a similar high affinity.
CC -!- SUBCELLULAR LOCATION: Rough endoplasmic reticulum {ECO:0000250}.
CC Cytoplasmic vesicle {ECO:0000250}. Synapse {ECO:0000250}.
CC Note=Associated with perikaryal rough endoplasmic reticulum as well as
CC cytoplasmic large granular vesicles at synapses. {ECO:0000250}.
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.
CC -!- PTM: Specific enzymatic cleavages at paired basic residues yield the
CC different active peptides.
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://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 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 PDB; 7L1U; EM; 3.20 A; L=70-97.
DR PDBsum; 1CQ0; -.
DR PDBsum; 1R02; -.
DR PDBsum; 1UVQ; -.
DR PDBsum; 1WSO; -.
DR PDBsum; 7L1U; -.
DR AlphaFoldDB; O43612; -.
DR SMR; O43612; -.
DR BioGRID; 109310; 15.
DR IntAct; O43612; 2.
DR STRING; 9606.ENSP00000293330; -.
DR DrugBank; DB03088; Pidolic acid.
DR BioMuta; HCRT; -.
DR PaxDb; O43612; -.
DR PeptideAtlas; O43612; -.
DR PRIDE; O43612; -.
DR Antibodypedia; 3468; 358 antibodies from 33 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 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 neXtProt; NX_O43612; -.
DR OpenTargets; ENSG00000161610; -.
DR Orphanet; 2073; Narcolepsy type 1.
DR Orphanet; 83465; Narcolepsy type 2.
DR PharmGKB; PA29221; -.
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; 1586513at2759; -.
DR PhylomeDB; O43612; -.
DR TreeFam; TF330756; -.
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 BioGRID-ORCS; 3060; 12 hits in 1068 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 70 other tissues.
DR Genevisible; O43612; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
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; 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; IBA:GO_Central.
DR GO; GO:0031771; F:type 1 hypocretin receptor binding; IBA:GO_Central.
DR GO; GO:0031772; F:type 2 hypocretin receptor binding; IBA:GO_Central.
DR GO; GO:0007268; P:chemical synaptic transmission; TAS:ProtInc.
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: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; IBA:GO_Central.
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; IBA:GO_Central.
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; 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; Cleavage on pair of basic residues;
KW Cytoplasmic vesicle; Disease variant; Disulfide bond;
KW Endoplasmic reticulum; Neuropeptide; Pyrrolidone carboxylic acid;
KW Reference proteome; Signal; Synapse.
FT SIGNAL 1..33
FT /evidence="ECO:0000250"
FT PEPTIDE 34..66
FT /note="Orexin-A"
FT /id="PRO_0000020261"
FT PEPTIDE 70..97
FT /note="Orexin-B"
FT /id="PRO_0000020262"
FT PROPEP 98..131
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"
FT MOD_RES 97
FT /note="Methionine amide"
FT /evidence="ECO:0000250"
FT DISULFID 39..45
FT DISULFID 40..47
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 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..86
FT /evidence="ECO:0007829|PDB:1CQ0"
FT TURN 87..89
FT /evidence="ECO:0007829|PDB:1CQ0"
FT HELIX 91..95
FT /evidence="ECO:0007829|PDB:1CQ0"
SQ SEQUENCE 131 AA; 13363 MW; 139D9C33E39E4EF1 CRC64;
MNLPSTKVSW AAVTLLLLLL LLPPALLSSG AAAQPLPDCC RQKTCSCRLY ELLHGAGNHA
AGILTLGKRR SGPPGLQGRL QRLLQASGNH AAGILTMGRR AGAEPAPRPC LGRRCSAPAA
ASVAPGGQSG I
