O43612 (OREX_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Orexin

Alternative name(s):
Hypocretin
Short name=Hcrt

Cleaved into the following 2 chains:

1. Orexin-A
   Alternative name(s):
   Hypocretin-1
   Short name=Hcrt1
2. Orexin-B
   Alternative name(s):
   Hypocretin-2
   Short name=Hcrt2

Gene names

Name:	HCRT
Synonyms:	OX, PPORX, PPOX

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	131 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Neuropeptides that play a significant role in the regulation of food intake and sleep-wakefulness, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions. A broader role in the homeostatic regulation of energy metabolism, autonomic function, hormonal balance and the regulation of body fluids, is also suggested. Orexin-A binds to both OX1R and OX2R with a high affinity, whereas orexin-B binds only to OX2R with a similar high affinity.
Subcellular location	Rough endoplasmic reticulum By similarity. Cytoplasmic vesicle By similarity. Cell junction › synapse By similarity. Note: Associated with perikaryal rough endoplasmic reticulum as well as cytoplasmic large granular vesicles at synapses By similarity.
Tissue specificity	Abundantly expressed in subthalamic nucleus but undetectable in other brain regions tested (hypothalamus was not tested) and in heart, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Post-translational modification	Specific enzymatic cleavages at paired basic residues yield the different active peptides.
Involvement in disease	Defects in HCRT are a cause of narcolepsy [MIM:161400]. Narcolepsy is a neurological disabling sleep disorder, characterized by excessive daytime sleepiness, sleep fragmentation, symptoms of abnormal rapid-eye-movement (REM) sleep, such as cataplexy, hypnagogic hallucinations, and sleep paralysis. Cataplexy is a sudden loss of muscle tone triggered by emotions, which is the most valuable clinical feature used to diagnose narcolepsy. Human narcolepsy is associated with a deficient orexin system. Orexins are absent and/or greatly diminished in the brain and cerebrospinal fluid (CSF) of most narcoleptic patients. Human narcolepsy is primarily a sporadically occurring disorder but familial clustering has been observed.
Sequence similarities	Belongs to the orexin family.

Ontologies

Keywords
Cellular component	Cell junction Cytoplasmic vesicle Endoplasmic reticulum Synapse
Disease	Disease mutation
Domain	Signal
Molecular function	Neuropeptide
PTM	Amidation Cleavage on pair of basic residues Disulfide bond Pyrrolidone carboxylic acid
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	neuropeptide signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cell junction Inferred from electronic annotation. Source: UniProtKB-KW rough endoplasmic reticulum Inferred from electronic annotation. Source: UniProtKB-SubCell synaptic vesicle Traceable author statement. Source: ProtInc
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 33

33

By similarity

Peptide

34 – 66

33

Orexin-A

PRO_0000020261

Peptide

70 – 97

28

Orexin-B

PRO_0000020262

Propeptide

98 – 131

34

PRO_0000020263

Amino acid modifications

Modified residue

34

1

Pyrrolidone carboxylic acid By similarity

Modified residue

66

1

Leucine amide By similarity

Modified residue

97

1

Methionine amide By similarity

Disulfide bond

39 ↔ 45

Ref.6 Ref.8

Disulfide bond

40 ↔ 47

Ref.6 Ref.8

Natural variations

Natural variant

16

1

L → R in narcolepsy; early-onset; impaired trafficking and processing. Ref.9

VAR_011633

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

131

Helix Strand Turn

Details...

Turn

40 – 42

3

Beta strand

43 – 45

3

Helix

47 – 54

8

Helix

58 – 64

7

Helix

76 – 86

11

Turn

87 – 89

3

Helix

91 – 95

5

Sequences

	Sequence		Length	Mass (Da)
	O43612-1 [UniParc]. Last modified June 1, 1998. Version 1. Checksum: 139D9C33E39E4EF1	FASTA	131	13,363
	10 20 30 40 50 60 MNLPSTKVSW AAVTLLLLLL LLPPALLSSG AAAQPLPDCC RQKTCSCRLY ELLHGAGNHA 70 80 90 100 110 120 AGILTLGKRR SGPPGLQGRL QRLLQASGNH AAGILTMGRR AGAEPAPRPC LGRRCSAPAA 130 ASVAPGGQSG I

References

[1]	"Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior." Sakurai T., Amemiya A., Ishii M., Matsuzaki I., Chemelli R.M., Tanaka H., Williams S.C., Richardson J.A., Kozlowski G.P., Wilson S., Arch J.R.S., Buckingham R.E., Haynes A.C., Carr S.A., Annan R.S., McNulty D.E., Liu W.-S., Terrett J.A. , Elshourbagy N.A., Bergsma D.J., Yanagisawa M. Cell 92:573-585(1998) [PubMed: 9491897] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Structure and function of human prepro-orexin gene." Sakurai T., Moriguchi T., Furuya K., Kajiwara N., Nakamura T., Yanagisawa M., Goto K. J. Biol. Chem. 274:17771-17776(1999) [PubMed: 10364220] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Solution structure of a new hypothalamic neuropeptide, human hypocretin-2/orexin-B." Lee J.-H., Bang E., Chae K.-J., Kim J.-Y., Lee D.W., Lee W. Eur. J. Biochem. 266:831-839(1999) [PubMed: 10583376] [Abstract] Cited for: STRUCTURE BY NMR OF 70-97.
[4]	"Hypocretin/orexin, sleep and narcolepsy." Hungs M., Mignot E. Bioessays 23:397-408(2001) [PubMed: 11340621] [Abstract] Cited for: REVIEW.
[5]	"To eat or to sleep? Orexin in the regulation of feeding and wakefulness." Willie J.T., Chemelli R.M., Sinton C.M., Yanagisawa M. Annu. Rev. Neurosci. 24:429-458(2001) [PubMed: 11283317] [Abstract] Cited for: REVIEW.
[6]	"Solution structure of human orexin-A: regulator of appetite and wakefulness." Kim H.Y., Hong E., Kim J.I., Lee W. J. Biochem. Mol. Biol. 37:565-573(2004) [PubMed: 15479620] [Abstract] Cited for: STRUCTURE BY NMR OF 34-66, DISULFIDE BONDS.
[7]	"Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy." Siebold C., Hansen B.E., Wyer J.R., Harlos K., Esnouf R.E., Svejgaard A., Bell J.I., Strominger J.L., Jones E.Y., Fugger L. Proc. Natl. Acad. Sci. U.S.A. 101:1999-2004(2004) [PubMed: 14769912] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 1-12 IN COMPLEX OF HLA-DQA1/HLA-DQB1 HETERODIMER (HLA-DQ0602).
[8]	"Orexin-A is composed of a highly conserved C-terminal and a specific, hydrophilic N-terminal region, revealing the structural basis of specific recognition by the orexin-1 receptor." Takai T., Takaya T., Nakano M., Akutsu H., Nakagawa A., Aimoto S., Nagai K., Ikegami T. J. Pept. Sci. 12:443-454(2006) [PubMed: 16429482] [Abstract] Cited for: STRUCTURE BY NMR OF 35-66, DISULFIDE BONDS.
[9]	"A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains." Peyron C., Faraco J., Rogers W., Ripley B., Overeem S., Charnay Y., Nevsimalova S., Aldrich M., Reynolds D., Albin R., Li R., Hungs M., Pedrazzoli M., Padigaru M., Kucherlapati M., Fan J., Maki R., Lammers G.J. , Bouras C., Kucherlapati R., Nishino S., Mignot E. Nat. Med. 6:991-997(2000) [PubMed: 10973318] [Abstract] Cited for: CHARACTERIZATION OF VARIANT NARCOLEPSY ARG-16.
+	Additional computationally mapped references.

Web resources

Protein Spotlight

Qui dort dine - Issue 15 of October 2001

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF041240 mRNA. Translation: AAC39600.1.
AF118885 Genomic DNA. Translation: AAD24459.1.

IPI

IPI00013373.

RefSeq

NP_001515.1.

UniGene

Hs.158348.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1CQ0	NMR	-	A	71-97	[»]
1R02	NMR	-	A	34-66	[»]
1UVQ	X-ray	1.80	C	1-12	[»]
1WSO	NMR	-	A	35-66	[»]

ProteinModelPortal

O43612.

ModBase

Search...

Protein-protein interaction databases

STRING

O43612.

Proteomic databases

PRIDE

O43612.

Genome annotation databases

Ensembl

ENST00000293330; ENSP00000293330; ENSG00000161610; Homo sapiens. [Genome view]

GeneID

3060.

KEGG

hsa:3060.

UCSC

uc002hzc.1. human.

Organism-specific databases

CTD

3060.

GeneCards

GC17M040337.

HGNC

HGNC:4847. HCRT.

HPA

CAB004758.

MIM

161400. phenotype.
602358. gene.

Orphanet

2073. Narcolepsy-cataplexy.

PharmGKB

PA29221.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG21317.

HOGENOM

HBG279250.

HOVERGEN

HBG000256.

InParanoid

O43612.

OMA

PCPGRRC.

OrthoDB

EOG96X1TV.

PhylomeDB

O43612.

Enzyme and pathway databases

Reactome

REACT_14797. Signaling by GPCR.

Gene expression databases

ArrayExpress

O43612.

Bgee

O43612.

CleanEx

HS_HCRT.
HS_PPOX.

Genevestigator

O43612.

GermOnline

ENSG00000161610. Homo sapiens.

Family and domain databases

InterPro

IPR001704. Orexin.
[Graphical view]

PANTHER

PTHR15173. Orexin. 1 hit.

Pfam

PF02072. Orexin. 1 hit.
[Graphical view]

PIRSF

PIRSF037824. Orexin. 1 hit.

PRINTS

PR01091. OREXINPP.

ProtoNet

Search...

Other Resources

NextBio

12107.

PMAP-CutDB

O43612.

SOURCE

Search...

Entry information

Entry name

OREX_HUMAN

Accession

Primary (citable) accession number: O43612

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
Last sequence update:	June 1, 1998
Last modified:	August 10, 2010
This is version 93 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.