Reviewed, UniProtKB/Swiss-Prot P01588 (EPO_HUMAN)

Names and origin

Protein names

Recommended name:
    Erythropoietin
Alternative name(s):
    INN=Epoetin

Gene names

Name:

EPO

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	193 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	Erythropoietin is the principal hormone involved in the regulation of erythrocyte differentiation and the maintenance of a physiological level of circulating erythrocyte mass.
Subcellular location	Secreted.
Tissue specificity	Produced by kidney or liver of adult mammals and by liver of fetal or neonatal mammals.
Involvement in disease	Genetic variation in EPO is associated with susceptbility to microvascular complications of diabetes type 2 (MVCD2) [MIM:612623]; also called susceptibility to proliferative diabetic retinopathy (PDR) or susceptbility to diabetic end-stage renal disease (ESRD). Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. PDR and ESRD are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. EPO is a potent angiogenic factor observed in the diabetic human and mouse eye.
Pharmaceutical use	Used for the treatment of anemia. Available under the names Epogen (Amgen), Epogin (Chugai), Epomax (Elanex), Eprex (Janssen-Cilag), NeoRecormon or Recormon (Roche), Dynepo (Shire Pharmaceuticals) and Procrit (Ortho Biotech). Variations in the glycosylation pattern of EPO distinguishes these products. Epogen, Epogin, Eprex and Procrit are generically known as epoetin alfa, NeoRecormon and Recormon as epoetin beta, Dynepo as epoetin delta and Epomax as epoetin omega. Epoetin zeta is the name used for some 'biosimilars' forms of epoetin alfa and is available under the names Silapo (Stada) and Retacrit (Hospira). Darbepoetin alfa is a form created by 5 substitutions (Asn-57, Thr-59, Val-114, Asn-115 and Thr-117) that create 2 new N-glycosylation sites. It has a longer circulating half-life in vivo. It is available under the name Aranesp (Amgen). EPO is being much misused as a performance-enhancing drug in endurance athletes.
Sequence similarities	Belongs to the EPO/TPO family.

Ontologies

Keywords
Biological process	Erythrocyte maturation
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Domain	Signal
Molecular function	Hormone
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Direct protein sequencing Pharmaceutical
Gene Ontology (GO)
Biological process	blood circulation Ref.1 Non-traceable author statement. Source: ProtInc erythrocyte maturation Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of DNA replication Inferred from direct assay. Source: UniProtKB positive regulation of Ras protein signal transduction Inferred from direct assay. Source: UniProtKB positive regulation of cell proliferation Inferred from direct assay. Source: UniProtKB positive regulation of gene-specific transcription Inferred from direct assay. Source: UniProtKB positive regulation of tyrosine phosphorylation of Stat5 protein Inferred from direct assay. Source: UniProtKB signal transduction Ref.1 Non-traceable author statement. Source: ProtInc
Cellular component	extracellular space Ref.1 Traceable author statement. Source: ProtInc
Molecular function	erythropoietin receptor binding Inferred from electronic annotation. Source: InterPro hormone activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
DOK2	O60496	1	EBI-1027362,EBI-1046024

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 27

27

Ref.8 Ref.9

Chain

28 – 193

166

Erythropoietin

PRO_0000008401

Propeptide

190 – 193

4

Removed in mature form (Partial)

PRO_0000008402

Propeptide

193

1

Removed in mature form (Partial)

PRO_0000313669

Amino acid modifications

Glycosylation

51

1

N-linked (GlcNAc...) Ref.8

CAR_000052

Glycosylation

65

1

N-linked (GlcNAc...) Ref.8

CAR_000166

Glycosylation

110

1

N-linked (GlcNAc...) Ref.8

CAR_000192

Glycosylation

153

1

O-linked (GalNAc...) Ref.8

Disulfide bond

34 ↔ 188

Ref.8

Disulfide bond

56 ↔ 60

Ref.8

Natural variations

Natural variant

131 – 132

2

SL → NF in an hepatocellular carcinoma.

VAR_009870

Natural variant

149

1

P → Q in an hepatocellular carcinoma. Ref.7

VAR_009871

Experimental info

Sequence conflict

40

1

E → Q in CAA26095. Ref.1

Sequence conflict

85

1

Q → QQ AA sequence Ref.8

Sequence conflict

140

1

G → R in CAA26095. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

193

Helix Strand Turn

Details...

Helix

32 – 34

3

Helix

36 – 52

17

Helix

53 – 55

3

Beta strand

61 – 68

8

Helix

75 – 78

4

Helix

83 – 109

27

Helix

118 – 138

21

Helix

141 – 147

7

Beta strand

160 – 164

5

Helix

165 – 177

13

Helix

179 – 188

10

Sequences

	Sequence		Length	Mass (Da)
	P01588-1 [UniParc]. Last modified July 21, 1986. Version 1. Checksum: C91F0E4C26A52033	FASTA	193	21,307
	10 20 30 40 50 60 MGVHECPAWL WLLLSLLSLP LGLPVLGAPP RLICDSRVLE RYLLEAKEAE NITTGCAEHC 70 80 90 100 110 120 SLNENITVPD TKVNFYAWKR MEVGQQAVEV WQGLALLSEA VLRGQALLVN SSQPWEPLQL 130 140 150 160 170 180 HVDKAVSGLR SLTTLLRALG AQKEAISPPD AASAAPLRTI TADTFRKLFR VYSNFLRGKL 190 KLYTGEACRT GDR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation and characterization of genomic and cDNA clones of human erythropoietin." Jacobs K., Shoemaker C., Rudersdorf R., Neill S.D., Kaufman R.J., Mufson A., Seehra J., Jones S.S., Hewick R., Fritsch E.F., Kawakita M., Shimizu T., Miyake T. Nature 313:806-810(1985) [PubMed: 3838366] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
[2]	"Cloning and expression of the human erythropoietin gene." Lin F.-K., Suggs S., Lin C.-H., Browne J.K., Smalling R., Egrie J.C., Chen K.K., Fox G.M., Martin F., Stabinsky Z., Badrawi S.M., Lai P.-H., Goldwasser E. Proc. Natl. Acad. Sci. U.S.A. 82:7580-7584(1985) [PubMed: 3865178] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Large-scale sequencing of two regions in human chromosome 7q22: analysis of 650 kb of genomic sequence around the EPO and CUTL1 loci reveals 17 genes." Gloeckner G., Scherer S., Schattevoy R., Boright A.P., Weber J., Tsui L.-C., Rosenthal A. Genome Res. 8:1060-1073(1998) [PubMed: 9799793] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Erythropoietin gene sequence in the Quechua, a high altitude native population." Rupert J.L., Hochachka P.W. Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"The DNA sequence of human chromosome 7." Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., Delehaunty K.D., Miner T.L. , Nash W.E., Cordes M., Du H., Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., Wilson R.K. Nature 424:157-164(2003) [PubMed: 12853948] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[7]	"Gene expression of mutant erythropoietin in hepatocellular carcinoma." Funakoshi A., Muta H., Baba T., Shimizu S. Biochem. Biophys. Res. Commun. 195:717-722(1993) [PubMed: 8396923] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 58-193, VARIANTS HEPATOCELLULAR CARCINOMA 131-ASN-PHE-132 AND GLN-149.
[8]	"Structural characterization of human erythropoietin." Lai P.H., Everett R., Wang F.F., Arakawa T., Goldwasser E. J. Biol. Chem. 261:3116-3121(1986) [PubMed: 3949763] [Abstract] Cited for: PROTEIN SEQUENCE OF 28-193, DISULFIDE BONDS. Tissue: Urine.
[9]	"Isolation of human erythropoietin with monoclonal antibodies." Yanagawa S., Hirade K., Ohnota H., Sasaki R., Chiba H., Ueda M., Goto M. J. Biol. Chem. 259:2707-2710(1984) [PubMed: 6698989] [Abstract] Cited for: PRELIMINARY PROTEIN SEQUENCE OF 28-57.
[10]	"Comparative study of the asparagine-linked sugar chains of human erythropoietins purified from urine and the culture medium of recombinant Chinese hamster ovary cells." Takeuchi M., Takasaki S., Miyazaki H., Kato T., Hoshi S., Kochibe N., Kobata A. J. Biol. Chem. 263:3657-3663(1988) [PubMed: 3346214] [Abstract] Cited for: STRUCTURE OF CARBOHYDRATES.
[11]	"Site-specific glycosylation of human recombinant erythropoietin: analysis of glycopeptides or peptides at each glycosylation site by fast atom bombardment mass spectrometry." Sasaki H., Ochi N., Dell A., Fukuda M. Biochemistry 27:8618-8626(1988) [PubMed: 3219367] [Abstract] Cited for: STRUCTURE OF CARBOHYDRATES.
[12]	"Structures and functional roles of the sugar chains of human erythropoietins." Takeuchi M., Kobata A. Glycobiology 1:337-346(1991) [PubMed: 1820196] [Abstract] Cited for: STRUCTURE OF CARBOHYDRATES.
[13]	"Sugar profiling proves that human serum erythropoietin differs from recombinant human erythropoietin." Skibeli V., Nissen-Lie G., Torjesen P. Blood 98:3626-3634(2001) [PubMed: 11739166] [Abstract] Cited for: STRUCTURE OF CARBOHYDRATES.
[14]	"Efficiency of signalling through cytokine receptors depends critically on receptor orientation." Syed R.S., Reid S.W., Li C., Cheetham J.C., Aoki K.H., Liu B., Zhan H., Osslund T.D., Chirino A.J., Zhang J., Finer-Moore J., Elliott S., Sitney K., Katz B.A., Matthews D.J., Wendoloski J.J., Egrie J., Stroud R.M. Nature 395:511-516(1998) [PubMed: 9774108] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
[15]	"NMR structure of human erythropoietin and a comparison with its receptor bound conformation." Cheetham J.C., Smith D.M., Aoki K.H., Stevenson J.L., Hoeffel T.J., Syed R.S., Egrie J., Harvey T.S. Nat. Struct. Biol. 5:861-866(1998) [PubMed: 9783743] [Abstract] Cited for: STRUCTURE BY NMR OF 28-193.
[16]	"Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications." Genetics of diabetes and diabetic complication study group Tong Z., Yang Z., Patel S., Chen H., Gibbs D., Yang X., Hau V.S., Kaminoh Y., Harmon J., Pearson E., Buehler J., Chen Y., Yu B., Tinkham N.H., Zabriskie N.A., Zeng J., Luo L., Sun J.K. , Prakash M., Hamam R.N., Tonna S., Constantine R., Ronquillo C.C., Sadda S., Avery R.L., Brand J.M., London N., Anduze A.L., King G.L., Bernstein P.S., Watkins S., Jorde L.B., Li D.Y., Aiello L.P., Pollak M.R., Zhang K. Proc. Natl. Acad. Sci. U.S.A. 105:6998-7003(2008) [PubMed: 18458324] [Abstract] Cited for: INVOLVEMENT IN SUSCEPTBILITY TO MICROVASCULAR COMPLICATIONS OF DIABETES TYPE 2.
+	Additional computationally mapped references.

Web resources

R&D Systems' cytokine source book: Erythropoietin

Wikipedia

Erythropoietin entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

X02158 Genomic DNA. Translation: CAA26095.1.
X02157 mRNA. Translation: CAA26094.1.
M11319 Genomic DNA. Translation: AAA52400.1.
AF053356 Genomic DNA. Translation: AAC78791.1.
AF202308, AF202306, AF202307 Genomic DNA. Translation: AAF23132.1.
AF202310, AF202309 Genomic DNA. Translation: AAF23133.1.
AF202311 Genomic DNA. Translation: AAF17572.1.
AF202314, AF202312, AF202313 Genomic DNA. Translation: AAF23134.1.
AC009488 Genomic DNA. Translation: AAP22357.1.
BC093628 mRNA. Translation: AAH93628.1.
BC111937 mRNA. Translation: AAI11938.1.
S65458 mRNA. Translation: AAD13964.1.

IPI

IPI00307226.

PIR

ZUHU. A01855.

RefSeq

NP_000790.2.

UniGene

Hs.2303

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1BUY	NMR	-	A	28-193	[»]
1CN4	X-ray	2.80	C	28-193	[»]
1EER	X-ray	1.90	A	28-193	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:5731N.

IntAct

P01588. 2 interactions.

PTM databases

GlycoSuiteDB

P01588.

Proteomic databases

PRIDE

P01588.

Genome annotation databases

Ensembl

ENSG00000130427. Homo sapiens. [Contig view]

GeneID

2056.

KEGG

hsa:2056.

Organism-specific databases

GeneCards

GC07P100156.

H-InvDB

HIX0033695.

HGNC

HGNC:3415. EPO.

HPA

CAB010336.

MIM

133170. gene.
612623. phenotype.

PharmGKB

PA27833.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P01588.

HOVERGEN

P01588.

OMA

P01588. NVTMGCA.

Enzyme and pathway databases

Pathway_Interaction_DB

epopathway. EPO signaling pathway.
hif1_tfpathway. HIF-1-alpha transcription factor network.
a4b1_paxindep_pathway. Paxillin-independent events mediated by a4b1 and a4b7.
kitpathway. Signaling events mediated by Stem cell factor receptor (c-Kit).

Gene expression databases

ArrayExpress

P01588.

Bgee

P01588.

CleanEx

HS_EPO.

GermOnline

ENSG00000130427. Homo sapiens.

Family and domain databases

InterPro

IPR012351. 4_helix_cytokine_core.
IPR019767. EPO/TPO_CS.
IPR001323. EPO_TPO.
IPR003013. Erythroptn.
[Graphical view]

Gene3D

G3DSA:1.20.1250.10. 4_helix_cytokine_core. 1 hit.

PANTHER

PTHR10370. Erythroptn. 1 hit.

Pfam

PF00758. EPO_TPO. 1 hit.
[Graphical view]

PIRSF

PIRSF001951. EPO. 1 hit.

PRINTS

PR00272. ERYTHROPTN.

PROSITE

PS00817. EPO_TPO. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00012. Darbepoetin alfa.
DB00016. Epoetin alfa.

NextBio

8361.

SOURCE

Search...

Entry information

Entry name

EPO_HUMAN

Accession

Primary (citable) accession number: P01588
Secondary accession number(s): Q2M2L6 , Q549U2, Q9UDZ0, Q9UEZ5, Q9UHA0

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	July 21, 1986
Last modified:	June 16, 2009
This is version 106 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)