Reviewed, UniProtKB/Swiss-Prot Q9GZT9 (EGLN1_HUMAN)

Names and origin

Protein names

Recommended name:
    Egl nine homolog 1
    EC=1.14.11.-
Alternative name(s):
    Hypoxia-inducible factor prolyl hydroxylase 2
      Short name=HIF-prolyl hydroxylase 2
      Short name=HIF-PH2
      Short name=HPH-2
    Prolyl hydroxylase domain-containing protein 2
      Short name=PHD2
    SM-20

Gene names

Name:	EGLN1
Synonyms:	C1orf12
ORF Names:	PNAS-118, PNAS-137

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	426 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates HIF-1 alpha at 'Pro-402' and 'Pro-564', and HIF-2 alpha. Functions as a cellular oxygen sensor and, under normoxic conditions, targets HIF through the hydroxylation for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Ref.7 Ref.8
Catalytic activity	An HIF alpha chain L-proline + 2-oxoglutarate + O2 = An HIF alpha chain trans-4-hydroxy-L-proline + succinate + CO2.
Cofactor	Binds 1 Fe2+ ion per subunit. Ascorbate.
Enzyme regulation	Following exposure to hypoxia, activated in HeLa cells but not in cardiovascular cells. Seems to be inhibited by ING4. Ref.10 Ref.11
Subunit structure	Monomer. Interacts with ING4. Ref.11 Ref.13
Tissue specificity	According to Ref.1 widely expressed with highest levels in skeletal muscle and heart, moderate levels in pancreas, brain (dopaminergic neurons of adult and fetal substantia nigra) and kidney, and lower levels in lung and liver. According to Ref.8 widely expressed with highest levels in brain, kidney and adrenal gland. Expressed in cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle. Ref.10 Ref.1 Ref.9
Involvement in disease	Defects in EGLN1 are the cause of erythrocytosis familial type 3 (ECYT3) [MIM:609820]. ECYT3 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels. Ref.14 Ref.15
Sequence similarities	Contains 1 MYND-type zinc finger. Contains 1 PKHD (prolyl/lysyl hydroxylase) domain.
Caution	It was previously reported that this protein was the ortholog of rat SM-20. However, EGLN3 is now considered the true ortholog of rat SM-20 since it shows substantially greater similarity.
Sequence caution	The sequence AAK07536.1 differs from that shown. Reason: Frameshift at position 239.

Ontologies

Keywords
Coding sequence diversity	Alternative splicing
Disease	Congenital erythrocytosis Disease mutation
Domain	Zinc-finger
Ligand	Iron Metal-binding Vitamin C Zinc
Molecular function	Dioxygenase Oxidoreductase
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	negative regulation of transcription factor activity Inferred from direct assay. Source: HGNC oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW oxygen homeostasis Inferred from direct assay. Source: HGNC response to hypoxia Inferred from direct assay. Source: HGNC
Cellular component	cytosol Traceable author statement. Source: ProtInc
Molecular function	L-ascorbic acid binding Inferred from electronic annotation. Source: UniProtKB-KW iron ion binding Inferred from electronic annotation. Source: UniProtKB-KW oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen Inferred from electronic annotation. Source: UniProtKB-KW peptidyl-proline dioxygenase activity Traceable author statement. Source: HGNC protein binding Inferred from physical interaction. Source: IntAct zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
OS9	Q13438	1	EBI-1174818,EBI-1174342

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9GZT9-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q9GZT9-2)

The sequence of this isoform differs from the canonical sequence as follows:
     337-358: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 426

426

Egl nine homolog 1

PRO_0000206661

Regions

Domain

205 – 391

187

PKHD

Zinc finger

21 – 58

38

MYND-type

Sites

Metal binding

313

1

Iron

Metal binding

315

1

Iron

Metal binding

374

1

Iron

Binding site

383

1

2-oxoglutarate Probable

Natural variations

Alternative sequence

337 – 358

22

Missing in isoform 2.

VSP_007569

Natural variant

317

1

P → R in ECYT3; marked decrease in enzyme activity. Ref.14

VAR_027371

Natural variant

371

1

R → H in ECYT3; decreased interaction with HIF1A and HIF2A and decreased enzyme activity. Ref.15

VAR_045902

Experimental info

Mutagenesis

303

1

Y → F: No effect. Ref.13

Mutagenesis

383

1

R → A: Reduces enzyme activity by 95%. Ref.13

Secondary structure

1

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426

Helix Strand Turn

Details...

Helix

190 – 196

7

Helix

198 – 205

8

Beta strand

206 – 214

9

Helix

216 – 232

17

Beta strand

255 – 259

5

Helix

267 – 282

16

Turn

283 – 286

4

Beta strand

287 – 289

3

Beta strand

292 – 295

4

Beta strand

298 – 303

6

Beta strand

305 – 307

3

Beta strand

310 – 313

4

Beta strand

321 – 329

9

Helix

336 – 339

4

Beta strand

343 – 345

3

Beta strand

354 – 356

3

Beta strand

362 – 367

6

Beta strand

374 – 376

3

Beta strand

379 – 381

3

Beta strand

383 – 392

10

Helix

393 – 399

7

Turn

400 – 402

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified March 1, 2001. Version 1. Checksum: 81A97FF772CAA14C	FASTA	426	46,021
	10 20 30 40 50 60 MANDSGGPGG PSPSERDRQY CELCGKMENL LRCSRCRSSF YCCKEHQRQD WKKHKLVCQG 70 80 90 100 110 120 SEGALGHGVG PHQHSGPAPP AAVPPPRAGA REPRKAAARR DNASGDAAKG KVKAKPPADP 130 140 150 160 170 180 AAAASPCRAA AGGQGSAVAA EAEPGKEEPP ARSSLFQEKA NLYPPSNTPG DALSPGGGLR 190 200 210 220 230 240 PNGQTKPLPA LKLALEYIVP CMNKHGICVV DDFLGKETGQ QIGDEVRALH DTGKFTDGQL 250 260 270 280 290 300 VSQKSDSSKD IRGDKITWIE GKEPGCETIG LLMSSMDDLI RHCNGKLGSY KINGRTKAMV 310 320 330 340 350 360 ACYPGNGTGY VRHVDNPNGD GRCVTCIYYL NKDWDAKVSG GILRIFPEGK AQFADIEPKF 370 380 390 400 410 420 DRLLFFWSDR RNPHEVQPAY ATRYAITVWY FDADERARAK VKYLTGEKGV RVELNKPSDS VGKDVF
	Isoform 2. Checksum: 32B08D27CD89A8B9	FASTA	404	43,666
	10 20 30 40 50 60 MANDSGGPGG PSPSERDRQY CELCGKMENL LRCSRCRSSF YCCKEHQRQD WKKHKLVCQG 70 80 90 100 110 120 SEGALGHGVG PHQHSGPAPP AAVPPPRAGA REPRKAAARR DNASGDAAKG KVKAKPPADP 130 140 150 160 170 180 AAAASPCRAA AGGQGSAVAA EAEPGKEEPP ARSSLFQEKA NLYPPSNTPG DALSPGGGLR 190 200 210 220 230 240 PNGQTKPLPA LKLALEYIVP CMNKHGICVV DDFLGKETGQ QIGDEVRALH DTGKFTDGQL 250 260 270 280 290 300 VSQKSDSSKD IRGDKITWIE GKEPGCETIG LLMSSMDDLI RHCNGKLGSY KINGRTKAMV 310 320 330 340 350 360 ACYPGNGTGY VRHVDNPNGD GRCVTCIYYL NKDWDAKFDR LLFFWSDRRN PHEVQPAYAT 370 380 390 400 RYAITVWYFD ADERARAKVK YLTGEKGVRV ELNKPSDSVG KDVF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Mapping, characterization, and expression analysis of the SM-20 human homologue, C1orf12, and identification of a novel related gene, SCAND2." Dupuy D., Aubert I., Duperat V.G., Petit J., Taine L., Stef M., Bloch B., Arveiler B. Genomics 69:348-354(2000) [PubMed: 11056053] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), TISSUE SPECIFICITY.
[2]	"Characterization and comparative analysis of the EGLN gene family." Taylor M.S. Gene 275:125-132(2001) [PubMed: 11574160] [Abstract] Cited for: NUCLEOTIDE SEQUENCE (ISOFORM 1).
[3]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed: 17974005] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 160-426 (ISOFORM 1). Tissue: Amygdala.
[4]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"Human acute promyelocytic leukemia cell line NB4's apoptosis related genes." Yu W.-Q., Sun B.-Z., Chai Y.-B., Zhu F., Liu X.-S., Li Z., Lu F., Yan W., Yang H., Zhao Z.-L. Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 136-426 (ISOFORM 2). Tissue: Promyelocytic leukemia.
[6]	"HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus." Semenza G.L. Cell 107:1-3(2001) [PubMed: 11595178] [Abstract] Cited for: REVIEW.
[7]	"C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation." Epstein A.C.R., Gleadle J.M., McNeill L.A., Hewitson K.S., O'Rourke J., Mole D.R., Mukherji M., Metzen E., Wilson M.I., Dhanda A., Tian Y.M., Masson N., Hamilton D.L., Jaakkola P., Barstead R., Hodgkin J., Maxwell P.H., Pugh C.W., Schofield C.J., Ratcliffe P.J. Cell 107:43-54(2001) [PubMed: 11595184] [Abstract] Cited for: FUNCTION.
[8]	"Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor." Ivan M., Haberberger T., Gervasi D.C., Michelson K.S., Guenzler V., Kondo K., Yang H., Sorokina I., Conaway R.C., Conaway J.W., Kaelin W.G. Jr. Proc. Natl. Acad. Sci. U.S.A. 99:13459-13464(2002) [PubMed: 12351678] [Abstract] Cited for: FUNCTION.
[9]	"Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors." Oehme F., Ellinghaus P., Kolkhof P., Smith T.J., Ramakrishnan S., Huetter J., Schramm M., Flamme I. Biochem. Biophys. Res. Commun. 296:343-349(2002) [PubMed: 12163023] [Abstract] Cited for: TISSUE SPECIFICITY.
[10]	"Differential regulation of HIF-1alpha prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells." Cioffi C.L., Qin Liu X., Kosinski P.A., Garay M., Bowen B.R. Biochem. Biophys. Res. Commun. 303:947-953(2003) [PubMed: 12670503] [Abstract] Cited for: TISSUE SPECIFICITY, ENZYME REGULATION.
[11]	"The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF)." Ozer A., Wu L.C., Bruick R.K. Proc. Natl. Acad. Sci. U.S.A. 102:7481-7486(2005) [PubMed: 15897452] [Abstract] Cited for: INTERACTION WITH ING4, ENZYME REGULATION.
[12]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[13]	"Cellular oxygen sensing: crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2)." McDonough M.A., Li V., Flashman E., Chowdhury R., Mohr C., Lienard B.M.R., Zondlo J., Oldham N.J., Clifton I.J., Lewis J., McNeill L.A., Kurzeja R.J., Hewitson K.S., Yang E., Jordan S., Syed R.S., Schofield C.J. Proc. Natl. Acad. Sci. U.S.A. 103:9814-9819(2006) [PubMed: 16782814] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 181-417 IN COMPLEXES WITH IRON AND COMPETITIVE INHIBITOR, MUTAGENESIS OF TYR-303 AND ARG-383, SUBUNIT.
[14]	"A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis." Percy M.J., Zhao Q., Flores A., Harrison C., Lappin T.R., Maxwell P.H., McMullin M.F., Lee F.S. Proc. Natl. Acad. Sci. U.S.A. 103:654-659(2006) [PubMed: 16407130] [Abstract] Cited for: VARIANT ECYT3 ARG-317, CHARACTERIZATION OF VARIANT ECYT3 ARG-317.
[15]	"A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove." Percy M.J., Furlow P.W., Beer P.A., Lappin T.R.J., McMullin M.F., Lee F.S. Blood 110:2193-2196(2007) [PubMed: 17579185] [Abstract] Cited for: VARIANT ECYT3 HIS-371, CHARACTERIZATION OF VARIANT EXCYT3 HIS-371.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBLGenBankDDBJ

AF246631, AF246630 Genomic DNA. Translation: AAG34568.1.
AF229245 mRNA. Translation: AAG33965.1.
AJ310543 mRNA. Translation: CAC42509.1.
AL833885 mRNA. Translation: CAD38741.2.
AF277174 mRNA. Translation: AAK07534.1. Different initiation.
AF277176 mRNA. Translation: AAK07536.1. Frameshift.
AL117352, AL445524 Genomic DNA. Translation: CAI23092.1.
AL445524, AL117352 Genomic DNA. Translation: CAH72105.1.

IPI

IPI00004928.
IPI00328822.

RefSeq

NP_071334.1.

UniGene

Hs.444450

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2G19	X-ray	1.70	A	181-417	[»]
2G1M	X-ray	2.20	A	181-426	[»]
2HBT	X-ray	1.60	A	188-426	[»]
2HBU	X-ray	1.85	A	188-426	[»]
3HQR	X-ray	2.00	A	181-426	[»]
3HQU	X-ray	2.30	A	181-426	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9GZT9. 2 interactions.

STRING

Q9GZT9.

PTM databases

PhosphoSite

Q9GZT9.

Proteomic databases

PRIDE

Q9GZT9.

Genome annotation databases

Ensembl

ENST00000366641; ENSP00000355601; ENSG00000135766; Homo sapiens. [Genome view]

GeneID

54583.

KEGG

hsa:54583.

UCSC

uc001huv.1. human.

Organism-specific databases

CTD

54583.

GeneCards

GC01M229566.

H-InvDB

HIX0019816.

HGNC

HGNC:1232. EGLN1.

HPA

HPA022129.

MIM

606425. gene.
609820. phenotype.

Orphanet

90042. Primary familial polycythemia.

PharmGKB

PA27670.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

Q9GZT9.

HOVERGEN

Q9GZT9.

OMA

QEKANLY.

Enzyme and pathway databases

BRENDA

1.14.11.2. 247.

Pathway_Interaction_DB

hif1_tfpathway. HIF-1-alpha transcription factor network.
hif1apathway. Hypoxic and oxygen homeostasis regulation of HIF-1-alpha.

Gene expression databases

ArrayExpress

Q9GZT9.

Bgee

Q9GZT9.

CleanEx

HS_EGLN1.

Genevestigator

Q9GZT9.

GermOnline

ENSG00000135766. Homo sapiens.

Family and domain databases

InterPro

IPR005123. Oxoglutarate/Fe-dep_oxygenase.
IPR006620. Pro_4_hyd_alph.
IPR002893. Znf_MYND.
[Graphical view]

Pfam

PF03171. 2OG-FeII_Oxy. 1 hit.
PF01753. zf-MYND. 1 hit.
[Graphical view]

SMART

SM00702. P4Hc. 1 hit.
[Graphical view]

PROSITE

PS01360. ZF_MYND_1. 1 hit.
PS50865. ZF_MYND_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00126. Vitamin C.

NextBio

57101.

SOURCE

Search...

Entry information

Entry name

EGLN1_HUMAN

Accession

Primary (citable) accession number: Q9GZT9
Secondary accession number(s): Q8N3M8, Q9BZS8, Q9BZT0

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 16, 2003
Last sequence update:	March 1, 2001
Last modified:	November 3, 2009
This is version 83 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.