Reviewed, UniProtKB/Swiss-Prot Q9NWT6 (HIF1N_HUMAN)

Names and origin

Protein names

Recommended name:
    Hypoxia-inducible factor 1-alpha inhibitor
    EC=1.14.11.16
Alternative name(s):
    Hypoxia-inducible factor asparagine hydroxylase
    Factor inhibiting HIF-1
      Short name=FIH-1

Gene names

Name:	HIF1AN
Synonyms:	FIH1

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	349 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	Hydroxylates HIF-1 alpha at 'Asp-803' in the C-terminal transactivation domain (CAD). Functions as an oxygen sensor and, under normoxic conditions, the hydroxylation prevents interaction of HIF-1 with transcriptional coactivators including Cbp/p300-interacting transactivator. Involved in transcriptional repression through interaction with HIF1A, VHL and histone deacetylases. Ref.6 Ref.7
Catalytic activity	Peptide L-aspartate + 2-oxoglutarate + O2 = peptide 3-hydroxy-L-aspartate + succinate + CO2. Ref.6 Ref.7
Cofactor	Iron.
Subunit structure	Homodimer. Interacts with VHL and HIF1A. Part of a complex with VHL, HIF1A and HDAC1 or HDAC2 or HDAC3. Ref.1 Ref.9
Subcellular location	Nucleus Potential.
Sequence similarities	Contains 1 JmjC domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Ligand	Iron Metal-binding
Molecular function	Dioxygenase Oxidoreductase
PTM	Acetylation
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW regulation of transcription Inferred from electronic annotation. Source: UniProtKB-KW transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	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 peptide-aspartate beta-dioxygenase activity Inferred from electronic annotation. Source: EC protein binding Ref.10 Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
HIF1A	Q16665	1	EBI-745632,EBI-447269

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed

Chain

2 – 349

348

Hypoxia-inducible factor 1-alpha inhibitor

PRO_0000083974

Regions

Domain

142 – 312

171

JmjC

Region

2 – 349

348

Interaction with VHL

Region

126 – 349

224

Interaction with HIF1A

Sites

Metal binding

199

1

Iron; catalytic

Metal binding

201

1

Iron; catalytic

Metal binding

279

1

Iron; catalytic

Binding site

145

1

2-oxoglutarate

Binding site

196

1

2-oxoglutarate

Binding site

214

1

2-oxoglutarate

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.8

Natural variations

Natural variant

41

1

P → A: dbSNP rs2295778.

VAR_051028

Experimental info

Mutagenesis

199

1

H → A: Prevents suppression of HIF CAD activity. Ref.6

Mutagenesis

201

1

D → A: Prevents suppression of HIF CAD activity. Ref.6

Sequence conflict

10

1

A → T in BAA91291. Ref.2

Sequence conflict

28

1

D → H in BAA91291. Ref.2

Sequence conflict

156

1

R → G in BAA91291. Ref.2

Secondary structure

1

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349

Helix Strand Turn

Details...

Turn

20 – 22

3

Helix

29 – 31

3

Beta strand

39 – 41

3

Helix

50 – 57

8

Beta strand

62 – 65

4

Helix

71 – 75

5

Helix

78 – 84

7

Beta strand

90 – 99

10

Helix

105 – 111

7

Beta strand

117 – 123

7

Helix

125 – 137

13

Beta strand

143 – 149

7

Helix

156 – 163

8

Helix

167 – 177

11

Beta strand

182 – 184

3

Beta strand

186 – 190

5

Beta strand

195 – 199

5

Beta strand

202 – 212

11

Beta strand

214 – 219

6

Helix

221 – 223

3

Helix

224 – 227

4

Turn

235 – 238

4

Turn

249 – 251

3

Helix

253 – 257

5

Beta strand

260 – 265

6

Beta strand

270 – 273

4

Beta strand

278 – 283

6

Beta strand

290 – 298

9

Helix

312 – 330

19

Helix

333 – 335

3

Helix

336 – 344

9

Turn

345 – 347

3

Sequences

	Sequence		Length	Mass (Da)
	Q9NWT6-1 [UniParc]. Last modified June 16, 2003. Version 2. Checksum: 96A033BA7B3BD8C7	FASTA	349	40,285
	10 20 30 40 50 60 MAATAAEAVA SGSGEPREEA GALGPAWDES QLRSYSFPTR PIPRLSQSDP RAEELIENEE 70 80 90 100 110 120 PVVLTDTNLV YPALKWDLEY LQENIGNGDF SVYSASTHKF LYYDEKKMAN FQNFKPRSNR 130 140 150 160 170 180 EEMKFHEFVE KLQDIQQRGG EERLYLQQTL NDTVGRKIVM DFLGFNWNWI NKQQGKRGWG 190 200 210 220 230 240 QLTSNLLLIG MEGNVTPAHY DEQQNFFAQI KGYKRCILFP PDQFECLYPY PVHHPCDRQS 250 260 270 280 290 300 QVDFDNPDYE RFPNFQNVVG YETVVGPGDV LYIPMYWWHH IESLLNGGIT ITVNFWYKGA 310 320 330 340 PTPKRIEYPL KAHQKVAIMR NIEKMLGEAL GNPQEVGPLL NTMIKGRYN

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity." Mahon P.C., Hirota K., Semenza G.L. Genes Dev. 15:2675-2686(2001) [PubMed: 11641274] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH HIF1A; VHL AND HISTONE DEACETYLASES. Tissue: Brain.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"The DNA sequence and comparative analysis of human chromosome 10." Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., Taylor A., Battles J. , Bird C.P., Ainscough R., Almeida J.P., Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J. Nature 429:375-381(2004) [PubMed: 15164054] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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: Muscle.
[5]	"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 89-349. Tissue: Melanoma.
[6]	"FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor." Lando D., Peet D.J., Gorman J.J., Whelan D.A., Whitelaw M.L., Bruick R.K. Genes Dev. 16:1466-1471(2002) [PubMed: 12080085] [Abstract] Cited for: CATALYTIC ACTIVITY, FUNCTION, MUTAGENESIS OF HIS-199 AND ASP-201.
[7]	"Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family." Hewitson K.S., McNeill L.A., Riordan M.V., Tian Y.-M., Bullock A.N., Welford R.W., Elkins J.M., Oldham N.J., Bhattacharya S., Gleadle J.M., Ratcliffe P.J., Pugh C.W., Schofield C.J. J. Biol. Chem. 277:26351-26355(2002) [PubMed: 12042299] [Abstract] Cited for: CATALYTIC ACTIVITY, FUNCTION.
[8]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY.
[9]	"Structure of factor-inhibiting hypoxia-inducible factor 1: an asparaginyl hydroxylase involved in the hypoxic response pathway." Dann C.E. III, Bruick R.K., Deisenhofer J. Proc. Natl. Acad. Sci. U.S.A. 99:15351-15356(2002) [PubMed: 12432100] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS), SUBUNIT.
[10]	"Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1 alpha." Elkins J.M., Hewitson K.S., McNeill L.A., Seibel J.F., Schlemminger I., Pugh C.W., Ratcliffe P.J., Schofield C.J. J. Biol. Chem. 278:1802-1806(2003) [PubMed: 12446723] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) IN COMPLEX WITH 786-826 OF HIF1A.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF395830 mRNA. Translation: AAL27308.1.
AK000622 mRNA. Translation: BAA91291.1.
AL133352 Genomic DNA. Translation: CAH73566.1.
BC007719 mRNA. Translation: AAH07719.1.
AL359615 mRNA. Translation: CAB94885.1.

IPI

IPI00941238.

PIR

T50633.

RefSeq

NP_060372.2.

UniGene

Hs.500788

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1H2K	X-ray	2.15	A	1-349	[»]
1H2L	X-ray	2.25	A	1-349	[»]
1H2M	X-ray	2.50	A	1-349	[»]
1H2N	X-ray	2.84	A	1-349	[»]
1IZ3	X-ray	2.80	A	1-349	[»]
1MZE	X-ray	2.20	A	1-349	[»]
1MZF	X-ray	2.40	A	1-349	[»]
1YCI	X-ray	2.70	A	1-349	[»]
2CGN	X-ray	2.40	A	1-349	[»]
2CGO	X-ray	2.30	A	1-349	[»]
2ILM	X-ray	2.30	A	1-349	[»]
2W0X	X-ray	2.12	A	1-349	[»]
3D8C	X-ray	2.10	A	11-349	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

Q9NWT6. 5 interactions.

STRING

Q9NWT6.

Proteomic databases

PRIDE

Q9NWT6.

Genome annotation databases

Ensembl

ENST00000299163; ENSP00000299163; ENSG00000166135; Homo sapiens. [Genome view]
ENST00000442724; ENSP00000399734; ENSG00000166135; Homo sapiens. [Genome view]

GeneID

55662.

KEGG

hsa:55662.

UCSC

uc001krj.2. human.

Organism-specific databases

CTD

55662.

GeneCards

GC10P102285.

H-InvDB

HIX0009127.

HGNC

HGNC:17113. HIF1AN.

MIM

606615. gene.

PharmGKB

PA29284.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG05011.

HOVERGEN

Q9NWT6.

InParanoid

Q9NWT6.

OrthoDB

EOG9M682Z.

PhylomeDB

Q9NWT6.

Enzyme and pathway databases

BRENDA

1.14.11.16. 247.

Pathway_Interaction_DB

hif1apathway. Hypoxic and oxygen homeostasis regulation of HIF-1-alpha.

Gene expression databases

ArrayExpress

Q9NWT6.

Bgee

Q9NWT6.

CleanEx

HS_HIF1AN.

Genevestigator

Q9NWT6.

GermOnline

ENSG00000166135. Homo sapiens.

Family and domain databases

InterPro

IPR003347. TF_JmjC_AAH.
[Graphical view]

SMART

SM00558. JmjC. 1 hit.
[Graphical view]

PROSITE

PS51184. JMJC. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

60403.

SOURCE

Search...

Entry information

Entry name

HIF1N_HUMAN

Accession

Primary (citable) accession number: Q9NWT6
Secondary accession number(s): Q5W147, Q969Q7, Q9NPV5

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 16, 2003
Last sequence update:	June 16, 2003
Last modified:	February 9, 2010
This is version 83 of the entry and version 2 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.