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Q9NXG6 (P4HTM_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 127. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Transmembrane prolyl 4-hydroxylase

Short name=P4H-TM
EC=1.14.11.-
Alternative name(s):
Hypoxia-inducible factor prolyl hydroxylase 4
Short name=HIF-PH4
Short name=HIF-prolyl hydroxylase 4
Short name=HPH-4
Gene names
Name:P4HTM
Synonyms:PH4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length502 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates HIF1A at 'Pro-402' and 'Pro-564'. May function as a cellular oxygen sensor and, under normoxic conditions, may target HIF through the hydroxylation for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Ref.5

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 By similarity.

Ascorbate By similarity.

Subunit structure

Homodimer. Ref.5

Subcellular location

Endoplasmic reticulum membrane; Single-pass type II membrane protein Ref.1 Ref.5.

Tissue specificity

Widely expressed with highest levels in adult pancreas, heart, skeletal muscle, brain, placenta, kidney and adrenal gland. Expressed at lower levels in epiphyseal cartilage and in fibroblasts. Ref.1 Ref.5

Induction

By hypoxia in many cultured cell lines. Ref.5

Post-translational modification

Glycosylated. Ref.5

Sequence similarities

Contains 2 EF-hand domains.

Contains 1 Fe2OG dioxygenase domain.

Sequence caution

The sequence AAH60321.1 differs from that shown. Reason: Intron retention.

The sequence BAA91045.1 differs from that shown. Reason: Erroneous initiation.

The sequence CAD28518.2 differs from that shown. Reason: Intron retention.

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q9NXG6-1)

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: Q9NXG6-2)

Also known as: b;

The sequence of this isoform differs from the canonical sequence as follows:
     359-502: YMTVLFYLNN...RAYRDARVEL → QVSPNWGLPS...WLERGGYWSS
Note: No experimental confirmation available.
Isoform 3 (identifier: Q9NXG6-3)

The sequence of this isoform differs from the canonical sequence as follows:
     358-358: R → RQVSPNWGLPSILRPGTPMTQAQPCTVGVPLGMGPGDHWVIPVSPWEHPQLGTCSVPPLPYS
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 502502Transmembrane prolyl 4-hydroxylase
PRO_0000206668

Regions

Topological domain1 – 6060Cytoplasmic Potential
Transmembrane61 – 8121Helical; Signal-anchor for type II membrane protein; Potential
Topological domain82 – 502421Lumenal Potential
Domain185 – 22036EF-hand 1
Domain224 – 25936EF-hand 2
Domain310 – 460151Fe2OG dioxygenase
Calcium binding198 – 210131 Potential
Calcium binding237 – 249132 Potential

Sites

Metal binding3281Iron By similarity
Metal binding3301Iron By similarity
Metal binding3741Iron By similarity
Binding site45112-oxoglutarate Potential

Amino acid modifications

Glycosylation3481N-linked (GlcNAc...) Potential
Glycosylation3681N-linked (GlcNAc...) Potential
Glycosylation3821N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence3581R → RQVSPNWGLPSILRPGTPMT QAQPCTVGVPLGMGPGDHWV IPVSPWEHPQLGTCSVPPLP YS in isoform 3.
VSP_007573
Alternative sequence359 – 502144YMTVL…ARVEL → QVSPNWGLPSILRPGTPMTQ AQPCTVGVPLGMGPGDHWVI PVSDALTSPHKLFTQWLERG GYWSS in isoform 2.
VSP_007574

Experimental info

Sequence conflict2131Q → K in AAH47566. Ref.3
Sequence conflict2401G → A in AAO43431. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified June 16, 2003. Version 2.
Checksum: A2DAE4ACF4A2E18C

FASTA50256,661
        10         20         30         40         50         60 
MAAAAVTGQR PETAAAEEAS RPQWAPPDHC QAQAAAGLGD GEDAPVRPLC KPRGICSRAY 

        70         80         90        100        110        120 
FLVLMVFVHL YLGNVLALLL FVHYSNGDES SDPGPQHRAQ GPGPEPTLGP LTRLEGIKVG 

       130        140        150        160        170        180 
HERKVQLVTD RDHFIRTLSL KPLLFEIPGF LTDEECRLII HLAQMKGLQR SQILPTEEYE 

       190        200        210        220        230        240 
EAMSTMQVSQ LDLFRLLDQN RDGHLQLREV LAQTRLGNGW WMTPESIQEM YAAIKADPDG 

       250        260        270        280        290        300 
DGVLSLQEFS NMDLRDFHKY MRSHKAESSE LVRNSHHTWL YQGEGAHHIM RAIRQRVLRL 

       310        320        330        340        350        360 
TRLSPEIVEL SEPLQVVRYG EGGHYHAHVD SGPVYPETIC SHTKLVANES VPFETSCRYM 

       370        380        390        400        410        420 
TVLFYLNNVT GGGETVFPVA DNRTYDEMSL IQDDVDLRDT RRHCDKGNLR VKPQQGTAVF 

       430        440        450        460        470        480 
WYNYLPDGQG WVGDVDDYSL HGGCLVTRGT KWIANNWINV DPSRARQALF QQEMARLARE 

       490        500 
GGTDSQPEWA LDRAYRDARV EL 

« Hide

Isoform 2 (b) [UniParc].

Checksum: 5540388F142E76E4
Show »

FASTA42347,211
Isoform 3 [UniParc].

Checksum: 9154ADD79EA6BE78
Show »

FASTA56363,112

References

« Hide 'large scale' references
[1]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[2]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Uterus.
[3]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 166-502 (ISOFORM 1).
Tissue: Duodenum, Hippocampus and Lung.
[4]"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. expand/collapse author list , 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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 84-502 (ISOFORM 2).
Tissue: Colon mucosa.
[5]"An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on hypoxia-inducible factor alpha."
Koivunen P., Tiainen P., Hyvaerinen J., Williams K.E., Sormunen R., Klaus S.J., Kivirikko K.I., Myllyharju J.
J. Biol. Chem. 282:30544-30552(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INDUCTION, TOPOLOGY, GLYCOSYLATION.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AY198406 mRNA. Translation: AAO43431.1.
AL713728 mRNA. Translation: CAD28518.2. Sequence problems.
BC000580 mRNA. Translation: AAH00580.1.
BC011710 mRNA. Translation: AAH11710.3.
BC047566 mRNA. Translation: AAH47566.1.
BC060321 mRNA. Translation: AAH60321.1. Sequence problems.
AK000269 mRNA. Translation: BAA91045.1. Different initiation.
CCDSCCDS2781.2. [Q9NXG6-3]
CCDS43089.1. [Q9NXG6-1]
RefSeqNP_808807.2. NM_177938.2. [Q9NXG6-3]
NP_808808.1. NM_177939.2. [Q9NXG6-1]
UniGeneHs.654944.

3D structure databases

ProteinModelPortalQ9NXG6.
SMRQ9NXG6. Positions 194-250, 263-462.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid120100. 5 interactions.
IntActQ9NXG6. 1 interaction.
STRING9606.ENSP00000341422.

Chemistry

BindingDBQ9NXG6.
ChEMBLCHEMBL3047.
DrugBankDB00126. Vitamin C.

PTM databases

PhosphoSiteQ9NXG6.

Polymorphism databases

DMDM32129516.

Proteomic databases

MaxQBQ9NXG6.
PaxDbQ9NXG6.
PRIDEQ9NXG6.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000343546; ENSP00000341422; ENSG00000178467. [Q9NXG6-3]
ENST00000383729; ENSP00000373235; ENSG00000178467. [Q9NXG6-1]
ENST00000475629; ENSP00000477191; ENSG00000178467.
GeneID54681.
KEGGhsa:54681.
UCSCuc003cvg.3. human. [Q9NXG6-1]
uc003cvh.3. human. [Q9NXG6-3]

Organism-specific databases

CTD54681.
GeneCardsGC03P049027.
HGNCHGNC:28858. P4HTM.
HPAHPA007199.
MIM614584. gene.
neXtProtNX_Q9NXG6.
PharmGKBPA164724295.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG284419.
HOGENOMHOG000115323.
KOK06711.
OMANMDLRDF.
OrthoDBEOG7VDXP9.
PhylomeDBQ9NXG6.
TreeFamTF332923.

Gene expression databases

BgeeQ9NXG6.
GenevestigatorQ9NXG6.

Family and domain databases

Gene3D1.10.238.10. 1 hit.
InterProIPR011992. EF-hand-dom_pair.
IPR018247. EF_Hand_1_Ca_BS.
IPR002048. EF_hand_dom.
IPR005123. Oxoglu/Fe-dep_dioxygenase.
IPR006620. Pro_4_hyd_alph.
[Graphical view]
PfamPF13640. 2OG-FeII_Oxy_3. 1 hit.
PF13202. EF-hand_5. 1 hit.
[Graphical view]
SMARTSM00702. P4Hc. 1 hit.
[Graphical view]
PROSITEPS00018. EF_HAND_1. 2 hits.
PS51471. FE2OG_OXY. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSP4HTM. human.
GenomeRNAi54681.
NextBio57244.
PROQ9NXG6.
SOURCESearch...

Entry information

Entry nameP4HTM_HUMAN
AccessionPrimary (citable) accession number: Q9NXG6
Secondary accession number(s): Q6PAG6 expand/collapse secondary AC list , Q8TCJ9, Q8WV55, Q96F22, Q9BW77
Entry history
Integrated into UniProtKB/Swiss-Prot: June 16, 2003
Last sequence update: June 16, 2003
Last modified: July 9, 2014
This is version 127 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 3

Human chromosome 3: entries, gene names and cross-references to MIM