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Protein

Transmembrane prolyl 4-hydroxylase

Gene

P4HTM

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.1 Publication

Catalytic activityi

An HIF alpha chain L-proline + 2-oxoglutarate + O2 = An HIF alpha chain trans-4-hydroxy-L-proline + succinate + CO2.

Cofactori

Protein has several cofactor binding sites:
  • Fe2+PROSITE-ProRule annotationNote: Binds 1 Fe2+ ion per subunit.PROSITE-ProRule annotation
  • L-ascorbateBy similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi328 – 3281IronPROSITE-ProRule annotation
Metal bindingi330 – 3301IronPROSITE-ProRule annotation
Metal bindingi374 – 3741IronPROSITE-ProRule annotation
Binding sitei451 – 45112-oxoglutaratePROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Calcium bindingi198 – 210131Sequence AnalysisAdd
BLAST
Calcium bindingi237 – 249132Sequence AnalysisAdd
BLAST

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Dioxygenase, Oxidoreductase

Keywords - Ligandi

Calcium, Iron, Metal-binding, Vitamin C

Names & Taxonomyi

Protein namesi
Recommended name:
Transmembrane prolyl 4-hydroxylase (EC:1.14.11.-)
Short name:
P4H-TM
Alternative name(s):
Hypoxia-inducible factor prolyl hydroxylase 4
Short name:
HIF-PH4
Short name:
HIF-prolyl hydroxylase 4
Short name:
HPH-4
Gene namesi
Name:P4HTM
Synonyms:PH4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640 Componenti: Chromosome 3

Organism-specific databases

HGNCiHGNC:28858. P4HTM.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 6060CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei61 – 8121Helical; Signal-anchor for type II membrane proteinSequence AnalysisAdd
BLAST
Topological domaini82 – 502421LumenalSequence AnalysisAdd
BLAST

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA164724295.

Chemistry

DrugBankiDB00126. Vitamin C.

Polymorphism and mutation databases

BioMutaiP4HTM.
DMDMi32129516.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 502502Transmembrane prolyl 4-hydroxylasePRO_0000206668Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi348 – 3481N-linked (GlcNAc...)Sequence Analysis
Glycosylationi368 – 3681N-linked (GlcNAc...)Sequence Analysis
Glycosylationi382 – 3821N-linked (GlcNAc...)Sequence Analysis

Post-translational modificationi

Glycosylated.1 Publication

Keywords - PTMi

Glycoprotein

Proteomic databases

MaxQBiQ9NXG6.
PaxDbiQ9NXG6.
PRIDEiQ9NXG6.

PTM databases

PhosphoSiteiQ9NXG6.

Expressioni

Tissue specificityi

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.2 Publications

Inductioni

By hypoxia in many cultured cell lines.1 Publication

Gene expression databases

BgeeiQ9NXG6.
ExpressionAtlasiQ9NXG6. baseline and differential.
GenevisibleiQ9NXG6. HS.

Organism-specific databases

HPAiHPA007199.

Interactioni

Subunit structurei

Homodimer.1 Publication

Protein-protein interaction databases

BioGridi120100. 5 interactions.
IntActiQ9NXG6. 1 interaction.
STRINGi9606.ENSP00000341422.

Structurei

3D structure databases

ProteinModelPortaliQ9NXG6.
SMRiQ9NXG6. Positions 193-252, 263-462.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini185 – 22036EF-hand 1Add
BLAST
Domaini224 – 25936EF-hand 2Add
BLAST
Domaini310 – 460151Fe2OG dioxygenasePROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

Contains 2 EF-hand domains.Curated
Contains 1 Fe2OG dioxygenase domain.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG284419.
GeneTreeiENSGT00390000014570.
HOGENOMiHOG000115323.
InParanoidiQ9NXG6.
KOiK06711.
OMAiNMDLRDF.
OrthoDBiEOG7VDXP9.
PhylomeDBiQ9NXG6.
TreeFamiTF332923.

Family and domain databases

Gene3Di1.10.238.10. 1 hit.
InterProiIPR011992. 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]
PfamiPF13640. 2OG-FeII_Oxy_3. 1 hit.
PF13202. EF-hand_5. 1 hit.
[Graphical view]
SMARTiSM00702. P4Hc. 1 hit.
[Graphical view]
PROSITEiPS00018. EF_HAND_1. 2 hits.
PS51471. FE2OG_OXY. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9NXG6-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MAAAAVTGQR PETAAAEEAS RPQWAPPDHC QAQAAAGLGD GEDAPVRPLC
60 70 80 90 100
KPRGICSRAY FLVLMVFVHL YLGNVLALLL FVHYSNGDES SDPGPQHRAQ
110 120 130 140 150
GPGPEPTLGP LTRLEGIKVG HERKVQLVTD RDHFIRTLSL KPLLFEIPGF
160 170 180 190 200
LTDEECRLII HLAQMKGLQR SQILPTEEYE EAMSTMQVSQ LDLFRLLDQN
210 220 230 240 250
RDGHLQLREV LAQTRLGNGW WMTPESIQEM YAAIKADPDG DGVLSLQEFS
260 270 280 290 300
NMDLRDFHKY MRSHKAESSE LVRNSHHTWL YQGEGAHHIM RAIRQRVLRL
310 320 330 340 350
TRLSPEIVEL SEPLQVVRYG EGGHYHAHVD SGPVYPETIC SHTKLVANES
360 370 380 390 400
VPFETSCRYM TVLFYLNNVT GGGETVFPVA DNRTYDEMSL IQDDVDLRDT
410 420 430 440 450
RRHCDKGNLR VKPQQGTAVF WYNYLPDGQG WVGDVDDYSL HGGCLVTRGT
460 470 480 490 500
KWIANNWINV DPSRARQALF QQEMARLARE GGTDSQPEWA LDRAYRDARV

EL
Length:502
Mass (Da):56,661
Last modified:June 16, 2003 - v2
Checksum:iA2DAE4ACF4A2E18C
GO
Isoform 2 (identifier: Q9NXG6-2) [UniParc]FASTAAdd to basket

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.
Show »
Length:423
Mass (Da):47,211
Checksum:i5540388F142E76E4
GO
Isoform 3 (identifier: Q9NXG6-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     358-358: R → RQVSPNWGLPSILRPGTPMTQAQPCTVGVPLGMGPGDHWVIPVSPWEHPQLGTCSVPPLPYS

Note: No experimental confirmation available.
Show »
Length:563
Mass (Da):63,112
Checksum:i9154ADD79EA6BE78
GO

Sequence cautioni

The sequence AAH60321.1 differs from that shown.Intron retention.Curated
The sequence BAA91045.1 differs from that shown. Reason: Erroneous initiation. Curated
The sequence CAD28518.2 differs from that shown.Intron retention.Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti213 – 2131Q → K in AAH47566 (PubMed:15489334).Curated
Sequence conflicti240 – 2401G → A in AAO43431 (PubMed:12163023).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei358 – 3581R → RQVSPNWGLPSILRPGTPMT QAQPCTVGVPLGMGPGDHWV IPVSPWEHPQLGTCSVPPLP YS in isoform 3. 1 PublicationVSP_007573
Alternative sequencei359 – 502144YMTVL…ARVEL → QVSPNWGLPSILRPGTPMTQ AQPCTVGVPLGMGPGDHWVI PVSDALTSPHKLFTQWLERG GYWSS in isoform 2. 2 PublicationsVSP_007574Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS2781.2. [Q9NXG6-3]
CCDS43089.1. [Q9NXG6-1]
RefSeqiNP_808807.2. NM_177938.2. [Q9NXG6-3]
NP_808808.1. NM_177939.2. [Q9NXG6-1]
UniGeneiHs.654944.

Genome annotation databases

EnsembliENST00000343546; ENSP00000341422; ENSG00000178467. [Q9NXG6-3]
ENST00000383729; ENSP00000373235; ENSG00000178467.
GeneIDi54681.
KEGGihsa:54681.
UCSCiuc003cvg.3. human. [Q9NXG6-1]
uc003cvh.3. human. [Q9NXG6-3]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS2781.2. [Q9NXG6-3]
CCDS43089.1. [Q9NXG6-1]
RefSeqiNP_808807.2. NM_177938.2. [Q9NXG6-3]
NP_808808.1. NM_177939.2. [Q9NXG6-1]
UniGeneiHs.654944.

3D structure databases

ProteinModelPortaliQ9NXG6.
SMRiQ9NXG6. Positions 193-252, 263-462.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi120100. 5 interactions.
IntActiQ9NXG6. 1 interaction.
STRINGi9606.ENSP00000341422.

Chemistry

BindingDBiQ9NXG6.
ChEMBLiCHEMBL3047.
DrugBankiDB00126. Vitamin C.

PTM databases

PhosphoSiteiQ9NXG6.

Polymorphism and mutation databases

BioMutaiP4HTM.
DMDMi32129516.

Proteomic databases

MaxQBiQ9NXG6.
PaxDbiQ9NXG6.
PRIDEiQ9NXG6.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000343546; ENSP00000341422; ENSG00000178467. [Q9NXG6-3]
ENST00000383729; ENSP00000373235; ENSG00000178467.
GeneIDi54681.
KEGGihsa:54681.
UCSCiuc003cvg.3. human. [Q9NXG6-1]
uc003cvh.3. human. [Q9NXG6-3]

Organism-specific databases

CTDi54681.
GeneCardsiGC03P049027.
HGNCiHGNC:28858. P4HTM.
HPAiHPA007199.
MIMi614584. gene.
neXtProtiNX_Q9NXG6.
PharmGKBiPA164724295.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG284419.
GeneTreeiENSGT00390000014570.
HOGENOMiHOG000115323.
InParanoidiQ9NXG6.
KOiK06711.
OMAiNMDLRDF.
OrthoDBiEOG7VDXP9.
PhylomeDBiQ9NXG6.
TreeFamiTF332923.

Miscellaneous databases

ChiTaRSiP4HTM. human.
GenomeRNAii54681.
NextBioi57244.
PROiQ9NXG6.
SOURCEiSearch...

Gene expression databases

BgeeiQ9NXG6.
ExpressionAtlasiQ9NXG6. baseline and differential.
GenevisibleiQ9NXG6. HS.

Family and domain databases

Gene3Di1.10.238.10. 1 hit.
InterProiIPR011992. 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]
PfamiPF13640. 2OG-FeII_Oxy_3. 1 hit.
PF13202. EF-hand_5. 1 hit.
[Graphical view]
SMARTiSM00702. P4Hc. 1 hit.
[Graphical view]
PROSITEiPS00018. EF_HAND_1. 2 hits.
PS51471. FE2OG_OXY. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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. 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.
    , 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.

Entry informationi

Entry nameiP4HTM_HUMAN
AccessioniPrimary (citable) accession number: Q9NXG6
Secondary accession number(s): Q6PAG6
, Q8TCJ9, Q8WV55, Q96F22, Q9BW77
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 16, 2003
Last sequence update: June 16, 2003
Last modified: July 22, 2015
This is version 136 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.