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Q9NXG6

- P4HTM_HUMAN

UniProt

Q9NXG6 - P4HTM_HUMAN

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Protein
Transmembrane prolyl 4-hydroxylase
Gene
P4HTM, PH4
Organism
Homo sapiens (Human)
Status
Reviewed - 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

Binds 1 Fe2+ ion per subunit By similarity.
Ascorbate By similarity.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi328 – 3281Iron By similarity
Metal bindingi330 – 3301Iron By similarity
Metal bindingi374 – 3741Iron By similarity
Binding sitei451 – 45112-oxoglutarate Reviewed prediction

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Calcium bindingi198 – 210131 Reviewed prediction
Add
BLAST
Calcium bindingi237 – 249132 Reviewed prediction
Add
BLAST

GO - Molecular functioni

  1. L-ascorbic acid binding Source: UniProtKB-KW
  2. calcium ion binding Source: InterPro
  3. iron ion binding Source: InterPro
  4. oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, 2-oxoglutarate as one donor, and incorporation of one atom each of oxygen into both donors Source: InterPro
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: Chromosome 3

Organism-specific databases

HGNCiHGNC:28858. P4HTM.

Subcellular locationi

Endoplasmic reticulum membrane; Single-pass type II membrane protein 2 Publications

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 6060Cytoplasmic Reviewed prediction
Add
BLAST
Transmembranei61 – 8121Helical; Signal-anchor for type II membrane protein; Reviewed prediction
Add
BLAST
Topological domaini82 – 502421Lumenal Reviewed prediction
Add
BLAST

GO - Cellular componenti

  1. endoplasmic reticulum membrane Source: UniProtKB-SubCell
  2. integral component of membrane Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

Pathology & Biotechi

Organism-specific databases

PharmGKBiPA164724295.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 502502Transmembrane prolyl 4-hydroxylase
PRO_0000206668Add
BLAST

Amino acid modifications

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

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.
GenevestigatoriQ9NXG6.

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 194-250, 263-462.

Family & Domainsi

Domains and Repeats

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

Sequence similaritiesi

Contains 2 EF-hand domains.

Keywords - Domaini

Repeat, Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG284419.
HOGENOMiHOG000115323.
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. Align

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

MAAAAVTGQR PETAAAEEAS RPQWAPPDHC QAQAAAGLGD GEDAPVRPLC    50
KPRGICSRAY FLVLMVFVHL YLGNVLALLL FVHYSNGDES SDPGPQHRAQ 100
GPGPEPTLGP LTRLEGIKVG HERKVQLVTD RDHFIRTLSL KPLLFEIPGF 150
LTDEECRLII HLAQMKGLQR SQILPTEEYE EAMSTMQVSQ LDLFRLLDQN 200
RDGHLQLREV LAQTRLGNGW WMTPESIQEM YAAIKADPDG DGVLSLQEFS 250
NMDLRDFHKY MRSHKAESSE LVRNSHHTWL YQGEGAHHIM RAIRQRVLRL 300
TRLSPEIVEL SEPLQVVRYG EGGHYHAHVD SGPVYPETIC SHTKLVANES 350
VPFETSCRYM TVLFYLNNVT GGGETVFPVA DNRTYDEMSL IQDDVDLRDT 400
RRHCDKGNLR VKPQQGTAVF WYNYLPDGQG WVGDVDDYSL HGGCLVTRGT 450
KWIANNWINV DPSRARQALF QQEMARLARE GGTDSQPEWA LDRAYRDARV 500
EL 502
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. Reason: Intron retention.
The sequence CAD28518.2 differs from that shown. Reason: Intron retention.
The sequence BAA91045.1 differs from that shown. Reason: Erroneous initiation.

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei358 – 3581R → RQVSPNWGLPSILRPGTPMT QAQPCTVGVPLGMGPGDHWV IPVSPWEHPQLGTCSVPPLP YS in isoform 3.
VSP_007573
Alternative sequencei359 – 502144YMTVL…ARVEL → QVSPNWGLPSILRPGTPMTQ AQPCTVGVPLGMGPGDHWVI PVSDALTSPHKLFTQWLERG GYWSS in isoform 2.
VSP_007574Add
BLAST

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti213 – 2131Q → K in AAH47566. 1 Publication
Sequence conflicti240 – 2401G → A in AAO43431. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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. [Q9NXG6-1]
ENST00000475629; ENSP00000477191; ENSG00000178467.
GeneIDi54681.
KEGGihsa:54681.
UCSCiuc003cvg.3. human. [Q9NXG6-1]
uc003cvh.3. human. [Q9NXG6-3]

Polymorphism databases

DMDMi32129516.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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.
CCDSi CCDS2781.2. [Q9NXG6-3 ]
CCDS43089.1. [Q9NXG6-1 ]
RefSeqi NP_808807.2. NM_177938.2. [Q9NXG6-3 ]
NP_808808.1. NM_177939.2. [Q9NXG6-1 ]
UniGenei Hs.654944.

3D structure databases

ProteinModelPortali Q9NXG6.
SMRi Q9NXG6. Positions 194-250, 263-462.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 120100. 5 interactions.
IntActi Q9NXG6. 1 interaction.
STRINGi 9606.ENSP00000341422.

Chemistry

BindingDBi Q9NXG6.
ChEMBLi CHEMBL3047.
DrugBanki DB00126. Vitamin C.

PTM databases

PhosphoSitei Q9NXG6.

Polymorphism databases

DMDMi 32129516.

Proteomic databases

MaxQBi Q9NXG6.
PaxDbi Q9NXG6.
PRIDEi Q9NXG6.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000343546 ; ENSP00000341422 ; ENSG00000178467 . [Q9NXG6-3 ]
ENST00000383729 ; ENSP00000373235 ; ENSG00000178467 . [Q9NXG6-1 ]
ENST00000475629 ; ENSP00000477191 ; ENSG00000178467 .
GeneIDi 54681.
KEGGi hsa:54681.
UCSCi uc003cvg.3. human. [Q9NXG6-1 ]
uc003cvh.3. human. [Q9NXG6-3 ]

Organism-specific databases

CTDi 54681.
GeneCardsi GC03P049027.
HGNCi HGNC:28858. P4HTM.
HPAi HPA007199.
MIMi 614584. gene.
neXtProti NX_Q9NXG6.
PharmGKBi PA164724295.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG284419.
HOGENOMi HOG000115323.
KOi K06711.
OMAi NMDLRDF.
OrthoDBi EOG7VDXP9.
PhylomeDBi Q9NXG6.
TreeFami TF332923.

Miscellaneous databases

ChiTaRSi P4HTM. human.
GenomeRNAii 54681.
NextBioi 57244.
PROi Q9NXG6.
SOURCEi Search...

Gene expression databases

Bgeei Q9NXG6.
Genevestigatori Q9NXG6.

Family and domain databases

Gene3Di 1.10.238.10. 1 hit.
InterProi IPR011992. 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 ]
Pfami PF13640. 2OG-FeII_Oxy_3. 1 hit.
PF13202. EF-hand_5. 1 hit.
[Graphical view ]
SMARTi SM00702. P4Hc. 1 hit.
[Graphical view ]
PROSITEi PS00018. EF_HAND_1. 2 hits.
PS51471. FE2OG_OXY. 1 hit.
[Graphical view ]
ProtoNeti Search...

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 9, 2014
This is version 127 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

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