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Q9NXG6

- P4HTM_HUMAN

UniProt

Q9NXG6 - P4HTM_HUMAN

Protein

Transmembrane prolyl 4-hydroxylase

Gene

P4HTM

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 128 (01 Oct 2014)
      Sequence version 2 (16 Jun 2003)
      Previous versions | rss
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    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.PROSITE-ProRule annotation
    Ascorbate.By 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

    1. calcium ion binding Source: InterPro
    2. iron ion binding Source: InterPro
    3. L-ascorbic acid binding Source: UniProtKB-KW
    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

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

    GO - Cellular componenti

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

    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-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.
    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.
    ModBaseiSearch...
    MobiDBiSearch...

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini1 – 6060CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini82 – 502421LumenalSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei61 – 8121Helical; Signal-anchor for type II membrane proteinSequence AnalysisAdd
    BLAST

    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.
    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.

    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:
    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

    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: October 1, 2014
    This is version 128 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