Q9NXG6 (P4HTM_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	502 AA.
Sequence status	Complete.
Protein existence	Evidence 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.

Ontologies

Keywords
Cellular component	Endoplasmic reticulum Membrane
Coding sequence diversity	Alternative splicing
Domain	Repeat Signal-anchor Transmembrane Transmembrane helix
Ligand	Calcium Iron Metal-binding Vitamin C
Molecular function	Dioxygenase Oxidoreductase
PTM	Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Cellular_component	endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	L-ascorbic acid binding Inferred from electronic annotation. Source: UniProtKB-KW calcium ion binding Inferred from electronic annotation. Source: InterPro iron ion binding Inferred from electronic annotation. Source: InterPro 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 Inferred from electronic annotation. Source: InterPro oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 502	502	Transmembrane prolyl 4-hydroxylase		PRO_0000206668
Regions
	Topological domain	1 – 60	60	Cytoplasmic Potential
	Transmembrane	61 – 81	21	Helical; Signal-anchor for type II membrane protein; Potential
	Topological domain	82 – 502	421	Lumenal Potential
	Domain	185 – 220	36	EF-hand 1
	Domain	224 – 259	36	EF-hand 2
	Domain	310 – 460	151	Fe2OG dioxygenase
	Calcium binding	198 – 210	13	1 Potential
	Calcium binding	237 – 249	13	2 Potential
Sites
	Metal binding	328	1	Iron By similarity
	Metal binding	330	1	Iron By similarity
	Metal binding	374	1	Iron By similarity
	Binding site	451	1	2-oxoglutarate Potential
Amino acid modifications
	Glycosylation	348	1	N-linked (GlcNAc...) Potential
	Glycosylation	368	1	N-linked (GlcNAc...) Potential
	Glycosylation	382	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	358	1	R → RQVSPNWGLPSILRPGTPMT QAQPCTVGVPLGMGPGDHWV IPVSPWEHPQLGTCSVPPLP YS in isoform 3.		VSP_007573
	Alternative sequence	359 – 502	144	YMTVL…ARVEL → QVSPNWGLPSILRPGTPMTQ AQPCTVGVPLGMGPGDHWVI PVSDALTSPHKLFTQWLERG GYWSS in isoform 2.		VSP_007574
Experimental info
	Sequence conflict	213	1	Q → K in AAH47566. Ref.3
	Sequence conflict	240	1	G → A in AAO43431. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified June 16, 2003. Version 2. Checksum: A2DAE4ACF4A2E18C	FASTA	502	56,661
	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
	Isoform 2 (b) [UniParc]. Checksum: 5540388F142E76E4	FASTA	423	47,211
	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 VPFETSCRQV 370 380 390 400 410 420 SPNWGLPSIL RPGTPMTQAQ PCTVGVPLGM GPGDHWVIPV SDALTSPHKL FTQWLERGGY WSS
	Isoform 3 [UniParc]. Checksum: 9154ADD79EA6BE78	FASTA	563	63,112
	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 VPFETSCRQV 370 380 390 400 410 420 SPNWGLPSIL RPGTPMTQAQ PCTVGVPLGM GPGDHWVIPV SPWEHPQLGT CSVPPLPYSY 430 440 450 460 470 480 MTVLFYLNNV TGGGETVFPV ADNRTYDEMS LIQDDVDLRD TRRHCDKGNL RVKPQQGTAV 490 500 510 520 530 540 FWYNYLPDGQ GWVGDVDDYS LHGGCLVTRG TKWIANNWIN VDPSRARQAL FQQEMARLAR 550 560 EGGTDSQPEW ALDRAYRDAR VEL

References

	« Hide 'large scale' referencesShow '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. , 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.
IPI	IPI00219456. IPI00328950. IPI00479623.
RefSeq	NP_808807.2. NM_177938.2. NP_808808.1. NM_177939.2.
UniGene	Hs.654944.
3D structure databases
ProteinModelPortal	Q9NXG6.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9NXG6. 1 interaction.
STRING	9606.ENSP00000341422.
PTM databases
PhosphoSite	Q9NXG6.
Polymorphism databases
DMDM	32129516.
Proteomic databases
PaxDb	Q9NXG6.
PRIDE	Q9NXG6.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000343546; ENSP00000341422; ENSG00000178467. ENST00000383729; ENSP00000373235; ENSG00000178467.
GeneID	54681.
KEGG	hsa:54681.
UCSC	uc003cvg.3. human. uc003cvh.3. human.
Organism-specific databases
CTD	54681.
GeneCards	GC03P049027.
HGNC	HGNC:28858. P4HTM.
HPA	HPA007199.
MIM	614584. gene.
neXtProt	NX_Q9NXG6.
PharmGKB	PA164724295.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG284419.
HOGENOM	HOG000115323.
KO	K06711.
OMA	QQGTAVF.
Gene expression databases
Bgee	Q9NXG6.
Genevestigator	Q9NXG6.
GermOnline	ENSG00000178467. Homo sapiens.
Family and domain databases
Gene3D	1.10.238.10. 1 hit.
InterPro	IPR011992. EF-hand-like_dom. IPR018247. EF_Hand_1_Ca_BS. IPR002048. EF_hand_dom. IPR005123. Oxoglu/Fe-dep_dioxygenase. IPR006620. Pro_4_hyd_alph. [Graphical view]
Pfam	PF13640. 2OG-FeII_Oxy_3. 1 hit. PF13202. EF_hand_3. 1 hit. [Graphical view]
SMART	SM00702. P4Hc. 1 hit. [Graphical view]
PROSITE	PS00018. EF_HAND_1. 2 hits. PS50222. EF_HAND_2. False negative. PS51471. FE2OG_OXY. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	Q9NXG6.
ChEMBL	CHEMBL3047.
ChiTaRS	P4HTM. human.
DrugBank	DB00126. Vitamin C.
GenomeRNAi	54681.
NextBio	57244.
SOURCE	Search...

Entry information

Entry name

P4HTM_HUMAN

Accession

Primary (citable) accession number: Q9NXG6
Secondary accession number(s): Q6PAG6 , Q8TCJ9, Q8WV55, Q96F22, Q9BW77

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 16, 2003
Last sequence update:	June 16, 2003
Last modified:	May 1, 2013
This is version 115 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

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.