P4HTM_MOUSE
ID P4HTM_MOUSE Reviewed; 503 AA.
AC Q8BG58; Q8CAF1; Q9D499;
DT 16-JUN-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 141.
DE RecName: Full=Transmembrane prolyl 4-hydroxylase;
DE Short=P4H-TM;
DE EC=1.14.11.29 {ECO:0000250|UniProtKB:Q9NXG6};
DE AltName: Full=Hypoxia-inducible factor prolyl hydroxylase 4;
DE Short=HIF-PH4;
DE Short=HIF-prolyl hydroxylase 4;
DE Short=HPH-4;
GN Name=P4htm; Synonyms=Ph4;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J; TISSUE=Corpus striatum, Medulla oblongata, and Testis;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [3]
RP TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=27466183; DOI=10.1093/hmg/ddw228;
RA Leinonen H., Rossi M., Salo A.M., Tiainen P., Hyvaerinen J., Pitkaenen M.,
RA Sormunen R., Miinalainen I., Zhang C., Soininen R., Kivirikko K.I.,
RA Koskelainen A., Tanila H., Myllyharju J., Koivunen P.;
RT "Lack of P4H-TM in mice results in age-related retinal and renal
RT alterations.";
RL Hum. Mol. Genet. 25:3810-3823(2016).
CC -!- FUNCTION: Catalyzes the post-translational formation of 4-
CC hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins.
CC Hydroxylates HIF1A at 'Pro-402' and 'Pro-564'. May function as a
CC cellular oxygen sensor and, under normoxic conditions, may target HIF
CC through the hydroxylation for proteasomal degradation via the von
CC Hippel-Lindau ubiquitination complex. {ECO:0000250|UniProtKB:Q9NXG6}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + L-prolyl-[hypoxia-inducible factor alpha
CC subunit] + O2 = CO2 + succinate + trans-4-hydroxy-L-prolyl-[hypoxia-
CC inducible factor alpha subunit]; Xref=Rhea:RHEA:48400, Rhea:RHEA-
CC COMP:12093, Rhea:RHEA-COMP:12094, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:30031,
CC ChEBI:CHEBI:50342, ChEBI:CHEBI:61965; EC=1.14.11.29;
CC Evidence={ECO:0000250|UniProtKB:Q9NXG6};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU00805};
CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000255|PROSITE-
CC ProRule:PRU00805};
CC -!- COFACTOR:
CC Name=L-ascorbate; Xref=ChEBI:CHEBI:38290; Evidence={ECO:0000250};
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:Q9NXG6}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000250};
CC Single-pass type II membrane protein {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8BG58-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8BG58-2; Sequence=VSP_007575, VSP_007576;
CC -!- TISSUE SPECIFICITY: Highest expression levels are detected in the eye
CC and brain, especially in the retinal epithelium cells and cortical
CC neurons. Also expressed in skeletal muscle, lung, heart, adrenal gland,
CC kidney, prostate, thyroid and testis. {ECO:0000269|PubMed:27466183}.
CC -!- PTM: Glycosylated. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Mutant mice exhibit inflammation and fibrosis of
CC renal tubuli, glomerular sclerosis, enlarged Bowman capsules, and
CC develop late-onset proteinuria. Vision is compromised, primarily due to
CC impairment of cone function. {ECO:0000269|PubMed:27466183}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB30379.2; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part.; Evidence={ECO:0000305};
CC Sequence=BAC30172.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AK046783; BAC32866.1; -; mRNA.
DR EMBL; AK047714; BAC33135.1; -; mRNA.
DR EMBL; AK016685; BAB30379.2; ALT_SEQ; mRNA.
DR EMBL; AK038927; BAC30172.1; ALT_SEQ; mRNA.
DR CCDS; CCDS23533.1; -. [Q8BG58-1]
DR RefSeq; NP_083220.3; NM_028944.3. [Q8BG58-1]
DR AlphaFoldDB; Q8BG58; -.
DR SMR; Q8BG58; -.
DR BioGRID; 216752; 14.
DR STRING; 10090.ENSMUSP00000006853; -.
DR GlyConnect; 2785; 4 N-Linked glycans (1 site).
DR GlyGen; Q8BG58; 3 sites, 4 N-linked glycans (1 site).
DR iPTMnet; Q8BG58; -.
DR PhosphoSitePlus; Q8BG58; -.
DR MaxQB; Q8BG58; -.
DR PaxDb; Q8BG58; -.
DR PRIDE; Q8BG58; -.
DR ProteomicsDB; 294232; -. [Q8BG58-1]
DR ProteomicsDB; 294233; -. [Q8BG58-2]
DR Antibodypedia; 2007; 245 antibodies from 22 providers.
DR Ensembl; ENSMUST00000006853; ENSMUSP00000006853; ENSMUSG00000006675. [Q8BG58-1]
DR GeneID; 74443; -.
DR KEGG; mmu:74443; -.
DR UCSC; uc009rqk.1; mouse. [Q8BG58-1]
DR UCSC; uc009rql.1; mouse. [Q8BG58-2]
DR CTD; 54681; -.
DR MGI; MGI:1921693; P4htm.
DR VEuPathDB; HostDB:ENSMUSG00000006675; -.
DR eggNOG; KOG1591; Eukaryota.
DR GeneTree; ENSGT00390000014570; -.
DR HOGENOM; CLU_035319_0_0_1; -.
DR InParanoid; Q8BG58; -.
DR OMA; PLPYSYM; -.
DR PhylomeDB; Q8BG58; -.
DR TreeFam; TF332923; -.
DR BioGRID-ORCS; 74443; 0 hits in 72 CRISPR screens.
DR ChiTaRS; P4htm; mouse.
DR PRO; PR:Q8BG58; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; Q8BG58; protein.
DR Bgee; ENSMUSG00000006675; Expressed in substantia nigra and 188 other tissues.
DR ExpressionAtlas; Q8BG58; baseline and differential.
DR Genevisible; Q8BG58; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016706; F:2-oxoglutarate-dependent dioxygenase activity; ISO:MGI.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0031418; F:L-ascorbic acid binding; IEA:UniProtKB-KW.
DR GO; GO:0004656; F:procollagen-proline 4-dioxygenase activity; IBA:GO_Central.
DR GO; GO:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; IBA:GO_Central.
DR GO; GO:0045646; P:regulation of erythrocyte differentiation; IMP:MGI.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR005123; Oxoglu/Fe-dep_dioxygenase.
DR InterPro; IPR045054; P4HA-like.
DR InterPro; IPR006620; Pro_4_hyd_alph.
DR InterPro; IPR044862; Pro_4_hyd_alph_FE2OG_OXY.
DR PANTHER; PTHR10869; PTHR10869; 1.
DR Pfam; PF13640; 2OG-FeII_Oxy_3; 1.
DR Pfam; PF13499; EF-hand_7; 1.
DR SMART; SM00702; P4Hc; 1.
DR SUPFAM; SSF47473; SSF47473; 1.
DR PROSITE; PS00018; EF_HAND_1; 2.
DR PROSITE; PS51471; FE2OG_OXY; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Calcium; Dioxygenase; Endoplasmic reticulum;
KW Glycoprotein; Iron; Membrane; Metal-binding; Oxidoreductase;
KW Reference proteome; Repeat; Signal-anchor; Transmembrane;
KW Transmembrane helix; Vitamin C; Zinc; Zinc-finger.
FT CHAIN 1..503
FT /note="Transmembrane prolyl 4-hydroxylase"
FT /id="PRO_0000206669"
FT TOPO_DOM 1..61
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 62..82
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 83..503
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT DOMAIN 186..221
FT /note="EF-hand 1"
FT DOMAIN 225..260
FT /note="EF-hand 2"
FT DOMAIN 310..461
FT /note="Fe2OG dioxygenase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT REGION 1..49
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 90..110
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 199
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10142"
FT BINDING 201
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10142"
FT BINDING 203
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10142"
FT BINDING 205
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10142"
FT BINDING 210
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10142"
FT BINDING 238
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10142"
FT BINDING 240
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10142"
FT BINDING 242
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10142"
FT BINDING 249
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10142"
FT BINDING 329
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 331
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 375
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 452
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT CARBOHYD 349
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 369
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 383
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 212..225
FT /note="LAQTRLGNGRWMTP -> RTPPAMWVGTGEN (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_007575"
FT VAR_SEQ 226..503
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_007576"
SQ SEQUENCE 503 AA; 57049 MW; C220CA0840F1BAFF CRC64;
MAAAVATVQR PEAETVEEAS NLQWPLPPEH RPSGAATRPG DSEDAPVRPL CKPRGICSRA
YFLVLMVFVH LYLGNVLALL LFVHYSNGDE STDPGPQRRE QSPQPVPTLG PLTRLEGIKV
GYERKVQVVA GRDHFIRTLS LKPLLFEIPG FLSDEECRLI IHLAQMKGLQ RSQILPTEEY
EEAMSAMQVS QLDLFQLLDQ NHDGRLQLRE VLAQTRLGNG RWMTPENIQE MYSAIKADPD
GDGVLSLQEF SNMDLRDFHK YMRSHKAESN ELVRNSHHTW LHQGEGAHHV MRAIRQRVLR
LTRLSPEIVE FSEPLQVVRY GEGGHYHAHV DSGPVYPETI CSHTKLVANE SVPFETSCRY
MTVLFYLNNV TGGGETVFPV ADNRTYDEMS LIQDDVDLRD TRRHCDKGNL RVKPQQGTAV
FWYNYLPDGQ GWVGEVDDYS LHGGCLVTRG TKWIANNWIN VDPSRARQAL FQQEMARLAR
EGGMDSQPEW ALDRAYSDAR VEL
