P4HA2_HUMAN
ID P4HA2_HUMAN Reviewed; 535 AA.
AC O15460; D3DQ85; D3DQ86; Q8WWN0;
DT 02-MAY-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 03-AUG-2022, entry version 205.
DE RecName: Full=Prolyl 4-hydroxylase subunit alpha-2;
DE Short=4-PH alpha-2;
DE EC=1.14.11.2 {ECO:0000269|PubMed:9211872};
DE AltName: Full=Procollagen-proline,2-oxoglutarate-4-dioxygenase subunit alpha-2;
DE Flags: Precursor;
GN Name=P4HA2; ORFNames=UNQ290/PRO330;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM IIB), FUNCTION, CATALYTIC ACTIVITY,
RP ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, SUBUNIT, COFACTOR, AND
RP TISSUE SPECIFICITY.
RC TISSUE=Lung;
RX PubMed=9211872; DOI=10.1074/jbc.272.28.17342;
RA Annunen P., Helaakoski T., Myllyharju J., Veijola J., Pihlajaniemi T.,
RA Kivirikko K.I.;
RT "Cloning of the human prolyl 4-hydroxylase alpha subunit isoform alpha(II)
RT and characterization of the type II enzyme tetramer. The alpha(I) and
RT alpha(II) subunits do not form a mixed alpha(I)alpha(II)beta2 tetramer.";
RL J. Biol. Chem. 272:17342-17348(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE (ISOFORMS IIA AND IIB).
RX PubMed=11606192; DOI=10.1046/j.0014-2956.2001.02464.x;
RA Nokelainen M., Nissi R., Kukkola L., Helaakoski T., Myllyharju J.;
RT "Characterization of the human and mouse genes for the alpha subunit of
RT type II prolyl 4-hydroxylase. Identification of a previously unknown
RT alternatively spliced exon and its expression in various tissues.";
RL Eur. J. Biochem. 268:5300-5309(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM IIA).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM IIA).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP INTERACTION WITH P4HB.
RX PubMed=7753822; DOI=10.1073/pnas.92.10.4427;
RA Helaakoski T., Annunen P., Vuori K., Macneil I.A., Pihlajaniemi T.,
RA Kivirikko K.I.;
RT "Cloning, baculovirus expression, and characterization of a second mouse
RT prolyl 4-hydroxylase alpha-subunit isoform: formation of an alpha 2 beta 2
RT tetramer with the protein disulfide-isomerase/beta subunit.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:4427-4431(1995).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [8]
RP INVOLVEMENT IN MYP25, VARIANTS IN MYP25 ARG-140; VAL-150 AND LYS-291, AND
RP CHARACTERIZATION OF VARIANT MYP25 LYS-291.
RX PubMed=25741866; DOI=10.1038/gim.2015.28;
RA Guo H., Tong P., Liu Y., Xia L., Wang T., Tian Q., Li Y., Hu Y., Zheng Y.,
RA Jin X., Li Y., Xiong W., Tang B., Feng Y., Li J., Pan Q., Hu Z., Xia K.;
RT "Mutations of P4HA2 encoding prolyl 4-hydroxylase 2 are associated with
RT nonsyndromic high myopia.";
RL Genet. Med. 17:300-306(2015).
CC -!- FUNCTION: Catalyzes the post-translational formation of 4-
CC hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other
CC proteins. {ECO:0000269|PubMed:9211872}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + L-prolyl-[collagen] + O2 = CO2 + succinate +
CC trans-4-hydroxy-L-prolyl-[collagen]; Xref=Rhea:RHEA:18945, Rhea:RHEA-
CC COMP:11676, Rhea:RHEA-COMP:11680, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:30031,
CC ChEBI:CHEBI:50342, ChEBI:CHEBI:61965; EC=1.14.11.2;
CC Evidence={ECO:0000269|PubMed:9211872};
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;
CC Evidence={ECO:0000305|PubMed:9211872};
CC -!- ACTIVITY REGULATION: Inhibited by poly(L-proline) only at very high
CC concentrations. {ECO:0000269|PubMed:9211872}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=22 uM for 2-oxoglutarate {ECO:0000269|PubMed:9211872};
CC -!- SUBUNIT: Heterotetramer of two alpha-2 chains and two beta chains
CC (P4HB) (the beta chain is the multi-functional PDI), where P4HB plays
CC the role of a structural subunit; this tetramer catalyzes the formation
CC of 4-hydroxyproline in collagen. {ECO:0000269|PubMed:9211872}.
CC -!- INTERACTION:
CC O15460-2; P50570-2: DNM2; NbExp=3; IntAct=EBI-10182841, EBI-10968534;
CC O15460-2; Q13643: FHL3; NbExp=3; IntAct=EBI-10182841, EBI-741101;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum lumen.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=IIb;
CC IsoId=O15460-1; Sequence=Displayed;
CC Name=IIa;
CC IsoId=O15460-2; Sequence=VSP_004506;
CC -!- TISSUE SPECIFICITY: Expressed in the heart, placenta, lung and
CC pancreas. {ECO:0000269|PubMed:9211872}.
CC -!- DISEASE: Myopia 25, autosomal dominant (MYP25) [MIM:617238]: A
CC refractive error of the eye, in which parallel rays from a distant
CC object come to focus in front of the retina, vision being better for
CC near objects than for far. {ECO:0000269|PubMed:25741866}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the P4HA family. {ECO:0000305}.
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DR EMBL; U90441; AAB71339.1; -; mRNA.
DR EMBL; AJ314859; CAC85688.1; -; Genomic_DNA.
DR EMBL; AJ314859; CAC85689.1; -; Genomic_DNA.
DR EMBL; AY358970; AAQ89329.1; -; mRNA.
DR EMBL; CH471062; EAW62341.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW62342.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW62343.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW62346.1; -; Genomic_DNA.
DR EMBL; BC035813; AAH35813.1; -; mRNA.
DR CCDS; CCDS34230.1; -. [O15460-2]
DR CCDS; CCDS4151.1; -. [O15460-1]
DR RefSeq; NP_001017973.1; NM_001017973.1.
DR RefSeq; NP_001017974.1; NM_001017974.1. [O15460-2]
DR RefSeq; NP_001136070.1; NM_001142598.1. [O15460-2]
DR RefSeq; NP_001136071.1; NM_001142599.1. [O15460-1]
DR RefSeq; NP_004190.1; NM_004199.2. [O15460-1]
DR RefSeq; XP_005272173.1; XM_005272116.4.
DR RefSeq; XP_005272174.1; XM_005272117.4. [O15460-1]
DR RefSeq; XP_005272175.1; XM_005272118.4. [O15460-1]
DR RefSeq; XP_005272176.1; XM_005272119.4. [O15460-1]
DR RefSeq; XP_005272177.1; XM_005272120.4. [O15460-1]
DR RefSeq; XP_006714791.1; XM_006714728.3. [O15460-1]
DR RefSeq; XP_006714792.1; XM_006714729.3.
DR RefSeq; XP_006714793.1; XM_006714730.3.
DR RefSeq; XP_016865500.1; XM_017010011.1.
DR PDB; 6EVL; X-ray; 1.87 A; A=163-257.
DR PDB; 6EVM; X-ray; 2.00 A; A=163-257.
DR PDB; 6EVN; X-ray; 1.48 A; A=163-257.
DR PDB; 6EVO; X-ray; 1.55 A; A=163-257.
DR PDB; 6EVP; X-ray; 1.68 A; A=163-257.
DR PDBsum; 6EVL; -.
DR PDBsum; 6EVM; -.
DR PDBsum; 6EVN; -.
DR PDBsum; 6EVO; -.
DR PDBsum; 6EVP; -.
DR AlphaFoldDB; O15460; -.
DR SMR; O15460; -.
DR BioGRID; 114464; 126.
DR IntAct; O15460; 98.
DR MINT; O15460; -.
DR STRING; 9606.ENSP00000384999; -.
DR ChEMBL; CHEMBL5640; -.
DR DrugBank; DB00172; Proline.
DR DrugBank; DB00139; Succinic acid.
DR GlyGen; O15460; 4 sites, 3 O-linked glycans (2 sites).
DR iPTMnet; O15460; -.
DR MetOSite; O15460; -.
DR PhosphoSitePlus; O15460; -.
DR BioMuta; P4HA2; -.
DR EPD; O15460; -.
DR jPOST; O15460; -.
DR MassIVE; O15460; -.
DR MaxQB; O15460; -.
DR PaxDb; O15460; -.
DR PeptideAtlas; O15460; -.
DR PRIDE; O15460; -.
DR ProteomicsDB; 48680; -. [O15460-1]
DR ProteomicsDB; 48681; -. [O15460-2]
DR Antibodypedia; 35136; 145 antibodies from 25 providers.
DR DNASU; 8974; -.
DR Ensembl; ENST00000166534.8; ENSP00000166534.4; ENSG00000072682.20. [O15460-1]
DR Ensembl; ENST00000360568.8; ENSP00000353772.3; ENSG00000072682.20. [O15460-2]
DR Ensembl; ENST00000379086.5; ENSP00000368379.1; ENSG00000072682.20. [O15460-2]
DR Ensembl; ENST00000379100.7; ENSP00000368394.2; ENSG00000072682.20. [O15460-2]
DR Ensembl; ENST00000379104.7; ENSP00000368398.2; ENSG00000072682.20. [O15460-1]
DR Ensembl; ENST00000401867.5; ENSP00000384999.1; ENSG00000072682.20. [O15460-1]
DR GeneID; 8974; -.
DR KEGG; hsa:8974; -.
DR MANE-Select; ENST00000360568.8; ENSP00000353772.3; NM_001017974.2; NP_001017974.1. [O15460-2]
DR UCSC; uc003kwg.4; human. [O15460-1]
DR CTD; 8974; -.
DR DisGeNET; 8974; -.
DR GeneCards; P4HA2; -.
DR HGNC; HGNC:8547; P4HA2.
DR HPA; ENSG00000072682; Low tissue specificity.
DR MalaCards; P4HA2; -.
DR MIM; 600608; gene.
DR MIM; 617238; phenotype.
DR neXtProt; NX_O15460; -.
DR OpenTargets; ENSG00000072682; -.
DR Orphanet; 397; Giant cell arteritis.
DR PharmGKB; PA32875; -.
DR VEuPathDB; HostDB:ENSG00000072682; -.
DR eggNOG; KOG1591; Eukaryota.
DR GeneTree; ENSGT00940000157695; -.
DR HOGENOM; CLU_024155_1_0_1; -.
DR InParanoid; O15460; -.
DR OMA; EEHEIVH; -.
DR PhylomeDB; O15460; -.
DR TreeFam; TF313393; -.
DR BRENDA; 1.14.11.2; 2681.
DR PathwayCommons; O15460; -.
DR Reactome; R-HSA-1650814; Collagen biosynthesis and modifying enzymes.
DR SignaLink; O15460; -.
DR BioGRID-ORCS; 8974; 10 hits in 1073 CRISPR screens.
DR ChiTaRS; P4HA2; human.
DR GeneWiki; P4HA2; -.
DR GenomeRNAi; 8974; -.
DR Pharos; O15460; Tbio.
DR PRO; PR:O15460; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; O15460; protein.
DR Bgee; ENSG00000072682; Expressed in stromal cell of endometrium and 183 other tissues.
DR ExpressionAtlas; O15460; baseline and differential.
DR Genevisible; O15460; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0009055; F:electron transfer activity; TAS:UniProtKB.
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; IDA:UniProtKB.
DR GO; GO:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; IBA:GO_Central.
DR Gene3D; 1.25.40.10; -; 1.
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 InterPro; IPR013547; Pro_4_hyd_alph_N.
DR InterPro; IPR011990; TPR-like_helical_dom_sf.
DR InterPro; IPR019734; TPR_repeat.
DR PANTHER; PTHR10869; PTHR10869; 1.
DR Pfam; PF13640; 2OG-FeII_Oxy_3; 1.
DR Pfam; PF08336; P4Ha_N; 1.
DR SMART; SM00702; P4Hc; 1.
DR SUPFAM; SSF48452; SSF48452; 1.
DR PROSITE; PS51471; FE2OG_OXY; 1.
DR PROSITE; PS50005; TPR; 1.
DR PROSITE; PS50293; TPR_REGION; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Dioxygenase; Disease variant;
KW Endoplasmic reticulum; Glycoprotein; Iron; Metal-binding; Oxidoreductase;
KW Reference proteome; Signal; TPR repeat; Vitamin C.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..535
FT /note="Prolyl 4-hydroxylase subunit alpha-2"
FT /id="PRO_0000022726"
FT REPEAT 207..240
FT /note="TPR"
FT DOMAIN 412..520
FT /note="Fe2OG dioxygenase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 430
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 432
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 501
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 511
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT MOD_RES 480
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q60716"
FT CARBOHYD 115
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 264
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 436..451
FT /note="NDERDTFKHLGTGNRV -> RPFDSGLKTEGNRL (in isoform IIa)"
FT /evidence="ECO:0000303|PubMed:12975309,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_004506"
FT VARIANT 140
FT /note="Q -> R (in MYP25; dbSNP:rs764211125)"
FT /evidence="ECO:0000269|PubMed:25741866"
FT /id="VAR_074026"
FT VARIANT 150
FT /note="I -> V (in MYP25; unknown pathological significance;
FT dbSNP:rs771208496)"
FT /evidence="ECO:0000269|PubMed:25741866"
FT /id="VAR_074027"
FT VARIANT 291
FT /note="E -> K (in MYP25; decreases protein abundance;
FT dbSNP:rs758872875)"
FT /evidence="ECO:0000269|PubMed:25741866"
FT /id="VAR_074028"
FT HELIX 166..178
FT /evidence="ECO:0007829|PDB:6EVN"
FT HELIX 182..197
FT /evidence="ECO:0007829|PDB:6EVN"
FT HELIX 206..219
FT /evidence="ECO:0007829|PDB:6EVN"
FT HELIX 223..236
FT /evidence="ECO:0007829|PDB:6EVN"
FT HELIX 241..253
FT /evidence="ECO:0007829|PDB:6EVN"
SQ SEQUENCE 535 AA; 60902 MW; FD04467B098F63CF CRC64;
MKLWVSALLM AWFGVLSCVQ AEFFTSIGHM TDLIYAEKEL VQSLKEYILV EEAKLSKIKS
WANKMEALTS KSAADAEGYL AHPVNAYKLV KRLNTDWPAL EDLVLQDSAA GFIANLSVQR
QFFPTDEDEI GAAKALMRLQ DTYRLDPGTI SRGELPGTKY QAMLSVDDCF GMGRSAYNEG
DYYHTVLWME QVLKQLDAGE EATTTKSQVL DYLSYAVFQL GDLHRALELT RRLLSLDPSH
ERAGGNLRYF EQLLEEEREK TLTNQTEAEL ATPEGIYERP VDYLPERDVY ESLCRGEGVK
LTPRRQKRLF CRYHHGNRAP QLLIAPFKEE DEWDSPHIVR YYDVMSDEEI ERIKEIAKPK
LARATVRDPK TGVLTVASYR VSKSSWLEED DDPVVARVNR RMQHITGLTV KTAELLQVAN
YGVGGQYEPH FDFSRNDERD TFKHLGTGNR VATFLNYMSD VEAGGATVFP DLGAAIWPKK
GTAVFWYNLL RSGEGDYRTR HAACPVLVGC KWVSNKWFHE RGQEFLRPCG STEVD
