HPHL1_HUMAN
ID HPHL1_HUMAN Reviewed; 1159 AA.
AC Q6MZM0; Q3C1W7;
DT 02-SEP-2008, integrated into UniProtKB/Swiss-Prot.
DT 02-SEP-2008, sequence version 2.
DT 03-AUG-2022, entry version 134.
DE RecName: Full=Ferroxidase HEPHL1 {ECO:0000305};
DE EC=1.16.3.1 {ECO:0000269|PubMed:31125343};
DE AltName: Full=Hephaestin-like protein 1;
DE Flags: Precursor;
GN Name=HEPHL1;
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 [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 469-559.
RA Totoki Y., Yada T., Sakaki Y., Takeda T.;
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 697-1159.
RC TISSUE=Esophageal carcinoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, GLYCOSYLATION AT ASN-161; ASN-407
RP AND ASN-772, INVOLVEMENT IN HJDD, VARIANTS HJDD 271-LEU--ALA-355 DEL;
RP THR-355 AND THR-1059, AND CHARACTERIZATION OF VARIANTS HJDD
RP 271-LEU--ALA-355 DEL AND THR-1059.
RX PubMed=31125343; DOI=10.1371/journal.pgen.1008143;
RA Sharma P., Reichert M., Lu Y., Markello T.C., Adams D.R., Steinbach P.J.,
RA Fuqua B.K., Parisi X., Kaler S.G., Vulpe C.D., Anderson G.J., Gahl W.A.,
RA Malicdan M.C.V.;
RT "Biallelic HEPHL1 variants impair ferroxidase activity and cause an
RT abnormal hair phenotype.";
RL PLoS Genet. 15:E1008143-E1008143(2019).
CC -!- FUNCTION: Is a copper-binding glycoprotein with ferroxidase activity.
CC It oxidizes Fe(2+) to Fe(3+) without releasing radical oxygen species
CC (PubMed:31125343). May be involved in the regulation of intracellular
CC iron content (PubMed:31125343). {ECO:0000269|PubMed:31125343}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4 Fe(2+) + 4 H(+) + O2 = 4 Fe(3+) + 2 H2O;
CC Xref=Rhea:RHEA:11148, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:29033, ChEBI:CHEBI:29034; EC=1.16.3.1;
CC Evidence={ECO:0000269|PubMed:31125343};
CC -!- COFACTOR:
CC Name=Cu cation; Xref=ChEBI:CHEBI:23378;
CC Evidence={ECO:0000269|PubMed:31125343};
CC Note=Binds 6 Cu cations per monomer. {ECO:0000250};
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass type I
CC membrane protein {ECO:0000305}.
CC -!- DISEASE: Abnormal hair, joint laxity, and developmental delay (HJDD)
CC [MIM:261990]: An autosomal recessive disease characterized by abnormal
CC hair, cognitive delay, speech articulation disorder, and increased
CC joint mobility. At birth patients have normal hair that gradually
CC becomes sparse, twisted, brittle, and easily broken, with pili torti
CC and trichorrhexis nodosa. {ECO:0000269|PubMed:31125343}. Note=The
CC disease may be caused by variants affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the multicopper oxidase family. {ECO:0000305}.
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DR EMBL; AP002795; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AB231719; BAE46880.1; -; mRNA.
DR EMBL; BX641008; CAE46009.1; -; mRNA.
DR CCDS; CCDS44710.1; -.
DR RefSeq; NP_001092142.1; NM_001098672.1.
DR AlphaFoldDB; Q6MZM0; -.
DR SMR; Q6MZM0; -.
DR BioGRID; 131121; 114.
DR IntAct; Q6MZM0; 26.
DR STRING; 9606.ENSP00000313699; -.
DR DrugBank; DB09130; Copper.
DR TCDB; 8.A.105.1.3; the multi-copper-containing ferroxidase (mcfo) family.
DR GlyGen; Q6MZM0; 6 sites.
DR iPTMnet; Q6MZM0; -.
DR PhosphoSitePlus; Q6MZM0; -.
DR BioMuta; HEPHL1; -.
DR DMDM; 205785679; -.
DR MassIVE; Q6MZM0; -.
DR PaxDb; Q6MZM0; -.
DR PeptideAtlas; Q6MZM0; -.
DR PRIDE; Q6MZM0; -.
DR ProteomicsDB; 66573; -.
DR Antibodypedia; 31604; 65 antibodies from 13 providers.
DR DNASU; 341208; -.
DR Ensembl; ENST00000315765.10; ENSP00000313699.9; ENSG00000181333.12.
DR GeneID; 341208; -.
DR KEGG; hsa:341208; -.
DR MANE-Select; ENST00000315765.10; ENSP00000313699.9; NM_001098672.2; NP_001092142.1.
DR UCSC; uc001pep.3; human.
DR CTD; 341208; -.
DR DisGeNET; 341208; -.
DR GeneCards; HEPHL1; -.
DR HGNC; HGNC:30477; HEPHL1.
DR HPA; ENSG00000181333; Group enriched (esophagus, lymphoid tissue, skin, vagina).
DR MalaCards; HEPHL1; -.
DR MIM; 261990; phenotype.
DR MIM; 618455; gene.
DR neXtProt; NX_Q6MZM0; -.
DR OpenTargets; ENSG00000181333; -.
DR PharmGKB; PA134873144; -.
DR VEuPathDB; HostDB:ENSG00000181333; -.
DR eggNOG; KOG1263; Eukaryota.
DR GeneTree; ENSGT00940000157994; -.
DR HOGENOM; CLU_005569_0_0_1; -.
DR InParanoid; Q6MZM0; -.
DR OMA; PEPDMCV; -.
DR OrthoDB; 454773at2759; -.
DR PhylomeDB; Q6MZM0; -.
DR TreeFam; TF329807; -.
DR PathwayCommons; Q6MZM0; -.
DR SignaLink; Q6MZM0; -.
DR BioGRID-ORCS; 341208; 10 hits in 1065 CRISPR screens.
DR ChiTaRS; HEPHL1; human.
DR GenomeRNAi; 341208; -.
DR Pharos; Q6MZM0; Tbio.
DR PRO; PR:Q6MZM0; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q6MZM0; protein.
DR Bgee; ENSG00000181333; Expressed in esophagus mucosa and 43 other tissues.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0005507; F:copper ion binding; IEA:InterPro.
DR GO; GO:0004322; F:ferroxidase activity; IDA:UniProtKB.
DR GO; GO:0016491; F:oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0006879; P:cellular iron ion homeostasis; IMP:UniProtKB.
DR GO; GO:0006825; P:copper ion transport; IEA:UniProtKB-KW.
DR GO; GO:0055072; P:iron ion homeostasis; IBA:GO_Central.
DR GO; GO:0006826; P:iron ion transport; IBA:GO_Central.
DR Gene3D; 2.60.40.420; -; 3.
DR InterPro; IPR011706; Cu-oxidase_C.
DR InterPro; IPR045087; Cu-oxidase_fam.
DR InterPro; IPR011707; Cu-oxidase_N.
DR InterPro; IPR033138; Cu_oxidase_CS.
DR InterPro; IPR002355; Cu_oxidase_Cu_BS.
DR InterPro; IPR008972; Cupredoxin.
DR PANTHER; PTHR11709; PTHR11709; 3.
DR Pfam; PF07731; Cu-oxidase_2; 2.
DR Pfam; PF07732; Cu-oxidase_3; 3.
DR SUPFAM; SSF49503; SSF49503; 6.
DR PROSITE; PS00079; MULTICOPPER_OXIDASE1; 3.
DR PROSITE; PS00080; MULTICOPPER_OXIDASE2; 1.
PE 1: Evidence at protein level;
KW Copper; Copper transport; Disease variant; Disulfide bond; Glycoprotein;
KW Ion transport; Membrane; Metal-binding; Oxidoreductase; Reference proteome;
KW Repeat; Signal; Transmembrane; Transmembrane helix; Transport.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT CHAIN 25..1159
FT /note="Ferroxidase HEPHL1"
FT /id="PRO_0000346771"
FT TOPO_DOM 25..1114
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 1115..1135
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1136..1159
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 25..207
FT /note="Plastocyanin-like 1"
FT DOMAIN 218..366
FT /note="Plastocyanin-like 2"
FT DOMAIN 379..561
FT /note="Plastocyanin-like 3"
FT DOMAIN 571..719
FT /note="Plastocyanin-like 4"
FT DOMAIN 731..907
FT /note="Plastocyanin-like 5"
FT DOMAIN 915..1092
FT /note="Plastocyanin-like 6"
FT BINDING 127
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="1"
FT /note="type 2 copper site"
FT /evidence="ECO:0000250"
FT BINDING 129
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="2"
FT /note="type 3 copper site"
FT /evidence="ECO:0000250"
FT BINDING 187
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="2"
FT /note="type 3 copper site"
FT /evidence="ECO:0000250"
FT BINDING 189
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="3"
FT /note="type 3 copper site"
FT /evidence="ECO:0000250"
FT BINDING 304
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="4"
FT /note="type 1 copper site"
FT /evidence="ECO:0000250"
FT BINDING 347
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="4"
FT /note="type 1 copper site"
FT /evidence="ECO:0000250"
FT BINDING 352
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="4"
FT /note="type 1 copper site"
FT /evidence="ECO:0000250"
FT BINDING 657
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="5"
FT /note="type 1 copper site"
FT /evidence="ECO:0000250"
FT BINDING 700
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="5"
FT /note="type 1 copper site"
FT /evidence="ECO:0000250"
FT BINDING 705
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="5"
FT /note="type 1 copper site"
FT /evidence="ECO:0000250"
FT BINDING 710
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="5"
FT /note="type 1 copper site"
FT /evidence="ECO:0000250"
FT BINDING 1003
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="6"
FT /note="type 1 copper site"
FT /evidence="ECO:0000250"
FT BINDING 1006
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="1"
FT /note="type 2 copper site"
FT /evidence="ECO:0000250"
FT BINDING 1008
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="3"
FT /note="type 3 copper site"
FT /evidence="ECO:0000250"
FT BINDING 1048
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="3"
FT /note="type 3 copper site"
FT /evidence="ECO:0000250"
FT BINDING 1049
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="6"
FT /note="type 1 copper site"
FT /evidence="ECO:0000250"
FT BINDING 1050
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="2"
FT /note="type 3 copper site"
FT /evidence="ECO:0000250"
FT BINDING 1054
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="6"
FT /note="type 1 copper site"
FT /evidence="ECO:0000250"
FT BINDING 1059
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /ligand_label="6"
FT /note="type 1 copper site"
FT /evidence="ECO:0000250"
FT CARBOHYD 161
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:31125343"
FT CARBOHYD 236
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 407
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:31125343"
FT CARBOHYD 589
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 772
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:31125343"
FT CARBOHYD 935
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 181..207
FT /evidence="ECO:0000255"
FT DISULFID 285..366
FT /evidence="ECO:0000255"
FT DISULFID 535..561
FT /evidence="ECO:0000255"
FT DISULFID 638..719
FT /evidence="ECO:0000255"
FT DISULFID 881..907
FT /evidence="ECO:0000255"
FT VARIANT 251
FT /note="N -> D (in dbSNP:rs1945783)"
FT /id="VAR_045903"
FT VARIANT 271..355
FT /note="Missing (in HJDD; due to a nucleotide substitution
FT that affects a canonical splice site; patient cells contain
FT transcripts lacking exon 5 and corresponding to protein
FT variant 271-L--A-355 del but also normally spliced
FT transcripts corresponding to protein variant T-355; loss of
FT ferroxidase activity)"
FT /evidence="ECO:0000269|PubMed:31125343"
FT /id="VAR_082699"
FT VARIANT 355
FT /note="A -> T (in HJDD; due to a nucleotide substitution
FT that affects a canonical splice site; patient cells contain
FT normally spliced transcripts corresponding to protein
FT variant T-355 but also transcripts lacking exon 5 and
FT corresponding to protein variant 271-L--A-355 del;
FT dbSNP:rs774463623)"
FT /evidence="ECO:0000269|PubMed:31125343"
FT /id="VAR_082700"
FT VARIANT 381
FT /note="R -> C (in dbSNP:rs12291622)"
FT /id="VAR_045904"
FT VARIANT 1059
FT /note="M -> T (in HJDD; loss of ferroxidase activity;
FT dbSNP:rs199856193)"
FT /evidence="ECO:0000269|PubMed:31125343"
FT /id="VAR_082701"
FT CONFLICT 553
FT /note="G -> A (in Ref. 2; BAE46880)"
FT /evidence="ECO:0000305"
FT CONFLICT 697
FT /note="R -> G (in Ref. 3; CAE46009)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1159 AA; 131603 MW; EC89C2ED620FAB3E CRC64;
MPRKQPAGCI FLLTFLGLSG LVGTVTRTYY IGIVEEYWNY VPQGKNVITG KSFTEDKLAT
LFLERGPNRI GSIYKKAVYR RFTDGTYSIE IPKPPWLGFL GPILRAEVGD VIVIHLKNFA
SRPYSLHPHG VFYNKDSEGA LYPDGTSGRN KNDDMVPPGK NYTYVWPVRE EYAPTPADAN
CLTWVYHSHI DAPKDICSGL IGPLLVCKEG ILNRYSGTRN DVDREFVIMF TLVDENQSWY
LNENIKHFCT NPDSVDKKDA VFQRSNKMHA LNGYLFGNFP EPDMCVGESV SWHLFGMGNE
IDIHSIYFYG NTFISRGHRT DVVNLFPATF LTTEMIAENP GKWMITCQVS DHLQAGMLGQ
YNVDNCKSDI FYPKMKGQQR RYFIAAEKIL WDYAPQGYNK FSGLPLNASG SDSDLYFTQG
DNRIGGKYWK VRYTEFVDAT FTKRKRLSAE EAHLGILGPV IKAEVGDTLL VTFANKADKV
YSILPHGVIY DKASDAAPNL DGFVKPGAHV KPGETFTYKW TVPESVSPTA GDPPCLTYLY
FSAVDPIKDT SSGLVGPLLV CKKGVLNADG TQKGIDKEFY LLFTVFDENL SRYFDENIQK
FIWHPFSIDK EDKEFVKSNR MHAVNGYMYG NQPGLNMCKR DRVSWHLIGL GTDTDMHGIV
FQGNTIHLRG THRDSLALFP HMATTAFMQP DHAGIFRVFC ATMPHLSRGM GQIYEVSSCD
NRDPSEQRYG MIRTFYIAAE EVEWDYAPNK NWEFEKQHVD ARGERHGDIF MNRTENWIGS
QYKKVVYREY TDGEFVEIKA RPPREEHLEL LGPMIHAEVG NTVLIIFKNK ASRPYSISAQ
GVEEMDSGKQ FQVPMTKPGE VKTYRWNIPK RSGPGPSDPN CIPWVYYSTV NFVKDTYSGL
MGPLITCRKG VLNEKGRRSD VDYEFALLFL VFNENESWYL DDNIKKYLNK DPRDFKRTDD
FEESNRMHAI NGKIFGNLHG LIMNEDTMTN WYLLGIGSEV DIHTIHYHAE SFLFKIDKSY
REDVYDLFPG TFQTIELFAD HPGTWLLHCH VSDHIHAGME TTYTVLRNID NRIPYSTTSP
GVASHPATVP SNERPGKEQL YFFGKNLGPT GAKAALVILF IIGLLLLITT VILSLRLCSA
MKQTDYQQVQ SCALPTDAL