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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
 
 
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