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Protein

Hemojuvelin

Gene

HFE2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Acts as a bone morphogenetic protein (BMP) coreceptor. Through enhancement of BMP signaling regulates hepcidin (HAMP) expression and regulates iron homeostasis.By similarity

GO - Molecular functioni

  • BMP binding Source: BHF-UCL
  • coreceptor activity Source: BHF-UCL
  • glycoprotein binding Source: BHF-UCL
  • receptor binding Source: BHF-UCL
  • transferrin receptor binding Source: BHF-UCL

GO - Biological processi

  • activin receptor signaling pathway Source: BHF-UCL
  • BMP signaling pathway Source: BHF-UCL
  • cellular iron ion homeostasis Source: BHF-UCL
  • cellular response to BMP stimulus Source: BHF-UCL
  • iron ion homeostasis Source: MGI
  • negative regulation of BMP signaling pathway Source: Ensembl
  • negative regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  • positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  • protein autoprocessing Source: BHF-UCL
Complete GO annotation...

Enzyme and pathway databases

ReactomeiR-HSA-373752. Netrin-1 signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
Hemojuvelin
Alternative name(s):
Hemochromatosis type 2 protein
RGM domain family member C
Gene namesi
Name:HFE2
Synonyms:HJV, RGMC
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:4887. HFE2.

Subcellular locationi

GO - Cellular componenti

  • anchored component of membrane Source: UniProtKB-KW
  • basolateral plasma membrane Source: Ensembl
  • BMP receptor complex Source: BHF-UCL
  • cell surface Source: Ensembl
  • extracellular space Source: UniProtKB
  • HFE-transferrin receptor complex Source: BHF-UCL
  • plasma membrane Source: BHF-UCL
  • plasma membrane protein complex Source: BHF-UCL
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Hemochromatosis 2A (HFE2A)4 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA juvenile form of hemochromatosis, a disorder of iron metabolism with excess deposition of iron in a variety of organs leading to their failure, bronze skin pigmentation, hepatic cirrhosis, arthropathy and diabetes. The most common symptoms of juvenile hemochromatosis at presentation are hypogonadism and cardiomyopathy.
See also OMIM:602390
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti80 – 801C → R in HFE2A. 1 Publication
Corresponds to variant rs28940586 [ dbSNP | Ensembl ].
VAR_019617
Natural varianti85 – 851S → P in HFE2A. 1 Publication
VAR_019618
Natural varianti99 – 991G → R in HFE2A. 1 Publication
VAR_019619
Natural varianti101 – 1011L → P in HFE2A. 1 Publication
Corresponds to variant rs74315327 [ dbSNP | Ensembl ].
VAR_019620
Natural varianti168 – 1681A → D in HFE2A. 1 Publication
Corresponds to variant rs782125244 [ dbSNP | Ensembl ].
VAR_019621
Natural varianti170 – 1701F → S in HFE2A. 1 Publication
VAR_019622
Natural varianti172 – 1721D → E in HFE2A. 1 Publication
Corresponds to variant rs782708481 [ dbSNP | Ensembl ].
VAR_019623
Natural varianti191 – 1911W → C in HFE2A. 1 Publication
VAR_019624
Natural varianti205 – 2051S → R in HFE2A. 1 Publication
VAR_019625
Natural varianti222 – 2221I → N in HFE2A. 2 Publications
Corresponds to variant rs74315325 [ dbSNP | Ensembl ].
VAR_019626
Natural varianti250 – 2501G → V in HFE2A. 1 Publication
VAR_019627
Natural varianti288 – 2881R → W in HFE2A. 1 Publication
VAR_019628
Natural varianti320 – 3201G → V in HFE2A. 4 Publications
Corresponds to variant rs74315323 [ dbSNP | Ensembl ].
VAR_019629
Natural varianti321 – 3211C → W in HFE2A. 1 Publication
Corresponds to variant rs121434374 [ dbSNP | Ensembl ].
VAR_019927

Keywords - Diseasei

Disease mutation

Organism-specific databases

MalaCardsiHFE2.
MIMi602390. phenotype.
Orphaneti79230. Hemochromatosis type 2.
PharmGKBiPA29264.

Polymorphism and mutation databases

BioMutaiHFE2.
DMDMi51316254.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 3535Sequence analysisAdd
BLAST
Chaini36 – 400365HemojuvelinPRO_0000030398Add
BLAST
Propeptidei401 – 42626Removed in mature formSequence analysisPRO_0000030399Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei46 – 461PhosphotyrosineBy similarity
Glycosylationi118 – 1181N-linked (GlcNAc...)Sequence analysis
Disulfide bondi148 ↔ 230By similarity
Disulfide bondi167 ↔ 317By similarity
Glycosylationi213 – 2131N-linked (GlcNAc...)Sequence analysis
Glycosylationi372 – 3721N-linked (GlcNAc...)Sequence analysis
Lipidationi400 – 4001GPI-anchor amidated aspartateSequence analysis

Post-translational modificationi

Autocatalytically cleaved at low pH; the two chains remain linked via two disulfide bonds. Also proteolytically processed by TMPRSS6, several fragments being released in the extracellular space; regulates HFE2 activity in BMP signaling and thefore iron homeostasis.By similarity1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei172 – 1732Cleavage; by autolysisBy similarity

Keywords - PTMi

Autocatalytic cleavage, Disulfide bond, Glycoprotein, GPI-anchor, Lipoprotein, Phosphoprotein

Proteomic databases

PaxDbiQ6ZVN8.
PeptideAtlasiQ6ZVN8.
PRIDEiQ6ZVN8.

PTM databases

iPTMnetiQ6ZVN8.
PhosphoSiteiQ6ZVN8.

Expressioni

Tissue specificityi

Adult and fetal liver, heart, and skeletal muscle.1 Publication

Gene expression databases

BgeeiENSG00000168509.
CleanExiHS_HFE2.
ExpressionAtlasiQ6ZVN8. baseline and differential.
GenevisibleiQ6ZVN8. HS.

Interactioni

Subunit structurei

Interacts with BMP2 and BMP4 (By similarity). Interacts with BMPR1B. Interacts with TMPRSS6.By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
TMPRSS6Q8IU80-43EBI-10900704,EBI-11686560

GO - Molecular functioni

  • BMP binding Source: BHF-UCL
  • glycoprotein binding Source: BHF-UCL
  • receptor binding Source: BHF-UCL
  • transferrin receptor binding Source: BHF-UCL

Protein-protein interaction databases

DIPiDIP-61608N.
IntActiQ6ZVN8. 2 interactions.
STRINGi9606.ENSP00000337014.

Structurei

Secondary structure

1
426
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi39 – 5113Combined sources
Helixi78 – 9316Combined sources
Helixi94 – 963Combined sources
Helixi101 – 11616Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
4UI1X-ray2.35C/D35-145[»]
ProteinModelPortaliQ6ZVN8.
SMRiQ6ZVN8. Positions 35-327.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi64 – 7815Poly-GlyAdd
BLAST
Compositional biasi127 – 1304Poly-Pro

Sequence similaritiesi

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiENOG410IFAH. Eukaryota.
ENOG410ZT7E. LUCA.
GeneTreeiENSGT00390000008488.
HOGENOMiHOG000013072.
HOVERGENiHBG057627.
InParanoidiQ6ZVN8.
KOiK06847.
OMAiRFSRLHG.
OrthoDBiEOG091G0NF6.
PhylomeDBiQ6ZVN8.
TreeFamiTF329836.

Family and domain databases

InterProiIPR033606. Hemojuvelin.
IPR009496. RGM_C.
IPR010536. RGM_N.
[Graphical view]
PANTHERiPTHR31428:SF3. PTHR31428:SF3. 1 hit.
PfamiPF06534. RGM_C. 1 hit.
PF06535. RGM_N. 1 hit.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform a (identifier: Q6ZVN8-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MGEPGQSPSP RSSHGSPPTL STLTLLLLLC GHAHSQCKIL RCNAEYVSST
60 70 80 90 100
LSLRGGGSSG ALRGGGGGGR GGGVGSGGLC RALRSYALCT RRTARTCRGD
110 120 130 140 150
LAFHSAVHGI EDLMIQHNCS RQGPTAPPPP RGPALPGAGS GLPAPDPCDY
160 170 180 190 200
EGRFSRLHGR PPGFLHCASF GDPHVRSFHH HFHTCRVQGA WPLLDNDFLF
210 220 230 240 250
VQATSSPMAL GANATATRKL TIIFKNMQEC IDQKVYQAEV DNLPVAFEDG
260 270 280 290 300
SINGGDRPGG SSLSIQTANP GNHVEIQAAY IGTTIIIRQT AGQLSFSIKV
310 320 330 340 350
AEDVAMAFSA EQDLQLCVGG CPPSQRLSRS ERNRRGAITI DTARRLCKEG
360 370 380 390 400
LPVEDAYFHS CVFDVLISGD PNFTVAAQAA LEDARAFLPD LEKLHLFPSD
410 420
AGVPLSSATL LAPLLSGLFV LWLCIQ
Length:426
Mass (Da):45,080
Last modified:July 5, 2004 - v1
Checksum:i031C835F9B6DC06C
GO
Isoform b (identifier: Q6ZVN8-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-113: Missing.

Show »
Length:313
Mass (Da):33,679
Checksum:i0B056ED5D92B26E6
GO
Isoform c (identifier: Q6ZVN8-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-226: Missing.

Show »
Length:200
Mass (Da):21,463
Checksum:i7A7F39D3AD7F8CC5
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti69 – 691G → GG in ABC40718 (Ref. 3) Curated
Sequence conflicti299 – 2991K → E in BAC03944 (PubMed:14702039).Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti80 – 801C → R in HFE2A. 1 Publication
Corresponds to variant rs28940586 [ dbSNP | Ensembl ].
VAR_019617
Natural varianti85 – 851S → P in HFE2A. 1 Publication
VAR_019618
Natural varianti99 – 991G → R in HFE2A. 1 Publication
VAR_019619
Natural varianti101 – 1011L → P in HFE2A. 1 Publication
Corresponds to variant rs74315327 [ dbSNP | Ensembl ].
VAR_019620
Natural varianti168 – 1681A → D in HFE2A. 1 Publication
Corresponds to variant rs782125244 [ dbSNP | Ensembl ].
VAR_019621
Natural varianti170 – 1701F → S in HFE2A. 1 Publication
VAR_019622
Natural varianti172 – 1721D → E in HFE2A. 1 Publication
Corresponds to variant rs782708481 [ dbSNP | Ensembl ].
VAR_019623
Natural varianti191 – 1911W → C in HFE2A. 1 Publication
VAR_019624
Natural varianti205 – 2051S → R in HFE2A. 1 Publication
VAR_019625
Natural varianti222 – 2221I → N in HFE2A. 2 Publications
Corresponds to variant rs74315325 [ dbSNP | Ensembl ].
VAR_019626
Natural varianti250 – 2501G → V in HFE2A. 1 Publication
VAR_019627
Natural varianti288 – 2881R → W in HFE2A. 1 Publication
VAR_019628
Natural varianti310 – 3101A → G.
Corresponds to variant rs7540883 [ dbSNP | Ensembl ].
VAR_053636
Natural varianti320 – 3201G → V in HFE2A. 4 Publications
Corresponds to variant rs74315323 [ dbSNP | Ensembl ].
VAR_019629
Natural varianti321 – 3211C → W in HFE2A. 1 Publication
Corresponds to variant rs121434374 [ dbSNP | Ensembl ].
VAR_019927

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 226226Missing in isoform c. 1 PublicationVSP_011320Add
BLAST
Alternative sequencei1 – 113113Missing in isoform b. 2 PublicationsVSP_011319Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY372521 mRNA. Translation: AAR22390.1.
AK092682 mRNA. Translation: BAC03944.1.
AK124273 mRNA. Translation: BAC85823.1.
AK092692 mRNA. Translation: BAC03947.1.
AK096905 mRNA. Translation: BAC04890.1.
DQ309445 Genomic DNA. Translation: ABC40718.1.
AL355505, AL138842 Genomic DNA. Translation: CAI22091.1.
AL138842, AL355505 Genomic DNA. Translation: CAI22349.1.
CH471244 Genomic DNA. Translation: EAW71408.1.
BC017926 mRNA. Translation: AAH17926.1.
BC085604 mRNA. Translation: AAH85604.1.
CCDSiCCDS72877.1. [Q6ZVN8-3]
CCDS72878.1. [Q6ZVN8-2]
CCDS72879.1. [Q6ZVN8-1]
RefSeqiNP_001303696.1. NM_001316767.1. [Q6ZVN8-3]
NP_660320.3. NM_145277.4. [Q6ZVN8-2]
NP_973733.1. NM_202004.3. [Q6ZVN8-3]
NP_998817.1. NM_213652.3. [Q6ZVN8-3]
NP_998818.1. NM_213653.3. [Q6ZVN8-1]
XP_005272989.1. XM_005272932.1. [Q6ZVN8-1]
UniGeneiHs.632436.

Genome annotation databases

EnsembliENST00000336751; ENSP00000337014; ENSG00000168509. [Q6ZVN8-1]
ENST00000357836; ENSP00000350495; ENSG00000168509. [Q6ZVN8-2]
ENST00000475797; ENSP00000425716; ENSG00000168509. [Q6ZVN8-3]
ENST00000497365; ENSP00000421820; ENSG00000168509. [Q6ZVN8-3]
GeneIDi148738.
KEGGihsa:148738.
UCSCiuc001eni.3. human. [Q6ZVN8-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY372521 mRNA. Translation: AAR22390.1.
AK092682 mRNA. Translation: BAC03944.1.
AK124273 mRNA. Translation: BAC85823.1.
AK092692 mRNA. Translation: BAC03947.1.
AK096905 mRNA. Translation: BAC04890.1.
DQ309445 Genomic DNA. Translation: ABC40718.1.
AL355505, AL138842 Genomic DNA. Translation: CAI22091.1.
AL138842, AL355505 Genomic DNA. Translation: CAI22349.1.
CH471244 Genomic DNA. Translation: EAW71408.1.
BC017926 mRNA. Translation: AAH17926.1.
BC085604 mRNA. Translation: AAH85604.1.
CCDSiCCDS72877.1. [Q6ZVN8-3]
CCDS72878.1. [Q6ZVN8-2]
CCDS72879.1. [Q6ZVN8-1]
RefSeqiNP_001303696.1. NM_001316767.1. [Q6ZVN8-3]
NP_660320.3. NM_145277.4. [Q6ZVN8-2]
NP_973733.1. NM_202004.3. [Q6ZVN8-3]
NP_998817.1. NM_213652.3. [Q6ZVN8-3]
NP_998818.1. NM_213653.3. [Q6ZVN8-1]
XP_005272989.1. XM_005272932.1. [Q6ZVN8-1]
UniGeneiHs.632436.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
4UI1X-ray2.35C/D35-145[»]
ProteinModelPortaliQ6ZVN8.
SMRiQ6ZVN8. Positions 35-327.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-61608N.
IntActiQ6ZVN8. 2 interactions.
STRINGi9606.ENSP00000337014.

PTM databases

iPTMnetiQ6ZVN8.
PhosphoSiteiQ6ZVN8.

Polymorphism and mutation databases

BioMutaiHFE2.
DMDMi51316254.

Proteomic databases

PaxDbiQ6ZVN8.
PeptideAtlasiQ6ZVN8.
PRIDEiQ6ZVN8.

Protocols and materials databases

DNASUi148738.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000336751; ENSP00000337014; ENSG00000168509. [Q6ZVN8-1]
ENST00000357836; ENSP00000350495; ENSG00000168509. [Q6ZVN8-2]
ENST00000475797; ENSP00000425716; ENSG00000168509. [Q6ZVN8-3]
ENST00000497365; ENSP00000421820; ENSG00000168509. [Q6ZVN8-3]
GeneIDi148738.
KEGGihsa:148738.
UCSCiuc001eni.3. human. [Q6ZVN8-1]

Organism-specific databases

CTDi148738.
GeneCardsiHFE2.
GeneReviewsiHFE2.
HGNCiHGNC:4887. HFE2.
MalaCardsiHFE2.
MIMi602390. phenotype.
608374. gene.
neXtProtiNX_Q6ZVN8.
Orphaneti79230. Hemochromatosis type 2.
PharmGKBiPA29264.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IFAH. Eukaryota.
ENOG410ZT7E. LUCA.
GeneTreeiENSGT00390000008488.
HOGENOMiHOG000013072.
HOVERGENiHBG057627.
InParanoidiQ6ZVN8.
KOiK06847.
OMAiRFSRLHG.
OrthoDBiEOG091G0NF6.
PhylomeDBiQ6ZVN8.
TreeFamiTF329836.

Enzyme and pathway databases

ReactomeiR-HSA-373752. Netrin-1 signaling.

Miscellaneous databases

GeneWikiiHemojuvelin.
GenomeRNAii148738.
PROiQ6ZVN8.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000168509.
CleanExiHS_HFE2.
ExpressionAtlasiQ6ZVN8. baseline and differential.
GenevisibleiQ6ZVN8. HS.

Family and domain databases

InterProiIPR033606. Hemojuvelin.
IPR009496. RGM_C.
IPR010536. RGM_N.
[Graphical view]
PANTHERiPTHR31428:SF3. PTHR31428:SF3. 1 hit.
PfamiPF06534. RGM_C. 1 hit.
PF06535. RGM_N. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiRGMC_HUMAN
AccessioniPrimary (citable) accession number: Q6ZVN8
Secondary accession number(s): B1ALI7
, Q2PQ63, Q6IMF6, Q8NAH2, Q8WVJ5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 16, 2004
Last sequence update: July 5, 2004
Last modified: September 7, 2016
This is version 118 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.