Q6ZVN8 (RGMC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Hemojuvelin

Alternative name(s):
Hemochromatosis type 2 protein
RGM domain family member C

Gene names

Name:	HFE2
Synonyms:	HJV, RGMC

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	426 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Member of the repulsive guidance molecule (RGM) family. Involved in iron metabolism. Acts as a bone morphogenetic protein (BMP) coreceptor By similarity. Enhancement of BMP signaling regulates hepcidin (HAMP) expression and iron metabolism By similarity. May cooperate with hepcidin to restrict iron absorption in the gut. Could represent the cellular receptor for hepcidin.
Subunit structure	Interacts with BMP2 and BMP4 By similarity. Interacts with BMPR1B. Interacts with TMPRSS6. Ref.7 Ref.8
Subcellular location	Cell membrane; Lipid-anchor › GPI-anchor By similarity.
Tissue specificity	Adult and fetal liver, heart, and skeletal muscle. Ref.1
Involvement in disease	Hemochromatosis 2A (HFE2A) [MIM:602390]: A 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.9 Ref.10 Ref.11
Sequence similarities	Belongs to the repulsive guidance molecule (RGM) family.

Ontologies

Keywords
Cellular component	Cell membrane Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Signal
PTM	GPI-anchor Glycoprotein Lipoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	BMP signaling pathway Inferred from electronic annotation. Source: Compara axon guidance Traceable author statement. Source: Reactome iron ion homeostasis Inferred from direct assay PubMed 16075058. Source: MGI positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara
Cellular_component	anchored to membrane Inferred from electronic annotation. Source: UniProtKB-KW cell surface Inferred from electronic annotation. Source: Compara extracellular space Inferred from electronic annotation. Source: Compara plasma membrane Inferred from direct assay PubMed 16075058. Source: MGI
Molecular_function	coreceptor activity Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform a (identifier: Q6ZVN8-1)

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.

Isoform b (identifier: Q6ZVN8-2)

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

Isoform c (identifier: Q6ZVN8-3)

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

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 35	35	Potential
	Chain	36 – 400	365	Hemojuvelin		PRO_0000030398
	Propeptide	401 – 426	26	Removed in mature form Potential		PRO_0000030399
Regions
	Compositional bias	64 – 78	15	Poly-Gly
	Compositional bias	127 – 130	4	Poly-Pro
Amino acid modifications
	Lipidation	400	1	GPI-anchor amidated aspartate Potential
	Glycosylation	118	1	N-linked (GlcNAc...) Potential
	Glycosylation	213	1	N-linked (GlcNAc...) Potential
	Glycosylation	372	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	1 – 226	226	Missing in isoform c.		VSP_011320
	Alternative sequence	1 – 113	113	Missing in isoform b.		VSP_011319
	Natural variant	80	1	C → R in HFE2A. Ref.10 Corresponds to variant rs28940586 [ dbSNP | Ensembl ].		VAR_019617
	Natural variant	85	1	S → P in HFE2A. Ref.9		VAR_019618
	Natural variant	99	1	G → R in HFE2A. Ref.9		VAR_019619
	Natural variant	101	1	L → P in HFE2A. Ref.10		VAR_019620
	Natural variant	168	1	A → D in HFE2A. Ref.9		VAR_019621
	Natural variant	170	1	F → S in HFE2A. Ref.9		VAR_019622
	Natural variant	172	1	D → E in HFE2A. Ref.9		VAR_019623
	Natural variant	191	1	W → C in HFE2A. Ref.9		VAR_019624
	Natural variant	205	1	S → R in HFE2A. Ref.9		VAR_019625
	Natural variant	222	1	I → N in HFE2A. Ref.1 Ref.10		VAR_019626
	Natural variant	250	1	G → V in HFE2A. Ref.9		VAR_019627
	Natural variant	288	1	R → W in HFE2A. Ref.9		VAR_019628
	Natural variant	310	1	A → G. Corresponds to variant rs7540883 [ dbSNP | Ensembl ].		VAR_053636
	Natural variant	320	1	G → V in HFE2A. Ref.1 Ref.9 Ref.10 Ref.11		VAR_019629
	Natural variant	321	1	C → W in HFE2A. Ref.11		VAR_019927
Experimental info
	Sequence conflict	69	1	G → GG in ABC40718. Ref.3
	Sequence conflict	299	1	K → E in BAC03944. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform a [UniParc]. Last modified July 5, 2004. Version 1. Checksum: 031C835F9B6DC06C	FASTA	426	45,080
	10 20 30 40 50 60 MGEPGQSPSP RSSHGSPPTL STLTLLLLLC GHAHSQCKIL RCNAEYVSST LSLRGGGSSG 70 80 90 100 110 120 ALRGGGGGGR GGGVGSGGLC RALRSYALCT RRTARTCRGD LAFHSAVHGI EDLMIQHNCS 130 140 150 160 170 180 RQGPTAPPPP RGPALPGAGS GLPAPDPCDY EGRFSRLHGR PPGFLHCASF GDPHVRSFHH 190 200 210 220 230 240 HFHTCRVQGA WPLLDNDFLF VQATSSPMAL GANATATRKL TIIFKNMQEC IDQKVYQAEV 250 260 270 280 290 300 DNLPVAFEDG SINGGDRPGG SSLSIQTANP GNHVEIQAAY IGTTIIIRQT AGQLSFSIKV 310 320 330 340 350 360 AEDVAMAFSA EQDLQLCVGG CPPSQRLSRS ERNRRGAITI DTARRLCKEG LPVEDAYFHS 370 380 390 400 410 420 CVFDVLISGD PNFTVAAQAA LEDARAFLPD LEKLHLFPSD AGVPLSSATL LAPLLSGLFV LWLCIQ
	Isoform b [UniParc]. Checksum: 0B056ED5D92B26E6	FASTA	313	33,679
	10 20 30 40 50 60 MIQHNCSRQG PTAPPPPRGP ALPGAGSGLP APDPCDYEGR FSRLHGRPPG FLHCASFGDP 70 80 90 100 110 120 HVRSFHHHFH TCRVQGAWPL LDNDFLFVQA TSSPMALGAN ATATRKLTII FKNMQECIDQ 130 140 150 160 170 180 KVYQAEVDNL PVAFEDGSIN GGDRPGGSSL SIQTANPGNH VEIQAAYIGT TIIIRQTAGQ 190 200 210 220 230 240 LSFSIKVAED VAMAFSAEQD LQLCVGGCPP SQRLSRSERN RRGAITIDTA RRLCKEGLPV 250 260 270 280 290 300 EDAYFHSCVF DVLISGDPNF TVAAQAALED ARAFLPDLEK LHLFPSDAGV PLSSATLLAP 310 LLSGLFVLWL CIQ
	Isoform c [UniParc]. Checksum: 7A7F39D3AD7F8CC5	FASTA	200	21,463
	10 20 30 40 50 60 MQECIDQKVY QAEVDNLPVA FEDGSINGGD RPGGSSLSIQ TANPGNHVEI QAAYIGTTII 70 80 90 100 110 120 IRQTAGQLSF SIKVAEDVAM AFSAEQDLQL CVGGCPPSQR LSRSERNRRG AITIDTARRL 130 140 150 160 170 180 CKEGLPVEDA YFHSCVFDVL ISGDPNFTVA AQAALEDARA FLPDLEKLHL FPSDAGVPLS 190 200 SATLLAPLLS GLFVLWLCIQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis." Papanikolaou G., Samuels M.E., Ludwig E.H., MacDonald M.L.E., Franchini P.L., Dube M.-P., Andres L., MacFarlane J., Sakellaropoulos N., Politou M., Nemeth E., Thompson J., Risler J.K., Zaborowska C., Babakaiff R., Radomski C.C., Pape T.D., Davidas O. , Christakis J., Brissot P., Lockitch G., Ganz T., Hayden M.R., Goldberg Y.P. Nat. Genet. 36:77-82(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A), ALTERNATIVE SPLICING, TISSUE SPECIFICITY, VARIANTS HFE2A ASN-222 AND VAL-320. Tissue: Liver.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS A AND B). Tissue: Liver and Skeletal muscle.
[3]	NIEHS SNPs program Submitted (NOV-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS B AND C). Tissue: PNS and Skeletal muscle.
[7]	"Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression." Babitt J.L., Huang F.W., Wrighting D.M., Xia Y., Sidis Y., Samad T.A., Campagna J.A., Chung R.T., Schneyer A.L., Woolf C.J., Andrews N.C., Lin H.Y. Nat. Genet. 38:531-539(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH BMPR1B.
[8]	"Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia." Silvestri L., Guillem F., Pagani A., Nai A., Oudin C., Silva M., Toutain F., Kannengiesser C., Beaumont C., Camaschella C., Grandchamp B. Blood 113:5605-5608(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TMPRSS6.
[9]	"Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis." Lanzara C., Roetto A., Daraio F., Rivard S., Ficarella R., Simard H., Cox T.M., Cazzola M., Piperno A., Gimenez-Roqueplo A.P., Grammatico P., Volinia S., Gasparini P., Camaschella C. Blood 103:4317-4321(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HFE2A PRO-85; ARG-99; ASP-168; SER-170; GLU-172; CYS-191; ARG-205; VAL-250; TRP-288 AND VAL-320.
[10]	"Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin." Lee P.L., Beutler E., Rao S.V., Barton J.C. Blood 103:4669-4671(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HFE2A ARG-80; PRO-101; ASN-222 AND VAL-320.
[11]	"Hemojuvelin (HJV) mutations in persons of European, African-American and Asian ancestry with adult onset haemochromatosis." Lee P.L., Barton J.C., Brandhagen D., Beutler E. Br. J. Haematol. 127:224-229(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HFE2A VAL-320 AND TRP-321.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	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.
IPI	IPI00329576. IPI00400863. IPI00419814.
RefSeq	NP_660320.3. NM_145277.4. NP_973733.1. NM_202004.3. NP_998817.1. NM_213652.3. NP_998818.1. NM_213653.3. XP_003960223.1. XM_003960174.1. XP_003960224.1. XM_003960175.1. XP_003960225.1. XM_003960176.1.
UniGene	Hs.632436.
3D structure databases
ProteinModelPortal	Q6ZVN8.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000337014.
PTM databases
PhosphoSite	Q6ZVN8.
Polymorphism databases
DMDM	51316254.
Proteomic databases
PaxDb	Q6ZVN8.
PRIDE	Q6ZVN8.
Protocols and materials databases
DNASU	148738.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000336751; ENSP00000337014; ENSG00000168509. ENST00000357836; ENSP00000350495; ENSG00000168509. ENST00000475797; ENSP00000425716; ENSG00000168509. ENST00000497365; ENSP00000421820; ENSG00000168509. ENST00000577520; ENSP00000463276; ENSG00000265970. ENST00000579423; ENSP00000464212; ENSG00000265970. ENST00000580693; ENSP00000464413; ENSG00000265970. ENST00000580823; ENSP00000462699; ENSG00000265970.
GeneID	101060525. 148738.
KEGG	hsa:101060525. hsa:148738.
UCSC	uc001eni.2. human. uc001enj.2. human.
Organism-specific databases
CTD	148738.
GeneCards	GC01P145413.
HGNC	HGNC:4887. HFE2.
HPA	HPA014472.
MIM	602390. phenotype. 608374. gene.
neXtProt	NX_Q6ZVN8.
Orphanet	79230. Hemochromatosis type 2.
PharmGKB	PA29264.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG87951.
HOGENOM	HOG000013072.
HOVERGEN	HBG057627.
InParanoid	Q6ZVN8.
KO	K06847.
OMA	PPGFLHC.
PhylomeDB	Q6ZVN8.
Enzyme and pathway databases
Pathway_Interaction_DB	bmppathway. BMP receptor signaling.
Reactome	REACT_111045. Developmental Biology.
Gene expression databases
ArrayExpress	Q6ZVN8.
Bgee	Q6ZVN8.
CleanEx	HS_HFE2.
Genevestigator	Q6ZVN8.
GermOnline	ENSG00000168509. Homo sapiens.
Family and domain databases
InterPro	IPR009496. RGM_C. IPR010536. RGM_N. [Graphical view]
Pfam	PF06534. RGM_C. 1 hit. PF06535. RGM_N. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	85978.
SOURCE	Search...

Entry information

Entry name

RGMC_HUMAN

Accession

Primary (citable) accession number: Q6ZVN8
Secondary accession number(s): B1ALI7 , Q2PQ63, Q6IMF6, Q8NAH2, Q8WVJ5

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 16, 2004
Last sequence update:	July 5, 2004
Last modified:	May 1, 2013
This is version 88 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.