P55789 (ALR_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
FAD-linked sulfhydryl oxidase ALR
EC=1.8.3.2

Alternative name(s):
Augmenter of liver regeneration
Short name=hERV1
Hepatopoietin

Gene names

Name:	GFER
Synonyms:	ALR, HERV1, HPO

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	205 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Isoform 1: FAD-dependent sulfhydryl oxidase that regenerates the redox-active disulfide bonds in CHCHD4/MIA40, a chaperone essential for disulfide bond formation and protein folding in the mitochondrial intermembrane space. The reduced form of CHCHD4/MIA40 forms a transient intermolecular disulfide bridge with GFER/ERV1, resulting in regeneration of the essential disulfide bonds in CHCHD4/MIA40, while GFER/ERV1 becomes re-oxidized by donating electrons to cytochrome c or molecular oxygen. Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Isoform 2: May act as an autocrine hepatotrophic growth factor promoting liver regeneration. Ref.12 Ref.13 Ref.14 Ref.15 Ref.16
Catalytic activity	2 R'C(R)SH + O2 = R'C(R)S-S(R)CR' + H2O2. Ref.14 Ref.16
Cofactor	FAD. Ref.15
Subunit structure	Homodimer; disulfide-linked. May form heterodimers of isoform 1 and isoform 2. Ref.9 Ref.14 Ref.15 Ref.16
Subcellular location	Isoform 1: Mitochondrion intermembrane space Ref.12 Ref.13. Isoform 2: Cytoplasm. Secreted Ref.12 Ref.13.
Tissue specificity	Ubiquitously expressed. Highest expression in the testis and liver and low expression in the muscle. Ref.17
Involvement in disease	Myopathy, mitochondrial progressive, with congenital cataract, hearing loss and developmental delay (MPMCHD) [MIM:613076]: A disease characterized by progressive myopathy and partial combined respiratory-chain deficiency, congenital cataract, sensorineural hearing loss, and developmental delay. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.14 Ref.17
Sequence similarities	Contains 1 ERV/ALR sulfhydryl oxidase domain.
Sequence caution	The sequence AAA96390.2 differs from that shown. Reason: Frameshift at position 70. The sequence AAD36986.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence AAD56538.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence AAH02429.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence AAH28348.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Ontologies

Keywords
Cellular component	Cytoplasm Mitochondrion Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Cataract Disease mutation
Ligand	FAD Flavoprotein
Molecular function	Growth factor Oxidoreductase
PTM	Disulfide bond Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cell proliferation Non-traceable author statement. Source: UniProtKB cellular protein metabolic process Traceable author statement. Source: Reactome protein targeting to mitochondrion Traceable author statement. Source: Reactome spermatogenesis Non-traceable author statement. Source: UniProtKB
Cellular_component	extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell mitochondrial intermembrane space Inferred from electronic annotation. Source: UniProtKB-SubCell mitochondrion Inferred from direct assay. Source: HPA
Molecular_function	flavin adenine dinucleotide binding Inferred from direct assay Ref.16. Source: UniProtKB protein disulfide oxidoreductase activity Inferred from direct assay Ref.16. Source: UniProtKB thiol oxidase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P55789-1)

Also known as: HPO-205; lfALR;

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 2 (identifier: P55789-2)

Also known as: HPO-125; sfALR;

The sequence of this isoform differs from the canonical sequence as follows:
     1-80: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 205

205

FAD-linked sulfhydryl oxidase ALR

PRO_0000208548

Regions

Domain

95 – 195

101

ERV/ALR sulfhydryl oxidase

Nucleotide binding

99 – 107

9

FAD

Nucleotide binding

171 – 183

13

FAD

Nucleotide binding

194 – 195

2

FAD

Sites

Binding site

111

1

FAD

Binding site

140

1

FAD

Amino acid modifications

Modified residue

59

1

Phosphoserine Ref.11

Disulfide bond

95

Interchain (with C-204) Ref.14 Ref.15 Ref.16

Disulfide bond

142 ↔ 145

Redox-active Ref.14 Ref.15 Ref.16

Disulfide bond

171 ↔ 188

Ref.14 Ref.15 Ref.16

Disulfide bond

204

Interchain (with C-95) Ref.14 Ref.15 Ref.16

Natural variations

Alternative sequence

1 – 80

80

Missing in isoform 2.

VSP_040393

Natural variant

166

1

F → L.
Corresponds to variant rs36041021 [ dbSNP | Ensembl ].

VAR_061994

Natural variant

194

1

R → H in MPMCHD; less stable than the wild-type protein within the mitochondria, increased rate of dissociation of FAD by about 45-fold. Ref.14 Ref.17
Corresponds to variant rs121908192 [ dbSNP | Ensembl ].

VAR_063435

Experimental info

Sequence conflict

30

1

L → S in AAA96390. Ref.7

Sequence conflict

127

1

Q → R in AAG38105. Ref.3

Sequence conflict

180

1

K → E in AAG38105. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

205

Helix Strand Turn

Details...

Helix

86 – 88

3

Beta strand

93 – 95

3

Helix

99 – 115

17

Helix

123 – 139

17

Helix

143 – 155

13

Helix

163 – 180

18

Helix

188 – 190

3

Helix

191 – 195

5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (HPO-205) (lfALR) [UniParc]. Last modified December 16, 2008. Version 2. Checksum: 43CBF8CCB5BA91C8	FASTA	205	23,449
	10 20 30 40 50 60 MAAPGERGRF HGGNLFFLPG GARSEMMDDL ATDARGRGAG RRDAAASAST PAQAPTSDSP 70 80 90 100 110 120 VAEDASRRRP CRACVDFKTW MRTQQKRDTK FREDCPPDRE ELGRHSWAVL HTLAAYYPDL 130 140 150 160 170 180 PTPEQQQDMA QFIHLFSKFY PCEECAEDLR KRLCRNHPDT RTRACFTQWL CHLHNEVNRK 190 200 LGKPDFDCSK VDERWRDGWK DGSCD
	Isoform 2 (HPO-125) (sfALR) [UniParc]. Checksum: 3F0B927DC64EF606	FASTA	125	15,029
	10 20 30 40 50 60 MRTQQKRDTK FREDCPPDRE ELGRHSWAVL HTLAAYYPDL PTPEQQQDMA QFIHLFSKFY 70 80 90 100 110 120 PCEECAEDLR KRLCRNHPDT RTRACFTQWL CHLHNEVNRK LGKPDFDCSK VDERWRDGWK DGSCD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Genomic structure, chromosomal localization, and characterization of a functional promoter for human hepatopoietin (HPO) gene." Liu M.-M., He F.-C., Wei H.-D., Zhou W.-Q. Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"HERV different transcription sequence." Li Y., Xing G.-C., He F.-C., Wei H.-D., Zhang C.-G., Zhu L., Yu Y.-T. Submitted (JAN-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). Tissue: Liver.
[3]	"Isolation of human HPO cDNA from human liver tissue." Jun L., Wangxiang X., Xiaoming Y. Submitted (SEP-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Fetal liver.
[4]	"Human augmenter of liver regeneration/hepatopoietin gene open reading frame sequence." Dai W.-J., Jiang H.-C. Submitted (FEB-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
[5]	"The sequence and analysis of duplication-rich human chromosome 16." Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J. , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A. Nature 432:988-994(2004) [PubMed] [Europe PMC] [Abstract] 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] OF 2-205. Tissue: Placenta and Skin.
[7]	"Cloning and sequence analysis of human genomic DNA of augmenter of liver regeneration hepatitis." Cheng J., Zhong Y. Zhonghua Gan Zang Bing Za Zhi 8:12-14(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 29-205.
[8]	"A new human gene located in the PKD1 region of chromosome 16 is a functional homologue to ERV1 of yeast." Lisowsky T., Weinstat-Saslow D.L., Barton N., Reeders S.T., Schneider M.C. Genomics 29:690-697(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 30-205. Tissue: Renal cyst lining cell.
[9]	"Identification of hepatopoietin dimerization, its interacting regions and alternative splicing of its transcription." Li Y., Wei K., Lu C., Li Y., Li M., Xing G., Wei H., Wang Q., Chen J., Wu C., Chen H., Yang S., He F. Eur. J. Biochem. 269:3888-3893(2002) [PubMed] [Europe PMC] [Abstract] Cited for: ALTERNATIVE SPLICING, SUBUNIT.
[10]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[11]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-59, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[12]	"Augmenter of liver regeneration: substrate specificity of a flavin-dependent oxidoreductase from the mitochondrial intermembrane space." Daithankar V.N., Farrell S.R., Thorpe C. Biochemistry 48:4828-4837(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[13]	"Disulfide bond formation: sulfhydryl oxidase ALR controls mitochondrial biogenesis of human MIA40." Sztolsztener M.E., Brewinska A., Guiard B., Chacinska A. Traffic 14:309-320(2013) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[14]	"Structure of the human sulfhydryl oxidase augmenter of liver regeneration and characterization of a human mutation causing an autosomal recessive myopathy." Daithankar V.N., Schaefer S.A., Dong M., Bahnson B.J., Thorpe C. Biochemistry 49:6737-6745(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 81-205, CATALYTIC ACTIVITY, FUNCTION, SUBUNIT, DISULFIDE BONDS, FAD-BINDING SITES, CHARACTERIZATION OF VARIANT MPMCHD HIS-194.
[15]	"Molecular recognition and substrate mimicry drive the electron-transfer process between MIA40 and ALR." Banci L., Bertini I., Calderone V., Cefaro C., Ciofi-Baffoni S., Gallo A., Kallergi E., Lionaki E., Pozidis C., Tokatlidis K. Proc. Natl. Acad. Sci. U.S.A. 108:4811-4816(2011) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 81-205 IN COMPLEX WITH FAD, FUNCTION, COFACTOR, SUBUNIT, DISULFIDE BONDS, INTERACTION WITH CHCHD4.
[16]	"An electron-transfer path through an extended disulfide relay system: the case of the redox protein ALR." Banci L., Bertini I., Calderone V., Cefaro C., Ciofi-Baffoni S., Gallo A., Tokatlidis K. J. Am. Chem. Soc. 134:1442-1445(2012) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 91-205, FUNCTION, CATALYTIC ACTIVITY, DISULFIDE BONDS, SUBUNIT.
[17]	"The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency." Di Fonzo A., Ronchi D., Lodi T., Fassone E., Tigano M., Lamperti C., Corti S., Bordoni A., Fortunato F., Nizzardo M., Napoli L., Donadoni C., Salani S., Saladino F., Moggio M., Bresolin N., Ferrero I., Comi G.P. Am. J. Hum. Genet. 84:594-604(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MPMCHD HIS-194, CHARACTERIZATION OF VARIANT MPMCHD HIS-194, TISSUE SPECIFICITY.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF183892 Genomic DNA. Translation: AAD56538.1. Different initiation.
AF124604 mRNA. Translation: AAD17328.1.
AF306863 mRNA. Translation: AAG38105.1.
AY550027 mRNA. Translation: AAS55642.1.
AC005606 Genomic DNA. No translation available.
BC002429 mRNA. Translation: AAH02429.1. Different initiation.
BC028348 mRNA. Translation: AAH28348.2. Different initiation.
AF146394 Genomic DNA. Translation: AAD36986.1. Different initiation.
U31176 mRNA. Translation: AAA96390.2. Frameshift.

IPI

IPI00472356.
IPI00902969.

RefSeq

NP_005253.3. NM_005262.2.

UniGene

Hs.741377.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3MBG	X-ray	1.85	A/B/C	81-205	[»]
3O55	X-ray	1.90	A	81-205	[»]
3TK0	X-ray	1.61	A	81-205	[»]
3U2L	X-ray	1.95	A	91-205	[»]
3U2M	X-ray	2.00	A	91-205	[»]
3U5S	X-ray	1.50	A	81-205	[»]

ProteinModelPortal

P55789.

ModBase

Search...

Protein-protein interaction databases

IntAct

P55789. 3 interactions.

MINT

MINT-263560.

STRING

9606.ENSP00000248114.

PTM databases

PhosphoSite

P55789.

Polymorphism databases

DMDM

218511915.

Proteomic databases

PaxDb

P55789.

PRIDE

P55789.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000248114; ENSP00000248114; ENSG00000127554.

GeneID

2671.

KEGG

hsa:2671.

UCSC

uc002cob.3. human.

Organism-specific databases

CTD

2671.

GeneCards

GC16P002056.

H-InvDB

HIX0012707.

HGNC

HGNC:4236. GFER.

HPA

HPA041227.

MIM

600924. gene.
613076. phenotype.

neXtProt

NX_P55789.

PharmGKB

PA28648.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5054.

HOGENOM

HOG000195924.

HOVERGEN

HBG000235.

InParanoid

P55789.

OMA

CTDFKSW.

OrthoDB

EOG4M91ST.

PhylomeDB

P55789.

Enzyme and pathway databases

Reactome

REACT_17015. Metabolism of proteins.

Gene expression databases

ArrayExpress

P55789.

Bgee

P55789.

CleanEx

HS_GFER.

Genevestigator

P55789.

GermOnline

ENSG00000127554. Homo sapiens.

Family and domain databases

Gene3D

1.20.120.310. 1 hit.

InterPro

IPR017905. ERV/ALR_sulphydryl_oxidase.
IPR006863. Evr1_Alr.
[Graphical view]

Pfam

PF04777. Evr1_Alr. 1 hit.
[Graphical view]

SUPFAM

SSF69000. Evr1_Alr. 1 hit.

PROSITE

PS51324. ERV_ALR. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChEMBL

CHEMBL1741189.

EvolutionaryTrace

P55789.

GenomeRNAi

2671.

NextBio

10542.

SOURCE

Search...

Entry information

Entry name

ALR_HUMAN

Accession

Primary (citable) accession number: P55789
Secondary accession number(s): Q53YM6 , Q8TAH6, Q9H290, Q9UK40

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	December 16, 2008
Last modified:	May 1, 2013
This is version 111 of the entry and version 2 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.