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)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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. Within the mitochondrial intermembrane space, participates in a chain of disulfide exchange reactions with MIA40, that generate disulfide bonds in a number of resident proteins with twin Cx3C and Cx9C motifs. Ref.9 Isoform 2: May act as an autocrine hepatotrophic growth factor promoting liver regeneration. Ref.9
Catalytic activity	2 R'C(R)SH + O2 = R'C(R)S-S(R)CR' + H2O2.
Cofactor	FAD.
Subunit structure	Homodimer; disulfide-linked. May form heterodimers of isoform 1 and isoform 2. Ref.7 Ref.10
Subcellular location	Isoform 1: Mitochondrion intermembrane space Ref.9. Isoform 2: Cytoplasm. Secreted Ref.9.
Tissue specificity	Ubiquitously expressed. Highest expression in the testis and liver and low expression in the muscle. Ref.11
Involvement in disease	Defects in GFER are a cause of mitochondrial progressive myopathy with congenital cataract hearing loss and developmental delay (MPMCHD) [MIM:613076]; also called combined mitochondrial complex deficiency. Ref.11
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. The sequence AAD56538.1 differs from that shown. Reason: Erroneous initiation. The sequence AAH02429.1 differs from that shown. Reason: Erroneous initiation. The sequence AAH28348.2 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Cellular component	Cytoplasm Mitochondrion Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	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 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
Molecular function	growth factor activity Inferred from electronic annotation. Source: UniProtKB-KW 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

Sites

Binding site

99

1

FAD

Binding site

100

1

FAD

Binding site

104

1

FAD

Binding site

171

1

FAD

Binding site

174

1

FAD

Binding site

180

1

FAD

Binding site

194

1

FAD

Amino acid modifications

Modified residue

59

1

Phosphoserine Ref.8

Disulfide bond

95

Interchain (with C-204) Ref.10

Disulfide bond

142 ↔ 145

Redox-active Ref.10

Disulfide bond

171 ↔ 188

Ref.10

Disulfide bond

204

Interchain (with C-95) Ref.10

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.10 Ref.11
Corresponds to variant rs121908192 [ dbSNP | Ensembl ].

VAR_063435

Experimental info

Sequence conflict

30

1

L → S in AAA96390. Ref.5

Sequence conflict

127

1

Q → R in AAG38105. Ref.2

Sequence conflict

180

1

K → E in AAG38105. Ref.2

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

205

Helix Strand Turn

Details...

Turn

99 – 101

3

Helix

105 – 115

11

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]	"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.
[3]	"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: 15616553] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2-205. Tissue: Placenta and Skin.
[5]	"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: 10712775] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 29-205.
[6]	"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: 8575761] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 30-205. Tissue: Renal cyst lining cell.
[7]	"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: 12180965] [Abstract] Cited for: ALTERNATIVE SPLICING, SUBUNIT.
[8]	"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: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-59, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[9]	"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: 19397338] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[10]	"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: 20593814] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 81-205, SUBUNIT, DISULFIDE BONDS, FAD-BINDING SITES, BASIS OF VARIANT HIS-194 DEFICIENCY.
[11]	"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: 19409522] [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.
AF306863 mRNA. Translation: AAG38105.1.
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.726325.

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	[»]

ProteinModelPortal

P55789.

SMR

P55789. Positions 94-205.

ModBase

Search...

Protein-protein interaction databases

IntAct

P55789. 3 interactions.

MINT

MINT-263560.

STRING

P55789.

PTM databases

PhosphoSite

P55789.

Polymorphism databases

DMDM

218511915.

Proteomic databases

PRIDE

P55789.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000248114; ENSP00000248114; ENSG00000127554.

GeneID

2671.

KEGG

hsa:2671.

Organism-specific databases

CTD

2671.

GeneCards

GC16P002045.

H-InvDB

HIX0012707.

HGNC

HGNC:4236. GFER.

HPA

HPA041227.

MIM

600924. gene.
613076. phenotype.

neXtProt

NX_P55789.

PharmGKB

PA28648.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG14883.

HOGENOM

HBG315946.

HOVERGEN

HBG000235.

InParanoid

P55789.

OMA

CTDFKSW.

OrthoDB

EOG4M91ST.

PhylomeDB

P55789.

Gene expression databases

ArrayExpress

P55789.

Bgee

P55789.

CleanEx

HS_GFER.

Genevestigator

P55789.

GermOnline

ENSG00000127554. Homo sapiens.

Family and domain databases

InterPro

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

Gene3D

G3DSA:1.20.120.310. Evr1_Alr. 1 hit.

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

SOURCE

Search...

Entry information

Entry name

ALR_HUMAN

Accession

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

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	December 16, 2008
Last modified:	January 25, 2012
This is version 97 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.