Affinage

GFER

FAD-linked sulfhydryl oxidase ALR · UniProt P55789

Length
205 aa
Mass
23.4 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GFER (augmenter of liver regeneration/ALR) is a homodimeric FAD-dependent sulfhydryl oxidase that operates as the terminal oxidase of the mitochondrial intermembrane space (IMS) disulfide relay, coupling oxidative protein folding to the respiratory chain. Its N-terminal shuttle domain (CxxC motif) accepts electrons from MIA40 (CHCHD4) via a transient mixed disulfide, transfers them through an intersubunit disulfide intermediate to the FAD-binding catalytic core of the partner subunit, and ultimately donates them to cytochrome c or, under anaerobic conditions, to the fumarate reductase Osm1, thereby regenerating oxidized MIA40 for successive rounds of IMS substrate import (PMID:19477928, PMID:22224850, PMID:28814504). Outside the IMS, cytosolic GFER suppresses Drp1-mediated mitochondrial fission by sequestering the transcription factor YY1 and reducing UBA2-dependent Drp1 SUMOylation (PMID:33110216, PMID:20147447). A homozygous R194H mutation causes autosomal-recessive mitochondrial myopathy with combined respiratory-chain deficiency, congenital cataract, and sensorineural hearing loss, mechanistically explained by progressive FAD cofactor release during catalysis (PMID:19409522, PMID:25269795).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1994 Medium

    Establishing that ALR is a homodimeric ~30 kDa secreted protein with hepatotrophic activity provided the first biochemical characterization but left its enzymatic function and subcellular site of action unknown.

    Evidence SDS-PAGE under reducing/non-reducing conditions, COS cell recombinant expression, canine Eck fistula bioassay

    PMID:8058770

    Open questions at the time
    • Enzymatic activity uncharacterized
    • Subcellular localization unknown
    • Single in vivo model system
  2. 2001 High

    Demonstrating that GFER localizes to the mitochondrial IMS and is required for cytosolic Fe/S protein maturation established its mitochondrial role and orthology to yeast Erv1, shifting the field from hepatotrophic cytokine to mitochondrial enzyme.

    Evidence Yeast erv1 mutant complementation by human ALR, subcellular fractionation

    PMID:11493598

    Open questions at the time
    • Direct substrates not identified
    • Enzymatic mechanism not resolved
  3. 2005 High

    Revealing that Erv1/GFER cooperates with Mia40 in the import and oxidative folding of small IMS proteins and that cytochrome c is its electron acceptor connected the disulfide relay to the respiratory chain and defined the pathway's biological logic.

    Evidence Temperature-sensitive erv1 yeast mutants, in vitro import assays, thiol trapping, co-immunoprecipitation

    PMID:16181637 PMID:16185707

    Open questions at the time
    • Electron transfer pathway within the enzyme unresolved
    • Thermodynamic parameters unknown
  4. 2006 High

    Structural determination of the ERV/ALR sulfhydryl oxidase domain showed how a four-helix bundle juxtaposes the CxxC motif with FAD, and chimeric enzyme experiments proved the shuttle domain determines substrate specificity, clarifying the modular architecture of catalysis.

    Evidence X-ray crystallography, chimeric enzyme construction and thioredoxin oxidase assays

    PMID:16893552

    Open questions at the time
    • Full-length structure not available
    • Intersubunit electron transfer not yet visualized
  5. 2009 High

    Full in vitro reconstitution of the Mia40–Erv1 disulfide relay with measured midpoint potentials established the thermodynamic basis for directional electron flow from substrate through Mia40 to Erv1, answering how electrons are vectorially funneled.

    Evidence Reconstitution with purified Tim13/Mia40/Erv1, midpoint potential measurements, cysteine mutagenesis

    PMID:19477928

    Open questions at the time
    • Intersubunit vs. intrasubunit electron transfer path not distinguished
    • In vivo electron acceptor specificity under different metabolic states unknown
  6. 2009 High

    Identification of homozygous R194H as the cause of autosomal-recessive mitochondrial myopathy with combined respiratory-chain deficiency linked GFER dysfunction to human disease and demonstrated that IMS protein import defects underlie the pathology.

    Evidence Homozygosity mapping, patient cell biochemistry, yeast erv1(R182H) complementation, electron microscopy

    PMID:19409522

    Open questions at the time
    • Molecular mechanism of R194H pathogenicity not resolved (answered later)
    • Genotype–phenotype spectrum across other mutations unknown
  7. 2010 High

    Demonstrating that Erv1 functions as a noncovalent homodimer with intersubunit electron exchange, and that the N-terminal shuttle domain is necessary and sufficient for Mia40 interaction, resolved the catalytic architecture and electron transfer trajectory within the enzyme.

    Evidence In vitro reconstitution with purified components, ITC binding measurements, domain mutagenesis and trans-complementation

    PMID:20188670 PMID:20367271

    Open questions at the time
    • Atomic-resolution structure of the intersubunit intermediate not yet obtained
    • Role of glutathione proofreading in vivo not tested
  8. 2010 High

    Discovery that GFER suppresses Drp1 levels to control mitochondrial fission in embryonic stem cells revealed a cytosolic, non-oxidase function of GFER in mitochondrial dynamics, expanding its role beyond IMS protein import.

    Evidence siRNA knockdown and overexpression in ESCs, Drp1 inhibitor/dominant-negative rescue, mitochondrial morphology imaging

    PMID:20147447

    Open questions at the time
    • Mechanism of Drp1 regulation not yet identified (clarified later)
    • Which GFER isoform mediates the cytosolic function unclear
  9. 2011 High

    NMR structure of the ALR–MIA40 mixed disulfide intermediate showed that ALR's N-terminal domain mimics substrates to bind MIA40's hydrophobic cleft, providing atomic-level understanding of how GFER is recognized by MIA40.

    Evidence NMR structure, disulfide intermediate trapping, mutagenesis

    PMID:21383138

    Open questions at the time
    • Dynamic sampling of the flexible N-terminal domain in the intact homodimer not resolved
  10. 2012 High

    Multiple studies converged to establish the complete intersubunit electron transfer pathway: electrons flow from shuttle Cys of one subunit to the FAD of the other subunit, and then via a two-electron to one-electron switch to two cytochrome c molecules; a ternary Erv1–Mia40–substrate complex ensures both substrate disulfides are inserted; and GFER additionally controls MIA40 mitochondrial targeting.

    Evidence NMR intermediate characterization, crystal structure at 2.0–3.0 Å, in organello and in vivo ternary complex trapping, yeast complementation with human proteins

    PMID:22224850 PMID:22296668 PMID:22910915 PMID:22918950 PMID:23186364

    Open questions at the time
    • Kinetic rate constants for each step of the relay in vivo unknown
    • Structural basis for ternary complex formation not resolved
  11. 2014 High

    Determining that the R182H (human R194H) disease mutation causes progressive FAD release during catalytic turnover provided the molecular explanation for GFER-associated myopathy and confirmed cofactor retention as essential for sustained enzyme activity.

    Evidence In vitro enzyme kinetics, FAD binding assays, yeast genetics

    PMID:25269795

    Open questions at the time
    • Whether pharmacological stabilization of FAD can rescue the defect is untested
    • Patient-specific variability in disease severity unexplained
  12. 2017 High

    Identification of Osm1/fumarate as an alternative anaerobic electron acceptor for Erv1 expanded the disulfide relay model to oxygen-independent conditions and explained how IMS import operates during hypoxia or anaerobiosis.

    Evidence Co-immunoprecipitation of Erv1–Osm1, in vitro reconstitution with fumarate, Tim13 oxidation assays

    PMID:28814504

    Open questions at the time
    • Mammalian anaerobic electron acceptor for GFER not identified
    • In vivo contribution under hypoxia not quantified
  13. 2020 Medium

    Elucidation of the YY1–UBA2–Drp1 SUMOylation axis mechanistically explained how cytosolic GFER suppresses mitochondrial fission, linking its non-oxidase function to transcriptional regulation of the SUMO pathway.

    Evidence ALR knockout mice, co-immunoprecipitation, YY1 nuclear translocation assays, UBA2 transcription analysis during hepatic ischemia-reperfusion

    PMID:33110216

    Open questions at the time
    • Single-lab study; independent replication needed
    • Which GFER isoform is responsible and whether this pathway operates in non-hepatic tissues is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the identity of the mammalian anaerobic electron acceptor for GFER; the structural basis of the ternary GFER–MIA40–substrate complex; whether the cytosolic Drp1-regulatory and IMS oxidoreductase functions of GFER are mediated by distinct isoforms; and the full genotype–phenotype spectrum of GFER mutations in human disease.
  • Mammalian anaerobic electron acceptor unidentified
  • Isoform-specific functional dissection lacking
  • No high-resolution structure of ternary import complex

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 6 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-9609507 Protein localization 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-1643685 Disease 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
CHCHD4CYCSDRP1UBA2YY1
Complex memberships
ALR homodimerMIA40-ALR disulfide relay complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 GFER (human ALR) and its yeast ortholog Erv1p are located in the mitochondrial intermembrane space and are specifically required for the maturation of cytosolic Fe/S proteins, but not mitochondrial Fe/S proteins. Human ALR can functionally replace Erv1p defects in yeast, demonstrating it is the mammalian orthologue. Yeast complementation, subcellular fractionation, genetic analysis of erv1 mutants EMBO reports High 11493598
2005 Erv1 (GFER ortholog) plays a central role in the import and assembly of small IMS proteins (small Tims) that are substrates of Mia40. Cytochrome c serves as the in vivo electron acceptor for Erv1, linking the Mia40-dependent protein import pathway to the mitochondrial respiratory chain. Temperature-sensitive erv1 yeast mutant, in vitro import assays, thiol trapping, complementation with purified Erv1 Journal of molecular biology High 16185707
2005 Erv1 (GFER ortholog) cooperates with Mia40 in the biogenesis of small IMS proteins. Erv1 associates with Mia40 in a reductant-sensitive manner, and small IMS precursors accumulate associated with Mia40 in erv1 mutant mitochondria without assembling into mature oligomeric complexes. Temperature-sensitive yeast erv1-2 mutant, import assays, co-immunoprecipitation Journal of molecular biology High 16181637
2007 Erv1 (GFER ortholog) is itself a substrate of the Mia40-dependent import pathway. After passage through the outer membrane translocase, Erv1 interacts with Mia40 via disulfide bonds. Erv1 does not require twin CX3C or CX9C motifs for import, making it an unusual substrate of this pathway. In organello import assays, thiol trapping, disulfide bond analysis FEBS letters High 17336303
2009 Mia40 and Erv1 constitute a disulfide relay: Mia40 directly oxidizes substrate Tim13 by inserting two disulfide bonds sequentially, and Erv1 is required to reoxidize Mia40. Electrons flow from Tim13 (midpoint potential -310 mV) through Mia40 (-290 mV) to the C130-C133 pair of Erv1 (-150 mV). Mutation of C133 or the shuttle C30-C33 pair of Erv1 abolishes Tim13 oxidation. In vitro reconstitution with purified components, midpoint potential measurements, cysteine mutagenesis, intermediate complex trapping Molecular biology of the cell High 19477928
2009 A homozygous mutation (R194H) in human GFER causes autosomal-recessive infantile mitochondrial disorder with progressive myopathy, combined respiratory-chain deficiency, congenital cataract, sensorineural hearing loss, and developmental delay. Patient cells show reduced cysteine-rich IMS protein content, mitochondrial ultrastructural abnormalities with enlarged IMS space, and accelerated mtDNA deletions. The yeast erv1(R182H) mutant reproduces complex IV deficiency and mtDNA instability. Homozygosity mapping, patient cell biochemistry, yeast erv1 mutant complementation, electron microscopy, respiratory chain enzyme assays American journal of human genetics High 19409522
2010 Erv1 (GFER ortholog) dimerizes noncovalently and subunits cooperate via intersubunit electron exchange. Mia40 promotes complete oxidation of substrate Cox19. Partially oxidized intermediates are efficiently cleared by reduced glutathione, indicating a proofreading role for glutathione in oxidative protein folding in the IMS. In vitro reconstitution with purified cytochrome c, Erv1, Mia40, and Cox19; biochemical characterization of intermediates Molecular cell High 20188670
2010 The N-terminal shuttle domain of Erv1 (GFER ortholog) is necessary and sufficient for interaction with Mia40, and mediates intramolecular electron transfer to the catalytic core domain. The two domains function in trans when added separately with Mia40. Isothermal titration calorimetry, in vitro reconstitution, cysteine mutant analysis, in organello assays Antioxidants & redox signaling High 20367271
2010 Gfer (murine GFER) modulates mitochondrial fission/fusion dynamics in embryonic stem cells by suppressing levels of the mitochondrial fission GTPase Drp1. Knockdown of Gfer leads to excessive mitochondrial fragmentation and mitophagy; inhibition of Drp1 or expression of dominant-negative Drp1 rescues mitochondrial function and pluripotency marker expression in Gfer-KD ESCs. siRNA knockdown, Gfer overexpression, Drp1 inhibitor treatment, dominant-negative Drp1 expression, mitochondrial morphology imaging, flow cytometry Molecular biology of the cell High 20147447
2011 ALR (GFER) interacts with MIA40 through its N-terminal unstructured domain, which mimics substrate binding to MIA40's substrate-binding cleft via hydrophobicity-driven recognition. The C-terminal FAD-binding domain performs the catalytic electron transfer. The covalent mixed disulfide intermediate between ALR and MIA40 was structurally characterized at atomic resolution. NMR structure, biochemical disulfide intermediate trapping, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 21383138
2012 Human ALR controls mitochondrial localization of human MIA40 in addition to its oxidase function. ALR/Erv1 are involved in the biogenesis and mitochondrial targeting of MIA40. The disease-causing ALR mutation (R194H) results in defective MIA40 accumulation in mitochondria. Yeast complementation with human proteins, mitochondrial import assays, patient cell analysis Traffic (Copenhagen, Denmark) High 23186364
2012 Within ALR (GFER), electrons flow from MIA40 through the shuttle domain of one ALR subunit to the FAD cofactor of the other subunit in the homodimer via an intersubunit disulfide intermediate. The flavoprotein ALR undergoes a switch from two-electron to one-electron transfer when donating electrons to two cytochrome c molecules sequentially. NMR characterization of ALR intermediates, biochemical electron transfer assays Journal of the American Chemical Society High 22224850
2012 Erv1 (GFER ortholog) directly participates in Mia40-substrate complex dynamics by forming a ternary Erv1-Mia40-substrate complex, ensuring both disulfide bonds are inserted into substrate proteins. This was demonstrated both in organello and in vivo. In organello and in vivo experiments, disulfide bond trapping, genetic analysis Molecular biology of the cell High 22918950
2012 The C-terminal FAD-binding domain of Erv1/ALR is essential for import into mitochondria by forming a transient intermolecular disulfide bond with Mia40. Complete maturation of Erv1/ALR requires both Mia40-mediated disulfide bond formation and FAD binding, which must occur in a specific sequential order. In vitro and in organello import assays, mutagenesis, biochemical characterization ACS chemical biology High 22296668
2012 Crystal structure of full-length yeast Erv1 reveals the N-terminal shuttle domain forms an amphipathic helix flanked by flexible loops. The structure shows an intermediate state of electron transfer from the NTD to the CTD of the adjacent subunit in the homodimer, establishing the mechanism of intersubunit electron transfer. X-ray crystallography at 2.0 Å (CTD) and 3.0 Å (full-length), computational simulation The Journal of biological chemistry High 22910915
2013 Nrf2 transcriptionally activates ALR (GFER) expression via an antioxidant response element (ARE) in the ALR promoter. In vivo, Nrf2 knockout mice show reduced ALR expression after partial hepatectomy compared to wild-type mice. Promoter luciferase assays, EMSA, Nrf2 knockout mouse hepatectomy model, ChIP Molecular medicine (Cambridge, Mass.) Medium 23887691
2014 The disease-associated R182H mutation (corresponding to human R194H) in yeast Erv1 causes progressive FAD cofactor release during the catalytic cycle, leading to enzyme inactivation. This reveals the molecular mechanism of GFER-related myopathy: impaired FAD cofactor binding during catalysis. In vitro enzyme kinetics, FAD binding assays, in vivo yeast genetics, protein stability studies The Biochemical journal High 25269795
2014 Both shuttle cysteine residues of Erv1 (GFER ortholog) are required for function, but play distinct roles: Cys30 dominantly interacts with the Mia40 CPC motif to receive electrons and resolves the Cys33-Cys130 intermediate; Cys33 is essential for forming the Cys33-Cys130' intersubunit intermediate and transferring electrons to the active site. Yeast genetic approaches, in organello import assays, in vitro enzyme assays, cysteine mutagenesis The Biochemical journal High 24625320
2003 GFER physically interacts with BNIPL (an apoptosis-associated protein), confirmed by both GST pull-down in vitro and co-immunoprecipitation in vivo. Yeast two-hybrid, GST pull-down, co-immunoprecipitation FEBS letters Medium 12681488
2010 ALR (GFER) binds to a high-affinity G-protein coupled receptor on Kupffer cells (Kd ~1.25 nM) and stimulates NO, TNF-α, and IL-6 synthesis via a cholera toxin-sensitive G-protein, p38-MAPK activity, and NF-κB nuclear translocation. ALR-stimulated Kupffer cells produce mediators that promote hepatocyte DNA synthesis. Radioligand binding assay, GTP/G-protein association assay, ELISA, pharmacological inhibitors Journal of cellular physiology Medium 19859909
2020 ALR (GFER) inhibits Drp1 SUMOylation to prevent mitochondrial fission during hepatic ischemia-reperfusion injury. Mechanistically, ALR interacts with the transcription factor YY1, inhibiting YY1 nuclear import and thereby reducing transcription of UBA2 (a SUMO-E1 enzyme subunit), leading to decreased Drp1 SUMOylation. Co-immunoprecipitation, Western blot for SUMOylation, ALR knockout mice, YY1 nuclear translocation assays, UBA2 transcriptional analysis Cell death and differentiation Medium 33110216
2021 BPA exposure reduces GFER levels in rat hippocampal neurons and causes GFER mislocalization from the IMS, resulting in defective COX17 import, cytochrome c release, and caspase-3-mediated apoptosis. GFER was localized in the IMS by immunogold electron microscopy. Immunogold electron microscopy, immunohistochemistry, Western blot, confocal microscopy, caspase-3 activity assay Neurotoxicology Medium 33878312
2006 The ERV/ALR sulfhydryl oxidase domain contains a four-helix bundle that juxtaposes a CxxC dithiol/disulfide motif with a bound FAD cofactor, enabling thiol-to-non-thiol electron transfer. The shuttle disulfide region is modular: transplanting the AtErv1 shuttle disulfide onto the ScErv2 core confers thioredoxin oxidase activity, demonstrating the shuttle domain determines substrate specificity. X-ray crystallography, chimeric enzyme construction, in vitro thioredoxin oxidase activity assays Journal of molecular biology High 16893552
2015 Mia40 can accept up to six electrons from substrates (functioning as an electron sink), undergoing conformational changes when fully reduced. Erv1 is required to reoxidize this fully reduced Mia40; in erv1-101 mutant mitochondria, Mia40 is trapped in a fully reduced state. In vitro oxidation assays with reductants, in organello import assays, protease sensitivity assay The Journal of biological chemistry High 26085103
2017 Osm1 (fumarate reductase) localizes to the mitochondrial IMS and assembles with Erv1 (GFER ortholog) in a complex, functioning as an anaerobic electron acceptor. In reconstitution studies, Osm1/fumarate completes the disulfide exchange pathway for Tim13 oxidation with efficiency comparable to cytochrome c. Co-immunoprecipitation, in vitro reconstitution with purified proteins, mitochondrial import assays Molecular biology of the cell High 28814504
2010 Foxa2 (HNF-3β) transcriptionally regulates ALR (GFER) expression by directly binding to the ALR promoter. This binding is enhanced by IL-6 co-stimulation, and results in increased ALR protein levels. Promoter luciferase assays, EMSA, supershift analysis with anti-Foxa2 antibody, Western blot Biochemical and biophysical research communications Medium 20382118
1994 ALR (GFER) rat protein has a homodimeric structure (~30 kDa under non-reducing conditions) consisting of 125 amino acids (~15 kDa monomer). Recombinant ALR produced in COS cells has equivalent biological potency to purified native ALR in the canine Eck fistula hepatotrophic model. SDS-PAGE under reducing/non-reducing conditions, COS cell expression, in vivo bioassay Proceedings of the National Academy of Sciences of the United States of America Medium 8058770
2012 Zebrafish Alr (ALR/GFER) functions as a flavin-linked sulfhydryl oxidase; mutation of the conserved cysteine in the CxxC motif (C131S) abolishes enzymatic activity. Both wild-type and enzyme-inactive Alr promote liver growth in zebrafish, indicating that ALR promotes liver outgrowth through both sulfhydryl oxidase-dependent and -independent mechanisms. Morpholino knockdown, overexpression, enzymatic activity assays, CxxC mutagenesis, zebrafish liver imaging PloS one Medium 22292055

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Molecular and cellular biology 313 17178841
2001 An essential function of the mitochondrial sulfhydryl oxidase Erv1p/ALR in the maturation of cytosolic Fe/S proteins. EMBO reports 233 11493598
2005 Erv1 mediates the Mia40-dependent protein import pathway and provides a functional link to the respiratory chain by shuttling electrons to cytochrome c. Journal of molecular biology 198 16185707
2010 Mitochondrial disulfide bond formation is driven by intersubunit electron transfer in Erv1 and proofread by glutathione. Molecular cell 158 20188670
1994 Cloning and sequence analysis of the rat augmenter of liver regeneration (ALR) gene: expression of biologically active recombinant ALR and demonstration of tissue distribution. Proceedings of the National Academy of Sciences of the United States of America 158 8058770
2011 Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome. American journal of medical genetics. Part A 149 21671394
2014 The PYRIN domain-only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses. Nature immunology 135 24531343
2005 The essential mitochondrial protein Erv1 cooperates with Mia40 in biogenesis of intermembrane space proteins. Journal of molecular biology 130 16181637
2000 An African swine fever virus ERV1-ALR homologue, 9GL, affects virion maturation and viral growth in macrophages and viral virulence in swine. Journal of virology 126 10627538
2000 A viral member of the ERV1/ALR protein family participates in a cytoplasmic pathway of disulfide bond formation. Proceedings of the National Academy of Sciences of the United States of America 125 11035794
2018 ERV1/ChemR23 Signaling Protects Against Atherosclerosis by Modifying Oxidized Low-Density Lipoprotein Uptake and Phagocytosis in Macrophages. Circulation 118 29739755
2009 The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency. American journal of human genetics 113 19409522
2010 A novel Gfer-Drp1 link in preserving mitochondrial dynamics and function in pluripotent stem cells. Autophagy 96 20581476
1986 Biosynthetic alanine racemase of Salmonella typhimurium: purification and characterization of the enzyme encoded by the alr gene. Biochemistry 96 3524677
2011 Molecular recognition and substrate mimicry drive the electron-transfer process between MIA40 and ALR. Proceedings of the National Academy of Sciences of the United States of America 95 21383138
2007 The Erv1-Mia40 disulfide relay system in the intermembrane space of mitochondria. Biochimica et biophysica acta 95 18179776
2010 Growth factor erv1-like modulates Drp1 to preserve mitochondrial dynamics and function in mouse embryonic stem cells. Molecular biology of the cell 93 20147447
1998 The quiescin Q6 gene (QSCN6) is a fusion of two ancient gene families: thioredoxin and ERV1. Genomics 92 9878249
2020 Inhibition of Drp1 SUMOylation by ALR protects the liver from ischemia-reperfusion injury. Cell death and differentiation 84 33110216
1997 Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax. Oncogene 82 9247308
1996 Analysis of the structure and expression of the augmenter of liver regeneration (ALR) gene. Molecular medicine (Cambridge, Mass.) 79 8900538
2017 Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway. Frontiers in cellular and infection microbiology 75 28149831
2013 Nrf2 activates augmenter of liver regeneration (ALR) via antioxidant response element and links oxidative stress to liver regeneration. Molecular medicine (Cambridge, Mass.) 71 23887691
2006 Gain of function in an ERV/ALR sulfhydryl oxidase by molecular engineering of the shuttle disulfide. Journal of molecular biology 70 16893552
2000 Augmenter of liver regeneration (ALR) may promote liver regeneration by reducing natural killer (NK) cell activity in human liver diseases. Journal of gastroenterology 66 10680666
1994 ERV1 is involved in the cell-division cycle and the maintenance of mitochondrial genomes in Saccharomyces cerevisiae. Current genetics 66 7954891
2009 Reconstitution of the mia40-erv1 oxidative folding pathway for the small tim proteins. Molecular biology of the cell 63 19477928
2002 Use of the alr gene as a food-grade selection marker in lactic acid bacteria. Applied and environmental microbiology 63 12406763
1999 Identification and characterization of receptor for mammalian hepatopoietin that is homologous to yeast ERV1. The Journal of biological chemistry 60 10206950
1995 A new human gene located in the PKD1 region of chromosome 16 is a functional homologue to ERV1 of yeast. Genomics 59 8575761
2005 Expression of augmenter of liver regeneration (ALR) in human liver cirrhosis and carcinoma. Histopathology 58 15982324
2007 The sulfhydryl oxidase Erv1 is a substrate of the Mia40-dependent protein translocation pathway. FEBS letters 55 17336303
1986 Biosynthetic alr alanine racemase from Salmonella typhimurium: DNA and protein sequence determination. Biochemistry 49 3524676
2013 Expression and functional analysis of the CorA-MRS2-ALR-type magnesium transporter family in rice. Plant & cell physiology 47 23926064
1996 Role of DNA sequences outside the cores of DNase hypersensitive sites (HSs) in functions of the beta-globin locus control region. Domain opening and synergism between HS2 and HS3. The Journal of biological chemistry 47 8662652
2012 Disulfide bond formation: sulfhydryl oxidase ALR controls mitochondrial biogenesis of human MIA40. Traffic (Copenhagen, Denmark) 46 23186364
2012 In vivo evidence for cooperation of Mia40 and Erv1 in the oxidation of mitochondrial proteins. Molecular biology of the cell 44 22918950
2005 Mechanisms underlying resistance of pancreatic islets from ALR/Lt mice to cytokine-induced destruction. Journal of immunology (Baltimore, Md. : 1950) 44 16002729
2001 Unusual resistance of ALR/Lt mouse beta cells to autoimmune destruction: role for beta cell-expressed resistance determinants. Proceedings of the National Academy of Sciences of the United States of America 44 11136257
2010 Augmenter of liver regeneration (ALR) protects human hepatocytes against apoptosis. Biochemical and biophysical research communications 43 21108930
2012 Divergence of Erv1-associated mitochondrial import and export pathways in trypanosomes and anaerobic protists. Eukaryotic cell 42 23264646
1999 Highly divergent amino termini of the homologous human ALR and yeast scERV1 gene products define species specific differences in cellular localization. European journal of cell biology 39 10384986
2017 ERV1 Overexpression in Myeloid Cells Protects against High Fat Diet Induced Obesity and Glucose Intolerance. Scientific reports 37 28993702
2012 An electron-transfer path through an extended disulfide relay system: the case of the redox protein ALR. Journal of the American Chemical Society 36 22224850
2010 Upregulation of MetC is essential for D-alanine-independent growth of an alr/dadX-deficient Escherichia coli strain. Journal of bacteriology 36 21193606
2005 Regulation of chemosensory and GABAergic motor neuron development by the C. elegans Aristaless/Arx homolog alr-1. Development (Cambridge, England) 36 15790968
2005 mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes. Diabetologia 35 15692809
2021 Epigenome-wide association study of sarcopenia: findings from the Hertfordshire Sarcopenia Study (HSS). Journal of cachexia, sarcopenia and muscle 34 34862756
2012 Augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis. PloS one 34 22292055
2003 Genetic analysis of resistance to Type-1 Diabetes in ALR/Lt mice, a NOD-related strain with defenses against autoimmune-mediated diabetogenic stress. Immunogenetics 34 14513297
2010 Liver regeneration associated protein (ALR) exhibits antimetastatic potential in hepatocellular carcinoma. Molecular medicine (Cambridge, Mass.) 33 21152698
2002 The alanine racemase gene alr is an alternative to antibiotic resistance genes in cloning systems for industrial Corynebacterium glutamicum strains. Journal of biotechnology 33 12204559
2017 Association of a variant in the gene encoding for ERV1/ChemR23 with reduced inflammation in visceral adipose tissue from morbidly obese individuals. Scientific reports 32 29146976
2010 The N-terminal shuttle domain of Erv1 determines the affinity for Mia40 and mediates electron transfer to the catalytic Erv1 core in yeast mitochondria. Antioxidants & redox signaling 32 20367271
1999 Resistance of ALR/Lt islets to free radical-mediated diabetogenic stress is inherited as a dominant trait. Diabetes 31 10535453
2008 Transcription factor Ap2delta associates with Ash2l and ALR, a trithorax family histone methyltransferase, to activate Hoxc8 transcription. Proceedings of the National Academy of Sciences of the United States of America 30 18495928
1984 Stimulation of HTC hepatoma cell growth in vitro by hepatic stimulator substance (HSS). Interactions with serum, insulin, glucagon, epidermal growth factor and platelet derived growth factor. Experimental cell research 30 6363107
2017 Osm1 facilitates the transfer of electrons from Erv1 to fumarate in the redox-regulated import pathway in the mitochondrial intermembrane space. Molecular biology of the cell 29 28814504
1993 The 92-min region of the Escherichia coli chromosome: location and cloning of the ubiA and alr genes. Gene 29 8335265
2012 Targeting and maturation of Erv1/ALR in the mitochondrial intermembrane space. ACS chemical biology 28 22296668
2010 Cholera toxin-sensitive GTP-binding protein-coupled activation of augmenter of liver regeneration (ALR) receptor and its function in rat kupffer cells. Journal of cellular physiology 28 19859909
2001 Novel human HALR (MLL3) gene encodes a protein homologous to ALR and to ALL-1 involved in leukemia, and maps to chromosome 7q36 associated with leukemia and developmental defects. Cancer detection and prevention 28 11718452
2013 Augmenter of liver regeneration (ALR) is a novel biomarker of hepatocellular stress/inflammation: in vitro, in vivo and in silico studies. Molecular medicine (Cambridge, Mass.) 27 23073658
2003 The apoptosis-associated protein BNIPL interacts with two cell proliferation-related proteins, MIF and GFER. FEBS letters 27 12681488
2003 Effect of acute ethanol exposure on hepatic stimulator substance (HSS) levels during liver regeneration: protective function of HSS. Digestive diseases and sciences 27 14627336
2017 ALR encoding dCMP deaminase is critical for DNA damage repair, cell cycle progression and plant development in rice. Journal of experimental botany 26 29186482
2015 The aspartate-less receiver (ALR) domains: distribution, structure and function. PLoS pathogens 25 25875291
2002 Genetic control of neutrophil superoxide production in diabetes-resistant ALR/Lt mice. Free radical biology & medicine 25 11937300
2017 Erv1 of Arabidopsis thaliana can directly oxidize mitochondrial intermembrane space proteins in the absence of redox-active Mia40. BMC biology 24 29117860
2012 Structure of yeast sulfhydryl oxidase erv1 reveals electron transfer of the disulfide relay system in the mitochondrial intermembrane space. The Journal of biological chemistry 24 22910915
2005 Expression of the sulfhydryl oxidase ALR (Augmenter of Liver Regeneration) in adult rat brain. Brain research 24 15916753
2021 Bisphenol-A inhibits mitochondrial biogenesis via impairment of GFER mediated mitochondrial protein import in the rat brain hippocampus. Neurotoxicology 22 33878312
2005 The Caenorhabditis elegans aristaless orthologue, alr-1, is required for maintaining the functional and structural integrity of the amphid sensory organs. Molecular biology of the cell 22 16055504
2005 Removal of arsenic and humic substances (HSs) by electro-ultrafiltration (EUF). Journal of hazardous materials 21 15943938
2004 ERK1/2 contributes negative regulation to STAT3 activity in HSS-transfected HepG2 cells. Cell research 21 15115615
2015 Adrenal Insufficiency in Mitochondrial Disease: A Rare Case of GFER-Related Mitochondrial Encephalomyopathy and Review of the Literature. Journal of child neurology 20 26018198
2018 Augmenter of liver regeneration (ALR) regulates acute pancreatitis via inhibiting HMGB1/TLR4/NF-κB signaling pathway. American journal of translational research 19 29511434
2015 Cytosolic Fe-S Cluster Protein Maturation and Iron Regulation Are Independent of the Mitochondrial Erv1/Mia40 Import System. The Journal of biological chemistry 19 26396185
2015 Skeletal muscle morphology in sarcopenia defined using the EWGSOP criteria: findings from the Hertfordshire Sarcopenia Study (HSS). BMC geriatrics 19 26678672
2022 Supervised dimensionality reduction for exploration of single-cell data by HSS-LDA. Patterns (New York, N.Y.) 18 36033591
2017 Further delineation of a rare recessive encephalomyopathy linked to mutations in GFER thanks to data sharing of whole exome sequencing data. Clinical genetics 18 28155230
2013 Tegillarca granosa extract Haishengsu (HSS) suppresses expression of mdr1, BCR/ABL and sorcin in drug-resistant K562/ADM tumors in mice. Advances in medical sciences 18 23729583
2010 Foxa2 (HNF-3beta) regulates expression of hepatotrophic factor ALR in liver cells. Biochemical and biophysical research communications 18 20382118
2003 Haemorrhagic smolt syndrome (HSS) in Norway: pathology and associated virus-like particles. Diseases of aquatic organisms 18 12718466
2020 The role of PIAS3, p-STAT3 and ALR in colorectal cancer: new translational molecular features for an old disease. European review for medical and pharmacological sciences 17 33155205
2018 Bile acid-induced apoptosis and bile acid synthesis are reduced by over-expression of Augmenter of Liver Regeneration (ALR) in a STAT3-dependent mechanism. Experimental cell research 17 30500391
2006 Expression of alr gene from Corynebacterium glutamicum ATCC 13032 in Escherichia coli and molecular characterization of the recombinant alanine racemase. Journal of biotechnology 17 16707184
2014 The disease-associated mutation of the mitochondrial thiol oxidase Erv1 impairs cofactor binding during its catalytic reaction. The Biochemical journal 16 25269795
2011 Augmenter of liver regeneration (ALR) gene therapy attenuates CCl₄-induced liver injury and fibrosis in rats. Biochemical and biophysical research communications 16 22033404
1994 A negative cis-acting G-fer element participates in the regulation of expression of the human H-ferritin-encoding gene (FERH). Gene 16 8144027
2018 Muscle Mass, Muscle Morphology and Bone Health Among Community-Dwelling Older Men: Findings from the Hertfordshire Sarcopenia Study (HSS). Calcified tissue international 15 29372275
2014 Mitochondrial thiol oxidase Erv1: both shuttle cysteine residues are required for its function with distinct roles. The Biochemical journal 15 24625320
2004 Effect of hepatic stimulator substance (HSS) on cadmium-induced acute hepatotoxicity in the rat liver. Digestive diseases and sciences 15 15309895
1987 Chromosomal localization of human endogenous retroviral element ERV1 to 18q22----q23 by in situ hybridization. Cytogenetics and cell genetics 15 3568764
2019 Overexpression of augmenter of liver regeneration (ALR) mitigates the effect of H2O2-induced endoplasmic reticulum stress in renal tubule epithelial cells. Apoptosis : an international journal on programmed cell death 14 30680481
2019 Santacruzamate A Ameliorates AD-Like Pathology by Enhancing ER Stress Tolerance Through Regulating the Functions of KDELR and Mia40-ALR in vivo and in vitro. Frontiers in cellular neuroscience 14 30886573
2015 Mia40 Protein Serves as an Electron Sink in the Mia40-Erv1 Import Pathway. The Journal of biological chemistry 14 26085103
2008 Cloning, expression and subcellular distribution of a Rana grylio virus late gene encoding ERV1 homologue. Molecular biology reports 14 18819018
2022 Identification of Putative Plant-Based ALR-2 Inhibitors to Treat Diabetic Peripheral Neuropathy. Current issues in molecular biology 13 35877418
2005 Recruitment of alkaloid-specific homospermidine synthase (HSS) from ubiquitous deoxyhypusine synthase: Does Crotalaria possess a functional HSS that still has DHS activity? Phytochemistry 13 15935411