GFER encodes ALR, a FAD-dependent sulfhydryl oxidase that regenerates CHCHD4/MIA40 in the mitochondrial intermembrane space. Its cysteine relay transfers electrons from reduced MIA40 through FAD to downstream acceptors, supporting oxidative folding and import of mitochondrial proteins. Cytochrome c and oxygen can accept electrons. The long natural product contains the N-terminal relay extension; the shorter product lacks it and has a reported cytoplasmic pool, while its human extracellular occurrence remains unresolved. Biallelic GFER variants cause a mitochondrial disorder with progressive myopathy, congenital cataract, hearing loss and respiratory-chain deficiency.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001889 liver development | IBA GO_REF:0000033 | UNDECIDED | Summary: Preserve the valid regenerative ancestry while the donor-assay participation question remains unresolved. Reason: The actual Tetrapoda IBD reaches human GFER and the rat donor. Liver regeneration is a verified descendant of liver development; adulthood and absent human testing are not objections. Positive rat knockdown and recombinant-protein bioassays remain intact. Uninspected full protocols leave unresolved whether the results distinguish a regenerative effector from general survival/redox dependence. This is an assay-participation question, not a faulty node, target loss or contradicted donor. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000291234 UNRESOLVED The actual Tetrapoda liver-development IBD and path to the human leaf are intact. Rat regeneration is a valid descendant process, and the current donor IMP has experimental grounding. The unresolved issue is interpretation of the original donor assays, not donor count, target-self circularity or absence of direct human testing. |
| GO:0005515 protein binding | IPI PMID:12681488 The apoptosis-associated protein BNIPL interacts with two ce... | REMOVE | Summary: The BNIPL interaction is positive but generic binding is uninformative. Reason: The authentic abstract reports yeast two-hybrid, pull-down and co-immunoprecipitation support. BNIPL has a tentative bridging model, which does not yet establish a specific partner-class replacement here. Remove only the generic annotation; retain the interaction and avoid assigning BNIPL-mediated cell-death or proliferation effects to GFER. |
| GO:0005515 protein binding | IPI PMID:23676665 Protein import and oxidative folding in the mitochondrial in... | MODIFY | Summary: Refine the functional interaction with the folding chaperone MIA40. Reason: The positive GFER–MIA40 interaction supports folding-chaperone binding, preserving substrate competition and redox regeneration without transferring MIA40 substrate recognition. Proposed replacements: protein-folding chaperone binding Supporting Evidence: UniProtKB:Q8N4Q1 file:human/GFER/GFER-external-evidence.md Functions as a chaperone |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Preserve the positive PLEKHF2 screen interaction without a generic MF claim. Reason: The original HI-II-14 table identifies GFER–PLEKHF2 in two screens, corroborated by three retained IntAct records. PLEKHF2 endosomal and lipid-binding roles do not by themselves define a supported specific binding class or confer membrane trafficking on GFER. This removal does not dispute the positive pair. |
| GO:0005515 protein binding | IPI PMID:32353859 A SARS-CoV-2 protein interaction map reveals targets for dru... | REMOVE | Summary: Retain the viral association as evidence, without generic protein-binding annotation. Reason: The exact curated pair is GFER with the processed nsp10 chain, not the whole polyprotein. The retained pull-down record supports an association; it need not be a direct binary contact. Nsp10 stimulates viral enzymes but is not thereby itself their catalyst. No specific GFER activity follows from this generic association. |
| GO:0005515 protein binding | IPI PMID:33060197 Comparative host-coronavirus protein interaction networks re... | REMOVE | Summary: The comparative coronavirus screen provides another positive nsp10 association. Reason: The retained source-specific pull-down record preserves GFER–nsp10 association. Remove the uninformative MF label without rejecting that result, inventing infected-cell co-localization, or assigning nsp10-dependent viral catalysis to GFER. A precise supported replacement is not established by this record. |
| GO:0005515 protein binding | IPI PMID:36217030 A comprehensive SARS-CoV-2-human protein-protein interactome... | REMOVE | Summary: Preserve the independently recovered binary GFER–nsp10 result. Reason: Original Supplementary Table1, sheetS1 row107, identifies nsp10–GFER (GeneID2671) by Y2H. This is positive assay evidence distinct from the earlier pull-down associations. The generic MF label adds no mechanism, and neither viral-enzyme regulation nor nsp10 catalytic activity can be transferred to GFER. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | UNDECIDED | Summary: The reported extracellular pool lacks resolved primary human secretion evidence. Reason: UniProt assigns a secreted pool to the short product, but the inspected location statement has no linked experimental evidence or primary secretion assay. Retain this positive database assertion while its human experimental basis remains unresolved. Neither the dominant mitochondrial role nor the absence of a conventional signal peptide disproves extracellular occurrence; no isoform field is added to the unqualified incoming row. Supporting Evidence: GO_REF:0000044 UniProtKB:P55789 |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Retain cytoplasmic occurrence with the source product context explicit. Reason: UniProt assigns cytoplasm to the short natural product, whereas the long product has the mitochondrial relay role. HPA independently reports a cytosolic pool but does not identify the responsible natural product. Keep the broad source-specific location without falsely reassigning isoform2 to mitochondria or treating HPA staining as an isoform-specific assay. Supporting Evidence: GO_REF:0000044 GO_REF:0000052 UniProtKB:P55789 |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: MitoCoP directly supports mitochondrial occurrence. Reason: The original MitoCoP target group experimentally includes P55789 and P55789-2. This supports the mitochondrion assertion but does not resolve a unique natural product or the intermembrane space. Retain the organelle observation alongside the separate IMS annotation. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the supported ancestral mitochondrial location. Reason: The Eukaryota IBD reaches the exact human GFER leaf without an intervening negative assertion, consistent with human mitochondrial evidence. Mitochondrion remains an informative core location; the separately supported IMS annotation does not replace this inherited organelle assertion. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000291228 SUPPORTS TRANSFER The actual AN0 mitochondrial IBD reaches the exact 205-residue human AN18 leaf without an intervening negative assertion. Both this inherited organelle location and the separate target IMS annotation are retained. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: HPA supports mitochondrial localization at the organelle level. Reason: The inspected HPA target metadata reports mitochondrial staining. Image pixels and product-specific localization were not independently examined. Retain this organelle-level observation without assigning subcompartment resolution to the microscopy; the separate IMS annotation remains. |
| GO:0005739 mitochondrion | IDA PMID:23676665 Protein import and oxidative folding in the mitochondrial in... | ACCEPT | Summary: Retain the human-cell mitochondrial localization assertion. Reason: The original human-cell evidence and the UniProt experimental evidence tag support mitochondrion. The supplemental localization images and construct sequences remain uninspected. Keep that evidence at its asserted organelle granularity, alongside the independently supported IMS annotation. |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: The mitochondrial mapping describes a core compartment. Reason: UniProt assigns the long product to mitochondria as well as the IMS. The mitochondrial mapping is correct and informative at gene level. Retain it alongside the existing IMS annotation without manufacturing an isoform-specific incoming assertion. |
| GO:0005758 mitochondrial intermembrane space | IEA GO_REF:0000044 | ACCEPT | Summary: Retain the mitochondrial intermembrane-space location of the long product. Reason: Retain long-product IMS localization without excluding the separately assigned cytoplasmic or secreted short-product pools. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Retain the experimentally reported cytosolic pool as non-core. Reason: Current HPA metadata reports enhanced-reliability cytosolic staining across several human cell lines and two antibodies. This supports genuine secondary occurrence alongside mitochondria. The actual image pixels were not independently examined, and these gene-level data do not assign the staining to a particular natural product or establish an additional cytosolic molecular mechanism. Supporting Evidence: GO_REF:0000052 |
| GO:0015035 protein-disulfide reductase activity | IDA PMID:22224850 An electron-transfer path through an extended disulfide rela... | ACCEPT | Summary: GFER catalyzes protein thiol/disulfide interconversion. Reason: The official definition describes protein thiol/disulfide interconversion without specifying reaction direction or terminal acceptor. Human ALR oxidizes reduced MIA40 while relaying electrons to cytochrome c. This core route is not exhausted by the O2-specific sulfhydryl-oxidase child term; ACCEPT does not imply generalized disulfide reduction. Supporting Evidence: |
| GO:0016971 flavin-dependent sulfhydryl oxidase activity | EXP PMID:20593814 Structure of the human sulfhydryl oxidase augmenter of liver... | ACCEPT | Summary: Human ALR supports FAD-dependent protein oxidation. Reason: Human protein-oxidation assays support the activity. The corroborating MIA40-substrate study principally uses engineered C154A/C165A ALR; model-DTT turnover and different terminal-acceptor assays remain distinct. |
| GO:0016971 flavin-dependent sulfhydryl oxidase activity | EXP PMID:22224850 An electron-transfer path through an extended disulfide rela... | ACCEPT | Summary: Retain the established sulfhydryl oxidase activity with its assay scope. Reason: This human relay reconstitution uses cytochrome c; independent earlier assays establish oxygen turnover. |
| GO:0016971 flavin-dependent sulfhydryl oxidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Retain the ancestral flavin-dependent sulfhydryl oxidase activity. Reason: The human leaf inherits the Eukaryota sulfhydryl-oxidase IBD without intervening loss. Direct human protein-oxidation experiments independently corroborate this conserved catalytic activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000291228 SUPPORTS TRANSFER Literal IBD at AN0; target AN18/PTN002489220 matches the official205-residue human sequence. All incoming donors map into the actual family; no negative assertion occurs on the target path. |
| GO:0016971 flavin-dependent sulfhydryl oxidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic sulfhydryl oxidase assertion agrees with human biochemistry. Reason: Human ALR catalyzes FAD-dependent protein oxidation, independently supporting the combined electronic mapping. The source-specific engineered reagent and electron-acceptor limits remain applicable. |
| GO:0016972 thiol oxidase activity | EXP PMID:20593814 Structure of the human sulfhydryl oxidase augmenter of liver... | KEEP AS NON CORE | Summary: The broad experimental thiol oxidase annotation retains useful substrate breadth. Reason: Retain directly measured DTT turnover by engineered reagents as secondary in-vitro activity. Supporting Evidence: |
| GO:0016972 thiol oxidase activity | EXP PMID:22224850 An electron-transfer path through an extended disulfide rela... | KEEP AS NON CORE | Summary: Retain the broader thiol activity with direct and independent support distinguished. Reason: Independent DTT assays support this broader activity; here they are prior work. |
| GO:0016972 thiol oxidase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Retain broader thiol oxidation as measured secondary substrate scope. Reason: Measured DTT oxidation preserves broader substrate scope without a physiological DTT claim. |
| GO:0050660 flavin adenine dinucleotide binding | IBA GO_REF:0000033 | ACCEPT | Summary: FAD binding is a conserved catalytic-cofactor property. Reason: The conserved FAD-binding IBD reaches human GFER without intervening loss. Human ALR biochemistry directly establishes the flavin cofactor used in the cysteine redox relay. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000291228 SUPPORTS TRANSFER Literal IBD at AN0; target AN18/PTN002489220 matches the official205-residue human sequence. All incoming donors map into the actual family; no negative assertion occurs on the target path. |
| GO:0050660 flavin adenine dinucleotide binding | IDA PMID:22224850 An electron-transfer path through an extended disulfide rela... | ACCEPT | Summary: Retain direct FAD binding by human ALR. Reason: Human ALR binds catalytic FAD; retain the engineered-construct limits. Supporting Evidence: |
| GO:0160203 protein import into the intermembrane space via the disulfide relay system | IDA PMID:21383138 Molecular recognition and substrate mimicry drive the electr... | ACCEPT | Summary: GFER performs the redox-regeneration step of disulfide-relay import. Reason: GFER regenerates MIA40 for disulfide-relay import. Human-cell GFER rescue additionally improves respiratory activity; that result is corroborative rather than a direct import-rate measurement. Human redox evidence remains distinct from yeast import experiments. |
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Download this section (compressed HTML)Q: Which source-specific donor experiments distinguish a regenerative effector role from general redox-dependent survival in the conserved liver-development assertion?
Q: How are the natural 205- and 125-residue products distributed and secreted in human cells, and which substrates do they oxidize in those compartments?
Experiment: Compare sequence-verified natural long and short products at matched expression for compartmental distribution, extracellular release and MIA40 redox state. Analyze engineered truncations and cysteine substitutions separately; do not equate secretion with a regenerative mechanism.
Type: Natural-product localization and redox function
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