ISCU is the primary scaffold protein of the mitochondrial iron-sulfur cluster (ISC) assembly machinery in human cells. It provides the structural platform upon which nascent [2Fe-2S] clusters are assembled de novo before transfer to recipient apoproteins. The mature mitochondrial form (isoform 1/ISCU2) functions in the mitochondrial matrix as part of a core ISC complex that includes the cysteine desulfurase NFS1-LYRM4-NDUFAB1 subcomplex, frataxin (FXN) as an allosteric activator, and ferredoxin-2 (FDX2) as the electron donor. During cluster assembly, persulfide sulfur is transferred from NFS1 Cys381 to ISCU Cys138, and FDX2 provides reducing equivalents to reduce persulfide to sulfide for [2Fe-2S] formation. ISCU dimerization, mediated by Tyr-35, is critical for de novo cluster synthesis. Following cluster assembly, the HSPA9-HSCB chaperone system catalyzes ATP-dependent cluster release from ISCU for transfer to downstream carriers (GLRX5, NFU1, ISCA1/ISCA2) and ultimately to recipient Fe-S proteins. A cytosolic isoform (isoform 2/ISCU1) participates in cytoplasmic Fe-S biogenesis. ISCU deficiency causes hereditary myopathy with exercise intolerance and lactic acidosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for cytoplasm localization based on phylogenetic inference. ISCU has two isoforms - isoform 2 (ISCU1) lacks the mitochondrial targeting sequence and localizes to the cytoplasm where it participates in cytoplasmic Fe-S cluster biogenesis (PMID:11060020, PMID:16527810). The IBA is phylogenetically consistent with yeast and other orthologs. Reason: The cytoplasmic localization is well-supported for isoform 2 (ISCU1). UniProt confirms cytoplasmic localization for this isoform, and functional studies demonstrate a cytoplasmic ISC assembly complex exists (PMID:11060020, PMID:16527810, PMID:29309586). Supporting Evidence: PMID:11060020 Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. PMID:16527810 Roles of the mammalian cytosolic cysteine desulfurase, ISCS, and scaffold protein, ISCU, in iron-sulfur cluster assembly. file:human/ISCU/ISCU-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0008198 ferrous iron binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for ferrous iron binding. ISCU binds Fe2+ as part of the [2Fe-2S] cluster assembly process. Structural and spectroscopic studies confirm iron coordination at the assembly site through conserved cysteine residues (Cys69, Cys95, Cys138) and His137 (PMID:38627381, PMID:24971490). Reason: Ferrous iron binding is a core function of ISCU as the scaffold for [2Fe-2S] cluster assembly. Recent 2024 cryo-EM and Mossbauer spectroscopy studies demonstrate Fe coordination during cluster assembly (Schulz et al. 2024, Nat Commun). Supporting Evidence: PMID:38627381 Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2 |
| GO:0006879 intracellular iron ion homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for iron ion homeostasis. ISCU's role in Fe-S cluster biogenesis is essential for maintaining cellular iron homeostasis, as Fe-S clusters regulate iron uptake and storage pathways. Studies show that ISCU knockdown affects cellular iron regulation (PMID:16517407, PMID:23508953). Reason: While ISCU's primary function is Fe-S cluster assembly, this directly impacts iron homeostasis. The IBA is phylogenetically appropriate. Studies demonstrate ISCU's role in iron regulation (PMID:16517407, PMID:23508953). Supporting Evidence: PMID:16517407 Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis. PMID:23508953 Mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation stabilizes ISCU protein: implications for iron metabolism. |
| GO:0005759 mitochondrial matrix | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for mitochondrial matrix localization. ISCU isoform 1 (ISCU2) contains a mitochondrial targeting sequence (residues 1-34) and functions in the mitochondrial matrix as the primary site for de novo Fe-S cluster assembly (PMID:11060020, PMID:26702583). Reason: Mitochondrial matrix localization is the primary site for ISCU function. UniProt confirms the N-terminal transit peptide (aa 1-34) and experimental evidence supports matrix localization (PMID:11060020, PMID:26702583). Supporting Evidence: PMID:11060020 Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly. |
| GO:0051537 2 iron, 2 sulfur cluster binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for [2Fe-2S] cluster binding. This is a core molecular function of ISCU as the scaffold protein for [2Fe-2S] assembly. The assembled cluster is coordinated by conserved cysteine residues (Cys69, Cys95, Cys138) before transfer to recipient proteins. Reason: [2Fe-2S] cluster binding is the defining molecular function of ISCU. Recent structural studies (PMID:34824239, PMID:31101807) and biochemical work (PMID:24971490) demonstrate this function directly. Supporting Evidence: PMID:34824239 N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by ISCU2 dimerization. PMID:24971490 Human frataxin activates Fe-S cluster biosynthesis by facilitating sulfur transfer chemistry. |
| GO:0005506 iron ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro domain mapping. While accurate, this is a more general term than ferrous iron binding (GO:0008198) which is already annotated with IBA evidence. Reason: The IEA is correct based on domain analysis. It is more general than the IBA annotation for ferrous iron binding, but both can coexist as the IEA provides independent computational evidence. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location mapping. Some nuclear localization has been reported for isoform 2 (cytoplasmic isoform) based on TAS evidence (PMID:16527810). Reason: Nuclear localization is supported by literature for the cytosolic isoform (PMID:16527810). This is a minor localization and not the primary functional site. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from UniProt subcellular location mapping for cytoplasm. Duplicate of the IBA annotation above but from a different evidence source. Reason: Cytoplasmic localization is well-supported for isoform 2 (ISCU1). Multiple evidence sources (IBA and IEA) appropriately capture this localization. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from automated annotation combining multiple sources. ISCU isoform 1 localizes to mitochondria where it functions in Fe-S cluster assembly. Reason: Mitochondrial localization is the primary site for ISCU function (isoform 1). This is well-established and supported by multiple experimental studies. |
| GO:0016226 iron-sulfur cluster assembly | IEA GO_REF:0000002 | ACCEPT | Summary: IEA from InterPro domain mapping for iron-sulfur cluster assembly. This is the core biological process that ISCU is involved in. Reason: Iron-sulfur cluster assembly is the primary biological process for ISCU. This is appropriate as the parent term for more specific [2Fe-2S] cluster assembly. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA from UniProt keyword mapping. Very general term - ISCU binds iron (for cluster assembly) and can also bind zinc (which modulates NFS1 activity). Reason: This general term is appropriate given ISCU's metal binding properties. More specific annotations (ferrous iron binding, zinc ion binding) provide greater detail. |
| GO:0051536 iron-sulfur cluster binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA from InterPro for iron-sulfur cluster binding. This is the parent term of [2Fe-2S] cluster binding (GO:0051537) which is annotated with IBA. Reason: General term for Fe-S cluster binding is appropriate as it encompasses the more specific [2Fe-2S] cluster binding function. Domain analysis supports this annotation. |
| GO:0005515 protein binding | IPI PMID:15778465 Targeted proteomic analysis of 14-3-3 sigma, a p53 effector ... | MARK AS OVER ANNOTATED | Summary: IPI for protein binding with SFN (14-3-3 sigma). This is a high-throughput proteomic study identifying 14-3-3 interactions. Reason: Protein binding is too vague. ISCU binds specific partners (NFS1, FXN, HSCB, HSPA9, GLRX5) as part of its Fe-S cluster assembly function. The 14-3-3 interaction may be related to phosphorylation-dependent regulation (Ser-14 phosphorylation) but is not well characterized functionally. Supporting Evidence: PMID:15778465 Epub 2005 Mar 18. Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer. |
| GO:0005515 protein binding | IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by... | MARK AS OVER ANNOTATED | Summary: IPI for protein binding from large-scale protein-protein interaction mapping study. High-throughput data with limited functional validation. Reason: Generic protein binding annotation from high-throughput study. More informative MF terms should be used to describe ISCU's specific protein interactions. Supporting Evidence: PMID:17353931 Large-scale mapping of human protein-protein interactions by mass spectrometry. |
| GO:0005515 protein binding | IPI PMID:24606901 Cochaperone binding to LYR motifs confers specificity of iro... | KEEP AS NON CORE | Summary: IPI for protein binding with SDHB. This study characterized cochaperone binding to LYR motifs and Fe-S cluster delivery to SDHB. Reason: This interaction is functionally relevant - ISCU participates in Fe-S cluster delivery to SDHB. However, protein binding is a vague term. The interaction represents a cluster transfer event rather than a core binding function. Supporting Evidence: PMID:24606901 Cochaperone binding to LYR motifs confers specificity of iron sulfur cluster delivery. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: IPI from proteome-scale interactome study. High-throughput Y2H data. Reason: High-throughput interaction data with many interactions reported. Protein binding is too general to be informative for GO annotation purposes. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:26749241 Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clu... | KEEP AS NON CORE | Summary: IPI for protein binding with SDHB, related to SDHAF1 mutations affecting Fe-S cluster transfer. Reason: This study shows ISCU participates in Fe-S cluster delivery pathway to SDHB. The interaction is functionally meaningful but protein binding is vague. Supporting Evidence: PMID:26749241 2015 Dec 31. Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clusters to SDHB. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: IPI from study of genetic variant effects on protein-protein interactions. Reason: High-throughput study. Protein binding is too generic for GO annotation. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI from human binary protein interactome reference map. Reason: High-throughput interactome study. Protein binding is too generic. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MARK AS OVER ANNOTATED | Summary: IPI from OpenCell endogenous tagging study for cellular organization mapping. Reason: Large-scale study. Protein binding annotation is not informative. Supporting Evidence: PMID:35271311 2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization. |
| GO:0005515 protein binding | IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c... | MARK AS OVER ANNOTATED | Summary: IPI for 14-3-3 protein interactions. Study on chaperone-like role of 14-3-3 proteins. Reason: 14-3-3 binding may relate to Ser-14 phosphorylation-dependent regulation of ISCU stability. However, protein binding is too generic and the functional significance is not well established. Supporting Evidence: PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human cells. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: IPI from multimodal cell maps study for structural and functional genomics. Reason: High-throughput study. Protein binding is too generic. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics. |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from ortholog transfer (mouse). ISCU dimerization is essential for [2Fe-2S] cluster assembly, mediated by Tyr-35. Reason: ISCU homodimerization is well-established and critical for its function. This is supported by experimental evidence (IDA) from PMID:29097656 and PMID:34824239. Supporting Evidence: PMID:34824239 N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by ISCU2 dimerization |
| GO:0044572 [4Fe-4S] cluster assembly | IEA GO_REF:0000120 | MODIFY | Summary: IEA for [4Fe-4S] cluster assembly. Recent evidence suggests ISCU primarily assembles [2Fe-2S] clusters, which are then converted to [4Fe-4S] by downstream carriers (ISCA1, ISCA2, IBA57, NFU1). Reason: Recent studies (PMID:34824239) clarify that ISCU assembles [2Fe-2S] clusters, not [4Fe-4S] directly. The [4Fe-4S] clusters are assembled by downstream carriers. UniProt CAUTION states: "Recent reports confirm that only [2Fe-2S] clusters are formed by the core ISC assembly complex." Proposed replacements: [2Fe-2S] cluster assembly Supporting Evidence: PMID:34824239 N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by ISCU2 dimerization |
| GO:0099128 mitochondrial [2Fe-2S] assembly complex | IEA GO_REF:0000120 | ACCEPT | Summary: IEA for membership in mitochondrial [2Fe-2S] assembly complex. ISCU is a core component of this complex along with NFS1, LYRM4, NDUFAB1, FXN, and FDX2. Reason: ISCU is a core component of the mitochondrial [2Fe-2S] assembly complex. This is well-established by structural studies (PMID:31101807, PMID:29097656). Supporting Evidence: PMID:31101807 Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: IDA from immunofluorescence data curation (Human Protein Atlas). Confirms mitochondrial localization. Reason: Mitochondrial localization is the primary site for ISCU isoform 1. Well-supported by multiple studies and imaging data. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: IDA from immunofluorescence data curation (Human Protein Atlas). Cytosolic localization likely reflects isoform 2 (ISCU1). Reason: Cytosolic localization is appropriate for isoform 2 which lacks the mitochondrial targeting sequence. |
| GO:0005739 mitochondrion | NAS PMID:27519411 Architecture of the Human Mitochondrial Iron-Sulfur Cluster ... | ACCEPT | Summary: NAS from ComplexPortal for mitochondrial localization. Study describes architecture of human mitochondrial Fe-S cluster assembly machinery. Reason: Mitochondrial localization is well-established for the functional ISCU isoform. Supporting Evidence: PMID:27519411 Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery. |
| GO:0016226 iron-sulfur cluster assembly | NAS PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S ... | ACCEPT | Summary: NAS from ComplexPortal for iron-sulfur cluster assembly process. This study characterized the structure and dynamics of the mitochondrial Fe/S cluster synthesis complex. Reason: Iron-sulfur cluster assembly is the core biological process for ISCU. Supporting Evidence: PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex. |
| GO:0008198 ferrous iron binding | IDA PMID:38627381 Mechanism and structural dynamics of sulfur transfer during ... | ACCEPT | Summary: IDA from 2024 structural study showing mechanism of sulfur transfer and Fe coordination during [2Fe-2S] cluster assembly on ISCU2. Reason: Direct experimental evidence for ferrous iron binding during cluster assembly. This is a core molecular function. Supporting Evidence: PMID:38627381 Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2. |
| GO:0044571 [2Fe-2S] cluster assembly | IDA PMID:38627381 Mechanism and structural dynamics of sulfur transfer during ... | ACCEPT | Summary: IDA from 2024 structural study on [2Fe-2S] cluster assembly mechanism. This is the defining biological process for ISCU. Reason: Direct experimental evidence for [2Fe-2S] cluster assembly as ISCU's core function. Supporting Evidence: PMID:38627381 Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2. |
| GO:0140132 iron-sulfur cluster chaperone activity | IDA PMID:38627381 Mechanism and structural dynamics of sulfur transfer during ... | ACCEPT | Summary: IDA for iron-sulfur cluster chaperone activity from 2024 structural study. Reason: ISCU functions as a scaffold/chaperone for Fe-S cluster assembly and transfer. This molecular function term captures the chaperone-like activity of holding and transferring clusters. Supporting Evidence: PMID:38627381 Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: HTP annotation from mitochondrial proteome study confirming mitochondrial localization. Reason: Mitochondrial localization is well-established. HTP provides quantitative proteomics support. Supporting Evidence: PMID:34800366 Epub 2021 Nov 19. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. |
| GO:0005515 protein binding | IPI PMID:31101807 Structure of the human frataxin-bound iron-sulfur cluster as... | MODIFY | Summary: IPI for protein binding with FXN (frataxin). This is a functionally important interaction - FXN binds the ISCU-NFS1 complex and activates sulfur transfer. Reason: While the protein binding is documented, a more specific term would be preferable. FXN interaction with ISCU is essential for Fe-S cluster assembly activation. Consider more specific annotation if available. Proposed replacements: iron-sulfur cluster chaperone activity Supporting Evidence: PMID:31101807 Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism. |
| GO:0006879 intracellular iron ion homeostasis | IDA PMID:16517407 Functions of mitochondrial ISCU and cytosolic ISCU in mammal... | ACCEPT | Summary: IDA for iron ion homeostasis. Study demonstrated that mitochondrial and cytosolic ISCU isoforms both contribute to iron homeostasis regulation. Reason: Direct experimental evidence showing ISCU's role in cellular iron homeostasis through its Fe-S cluster assembly function. Supporting Evidence: PMID:16517407 Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis. |
| GO:0044572 [4Fe-4S] cluster assembly | IDA PMID:23940031 Human mitochondrial chaperone (mtHSP70) and cysteine desulfu... | MODIFY | Summary: IDA for [4Fe-4S] cluster assembly. Earlier studies suggested ISCU could assemble [4Fe-4S], but recent evidence indicates ISCU primarily assembles [2Fe-2S] which is converted to [4Fe-4S] by downstream carriers (ISCA1, ISCA2, IBA57, NFU1). Reason: Recent studies (PMID:34824239) clarify that ISCU assembles [2Fe-2S] clusters, not [4Fe-4S] directly. The [4Fe-4S] clusters are assembled by downstream carriers. This annotation should be modified to [2Fe-2S] cluster assembly. Proposed replacements: [2Fe-2S] cluster assembly Supporting Evidence: PMID:23940031 Human mitochondrial chaperone (mtHSP70) and cysteine desulfurase (NFS1) bind preferentially to the disordered conformation, whereas co-chaperone (HSC20) binds to the structured conformation of the iron-sulfur cluster scaffold protein (ISCU) |
| GO:0099128 mitochondrial [2Fe-2S] assembly complex | IDA PMID:31101807 Structure of the human frataxin-bound iron-sulfur cluster as... | ACCEPT | Summary: IDA for membership in mitochondrial [2Fe-2S] assembly complex from structural study of the human frataxin-bound complex. Reason: Direct structural evidence showing ISCU as a component of the complex. Supporting Evidence: PMID:31101807 Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism. |
| GO:0044571 [2Fe-2S] cluster assembly | IDA PMID:24971490 Human frataxin activates Fe-S cluster biosynthesis by facili... | ACCEPT | Summary: IDA for [2Fe-2S] cluster assembly. Study demonstrated FXN activates Fe-S cluster biosynthesis by facilitating sulfur transfer chemistry on ISCU. Reason: Direct biochemical evidence for [2Fe-2S] cluster assembly on ISCU. Supporting Evidence: PMID:24971490 Human frataxin activates Fe-S cluster biosynthesis by facilitating sulfur transfer chemistry. |
| GO:0008270 zinc ion binding | IDA PMID:30031876 Zinc(II) binding on human wild-type ISCU and Met140 variants... | ACCEPT | Summary: IDA for zinc ion binding. ISCU can bind Zn2+ at the active site, which modulates NFS1 desulfurase activity. Zn2+ binding is competitive with Fe2+ and may serve a regulatory role. Reason: Direct experimental evidence for Zn2+ binding. UniProt confirms Zn2+ coordination by Cys71, Cys95, and Cys138. This may be important for protein stability or regulation. Supporting Evidence: PMID:30031876 Zinc(II) binding on human wild-type ISCU and Met140 variants modulates NFS1 desulfurase activity. |
| GO:0042803 protein homodimerization activity | IDA PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S ... | ACCEPT | Summary: IDA for homodimerization from structural study. Crystal structure revealed ISCU dimerization in complex with NFS1-LYRM4. Reason: Direct structural evidence for ISCU homodimerization. This is functionally important for cluster assembly. Supporting Evidence: PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex. |
| GO:0042803 protein homodimerization activity | IDA PMID:34824239 N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synth... | ACCEPT | Summary: IDA for homodimerization. Key study showing Tyr-35-mediated dimerization triggers [2Fe-2S] cluster synthesis. Reason: Direct experimental evidence showing Tyr-35-mediated dimerization is essential for cluster assembly. This is a core function. Supporting Evidence: PMID:34824239 N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by ISCU2 dimerization. |
| GO:0005515 protein binding | IPI PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S ... | KEEP AS NON CORE | Summary: IPI for protein binding with NFS1 and LYRM4 from structural study. These are functionally critical interactions for Fe-S cluster assembly. Reason: The interaction with NFS1 and LYRM4 is essential for ISCU function, but protein binding is too generic. The complex membership annotation (GO:0099128) better captures this. Supporting Evidence: PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex. |
| GO:0005515 protein binding | IPI PMID:23940031 Human mitochondrial chaperone (mtHSP70) and cysteine desulfu... | KEEP AS NON CORE | Summary: IPI for protein binding with NFS1. Functionally important interaction - NFS1 binds preferentially to the D-state of ISCU. Reason: Important functional interaction but protein binding is too generic. Complex membership annotation is more informative. Supporting Evidence: PMID:23940031 NFS1 binds preferentially to the D-state of ISCU as does the NFS1-ISD11 complex. |
| GO:0006879 intracellular iron ion homeostasis | IDA PMID:23508953 Mammalian target of rapamycin complex 1 (mTORC1)-mediated ph... | ACCEPT | Summary: IDA for iron homeostasis. Study on mTORC1-mediated phosphorylation of ISCU and its implications for iron metabolism. Reason: Direct evidence linking ISCU stability/function to iron metabolism regulation. Supporting Evidence: PMID:23508953 Mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation stabilizes ISCU protein: implications for iron metabolism. |
| GO:0044571 [2Fe-2S] cluster assembly | IDA PMID:23940031 Human mitochondrial chaperone (mtHSP70) and cysteine desulfu... | ACCEPT | Summary: IDA for [2Fe-2S] cluster assembly. In vitro reconstitution showing cluster assembly on ISCU. Reason: Direct biochemical evidence for [2Fe-2S] cluster assembly on ISCU. Supporting Evidence: PMID:23940031 In vitro Fe-S cluster assembly assays |
| GO:0099128 mitochondrial [2Fe-2S] assembly complex | IDA PMID:21298097 Mammalian frataxin - an essential function for cellular viab... | ACCEPT | Summary: IDA for complex membership. Study showed FXN interacts with preformed ISCU/NFS1/ISD11 complex. Reason: Direct evidence for ISCU as component of the core ISC assembly complex. Supporting Evidence: PMID:21298097 Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex. |
| GO:0005515 protein binding | IPI PMID:11060020 Distinct iron-sulfur cluster assembly complexes exist in the... | KEEP AS NON CORE | Summary: IPI for protein binding with NFS1 from the initial characterization of human ISC assembly complexes. Reason: Foundational study establishing ISCU-NFS1 interaction. Protein binding is generic but this is a key functional interaction. Supporting Evidence: PMID:11060020 Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9771686 | ACCEPT | Summary: TAS from Reactome for cytosolic localization, related to SARS-CoV-2 nsp12 Fe-S cluster acquisition pathway. Reason: Cytosolic localization is appropriate for isoform 2. The Reactome pathway describes viral protein utilizing host Fe-S machinery. |
| GO:1902958 positive regulation of mitochondrial electron transport, NADH to ubiquinone | IMP PMID:20436681 MicroRNA-210 regulates mitochondrial free radical response t... | KEEP AS NON CORE | Summary: IMP for positive regulation of Complex I activity. Study on miR-210 targeting of ISCU in hypoxia and cancer. Reason: This is a downstream effect of ISCU's role in providing Fe-S clusters to respiratory complex subunits. Not a core function but a physiological consequence of Fe-S biogenesis. Supporting Evidence: PMID:20436681 MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU. |
| GO:1904439 negative regulation of iron ion import across plasma membrane | IMP PMID:20436681 MicroRNA-210 regulates mitochondrial free radical response t... | KEEP AS NON CORE | Summary: IMP for negative regulation of iron import. ISCU knockdown increases cellular iron import, likely due to IRP activation from Fe-S cluster deficiency. Reason: This is an indirect effect of ISCU's role in Fe-S biogenesis on iron homeostasis signaling. Not a direct function but reflects the IRP-mediated iron sensing response to Fe-S deficiency. Supporting Evidence: PMID:20436681 MicroRNA-210 regulates mitochondrial free radical response to hypoxia and krebs cycle in cancer cells by targeting iron sulfur cluster protein ISCU. |
| GO:0005515 protein binding | IPI PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentia... | KEEP AS NON CORE | Summary: IPI for protein binding with HSPA9. Functionally important interaction - HSPA9 (mortalin/mtHsp70) mediates cluster release from ISCU. Reason: Important functional interaction for cluster transfer. Protein binding is generic but the HSPA9 interaction is critical for ISCU function. Supporting Evidence: PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly. |
| GO:0005739 mitochondrion | IDA PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentia... | ACCEPT | Summary: IDA for mitochondrial localization from study on HSPA9-ISCU interaction. Reason: Direct experimental evidence for mitochondrial localization. Supporting Evidence: PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-1362408 | ACCEPT | Summary: TAS from Reactome for mitochondrial matrix localization. Reactome pathway: FXN:NFS1:ISD11:ISCU assembles 2Fe-2S iron-sulfur cluster. Reason: Mitochondrial matrix is the correct subcompartment for ISCU function. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-1362416 | ACCEPT | Summary: TAS from Reactome for mitochondrial matrix. Reactome pathway: Frataxin binds iron. Reason: Mitochondrial matrix localization is well-established. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9854984 | ACCEPT | Summary: TAS from Reactome for mitochondrial matrix. Reactome pathway: Transfer of Fe-S clusters to SDHB. Reason: Mitochondrial matrix localization is appropriate. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9866272 | ACCEPT | Summary: TAS from Reactome for mitochondrial matrix. Reactome pathway: 2Fe-2S is inserted in UQCRFS1. Reason: Mitochondrial matrix localization is correct for ISCU's function in providing Fe-S clusters to respiratory complex subunits. |
| GO:0005515 protein binding | IPI PMID:20668094 Characterization of the human HSC20, an unusual DnaJ type II... | KEEP AS NON CORE | Summary: IPI for protein binding with HSCB (HSC20). Functionally critical interaction - HSCB is the J-domain co-chaperone that mediates cluster transfer from ISCU. Reason: Important functional interaction. HSCB binds the structured (S) state of ISCU and stimulates HSPA9 ATPase activity for cluster release. Protein binding is generic but this is a key functional partner. Supporting Evidence: PMID:20668094 Here, we show that the human HSC20 protein can complement for its counterpart in yeast, Jac1p, and interacts with its proposed human partners, hISCU and hHSPA9 |
| GO:0005737 cytoplasm | IDA GO_REF:0000054 | ACCEPT | Summary: IDA from LIFEdb fusion protein localization study. Cytoplasmic localization appropriate for isoform 2. Reason: Cytoplasmic localization is appropriate for the cytosolic isoform. |
| GO:0005515 protein binding | IPI PMID:16527810 Roles of the mammalian cytosolic cysteine desulfurase, ISCS,... | KEEP AS NON CORE | Summary: IPI for protein binding with NFS1 (cytosolic form). Study on roles of cytosolic ISCS and ISCU in Fe-S cluster assembly. Reason: Functionally important interaction between cytosolic ISCU and NFS1. Supporting Evidence: PMID:16527810 Roles of the mammalian cytosolic cysteine desulfurase, ISCS, and scaffold protein, ISCU, in iron-sulfur cluster assembly. |
| GO:0005634 nucleus | TAS PMID:16527810 Roles of the mammalian cytosolic cysteine desulfurase, ISCS,... | ACCEPT | Summary: TAS for nuclear localization from study on cytosolic ISCU function. Reason: Some nuclear localization has been reported for the cytosolic isoform. This is a minor localization. Supporting Evidence: PMID:16527810 2006 Mar 9. Roles of the mammalian cytosolic cysteine desulfurase, ISCS, and scaffold protein, ISCU, in iron-sulfur cluster assembly. |
| GO:0005829 cytosol | IDA PMID:16527810 Roles of the mammalian cytosolic cysteine desulfurase, ISCS,... | ACCEPT | Summary: IDA for cytosolic localization from study on cytosolic ISCU. Reason: Direct evidence for cytosolic localization of isoform 2. Supporting Evidence: PMID:16527810 Roles of the mammalian cytosolic cysteine desulfurase, ISCS, and scaffold protein, ISCU, in iron-sulfur cluster assembly. |
| GO:0060090 molecular adaptor activity | IDA PMID:16527810 Roles of the mammalian cytosolic cysteine desulfurase, ISCS,... | ACCEPT | Summary: IDA for molecular adaptor activity. ISCU serves as a scaffold/adaptor that brings together Fe, S, and protein partners for cluster assembly. Reason: ISCU functions as a molecular scaffold/adaptor, coordinating multiple components for Fe-S cluster assembly and transfer. This MF term is more informative than generic protein binding. Supporting Evidence: PMID:16527810 Roles of the mammalian cytosolic cysteine desulfurase, ISCS, and scaffold protein, ISCU, in iron-sulfur cluster assembly. |
| GO:0005737 cytoplasm | IDA PMID:11060020 Distinct iron-sulfur cluster assembly complexes exist in the... | ACCEPT | Summary: IDA for cytoplasmic localization from initial study identifying distinct cytosolic and mitochondrial ISC complexes. Reason: Foundational study establishing dual localization of ISCU. Supporting Evidence: PMID:11060020 Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. |
| GO:0005739 mitochondrion | IDA PMID:11060020 Distinct iron-sulfur cluster assembly complexes exist in the... | ACCEPT | Summary: IDA for mitochondrial localization from initial study characterizing human ISC assembly complexes. Reason: Foundational study establishing mitochondrial localization. Supporting Evidence: PMID:11060020 Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. |
| GO:0005506 iron ion binding | TAS PMID:11060020 Distinct iron-sulfur cluster assembly complexes exist in the... | ACCEPT | Summary: TAS for iron ion binding from initial characterization study. Reason: Iron ion binding is a core function for ISCU as the scaffold for Fe-S cluster assembly. Supporting Evidence: PMID:11060020 Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. |
| GO:0016226 iron-sulfur cluster assembly | TAS PMID:11060020 Distinct iron-sulfur cluster assembly complexes exist in the... | ACCEPT | Summary: TAS for iron-sulfur cluster assembly from initial characterization study. Reason: Iron-sulfur cluster assembly is the core biological process for ISCU. Supporting Evidence: PMID:11060020 Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. |
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