ISCA2 is a mitochondrial A-type iron-sulfur cluster assembly protein of the HesB/IscA family that functions in the late-stage maturation of mitochondrial [4Fe-4S] proteins. It works in concert with ISCA1 and IBA57 to assemble [4Fe-4S] clusters by reductive fusion of two [2Fe-2S] clusters donated by GLRX5. The electron input for this fusion reaction is provided by ferredoxin FDX2 via FDXR. ISCA2 forms homodimers and heterodimers with ISCA1 (the ISCA1:ISCA2 complex), and also forms an oxidation-resistant [2Fe-2S]-bridged heterocomplex with IBA57 (the ISCA2:IBA57 complex). Biallelic loss-of-function mutations in ISCA2 cause Multiple Mitochondrial Dysfunctions Syndrome type 4 (MMDS4), characterized by early-onset leukodystrophy, hyperglycinemia, impaired protein lipoylation, and mtDNA depletion.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: ISCA2 is confirmed to localize to mitochondria based on phylogenetic inference (IBA) and multiple experimental studies. The protein functions in the mitochondrial matrix as part of the late-stage ISC assembly pathway (PMID:22323289, PMID:25347204). Reason: Mitochondrial localization is well-established for ISCA2. The IBA annotation is consistent with experimental evidence showing ISCA2 functions in mitochondrial [4Fe-4S] cluster assembly. Direct experimental evidence (IDA from PMID:22323289) also confirms this localization. Supporting Evidence: PMID:25347204 The generation of [4Fe-4S] clusters in mitochondria critically depends, in both yeast and human cells, on two A-type ISC proteins (in mammals named ISCA1 and ISCA2) |
| GO:0016226 iron-sulfur cluster assembly | IBA GO_REF:0000033 | ACCEPT | Summary: ISCA2 is directly involved in iron-sulfur cluster assembly, specifically in the late-stage [4Fe-4S] cluster assembly pathway. The IBA annotation appropriately captures this core function (PMID:25347204). Reason: While ISCA2's role is specifically in [4Fe-4S] cluster assembly, the general term iron-sulfur cluster assembly is still correct and appropriate. The ISCA1:ISCA2 heterodimeric complex receives [2Fe-2S] clusters from GRX5 and assembles them into [4Fe-4S] clusters (PMID:25347204). The IBA annotation from PANTHER is valid. Supporting Evidence: PMID:25347204 The generation of [4Fe-4S] clusters in mitochondria critically depends, in both yeast and human cells, on two A-type ISC proteins (in mammals named ISCA1 and ISCA2) file:human/ISCA2/ISCA2-deep-research-falcon.md ISCA2 is a mitochondrial A-type Fe-S assembly factor in the HesB/IscA family. It acts as a late-acting secondary carrier in the ISC pathway |
| GO:0051604 protein maturation | IBA GO_REF:0000033 | ACCEPT | Summary: ISCA2 contributes to the maturation of mitochondrial [4Fe-4S] proteins by facilitating the assembly and transfer of [4Fe-4S] clusters to apo-proteins including aconitase and lipoic acid synthase (PMID:22323289, PMID:25347204). Reason: This annotation correctly captures ISCA2's role in promoting the maturation of [4Fe-4S]-containing proteins. The term is appropriate as ISCA2 is required for the functional maturation of mitochondrial [4Fe-4S] proteins. Supporting Evidence: PMID:25347204 These findings imply that such heterodimeric complex is the functional unit in mitochondria receiving [2Fe-2S] clusters from hGRX5 and assembling [4Fe-4S] clusters before their transfer to the final target apo proteins |
| GO:0005506 iron ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: ISCA2 binds iron ions as part of its [2Fe-2S] and [4Fe-4S] cluster-binding capacity. The iron binding is integral to its function in Fe-S cluster assembly. Reason: Iron ion binding is inherent to ISCA2's function as an Fe-S cluster assembly protein. The protein coordinates iron through conserved cysteine residues (Cys79, Cys144, Cys146) as documented in UniProt and structural studies. This is a valid but somewhat generic annotation that is subsumed by the more specific cluster binding annotations. Supporting Evidence: PMID:25347204 ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a dimeric state |
| GO:0051537 2 iron, 2 sulfur cluster binding | IBA GO_REF:0000033 | ACCEPT | Summary: ISCA2 binds [2Fe-2S] clusters as part of its role in Fe-S cluster assembly. The [2Fe-2S] cluster is received from GLRX5 and is an intermediate in [4Fe-4S] assembly (PMID:25347204, PMID:31831856). Reason: [2Fe-2S] cluster binding by ISCA2 is well-documented. ISCA2 can hold a [2Fe-2S] cluster and forms a [2Fe-2S]-bridged heterocomplex with IBA57. The cluster is an intermediate received from GLRX5 that is subsequently converted to [4Fe-4S]. Supporting Evidence: PMID:25347204 ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a dimeric state PMID:31831856 The [2Fe-2S] cluster is out of the ISCA2 core while being shared with IBA57 in the dimer |
| GO:0051539 4 iron, 4 sulfur cluster binding | IBA GO_REF:0000033 | ACCEPT | Summary: ISCA2, as part of the ISCA1:ISCA2 heterodimeric complex, binds [4Fe-4S] clusters that are assembled from two [2Fe-2S] precursors (PMID:25347204). Reason: [4Fe-4S] cluster binding is a core function of the ISCA1:ISCA2 complex. The heterodimeric complex assembles and transiently holds a [4Fe-4S] cluster before transfer to target apo-proteins. Supporting Evidence: PMID:25347204 ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a dimeric state PMID:25347204 the two GRX5-donated [2Fe-2S](2+) clusters generate a [4Fe-4S](2+) cluster |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation for mitochondrial localization based on UniProt subcellular location vocabulary. Consistent with experimental evidence. Reason: This IEA annotation is consistent with the IBA and IDA evidence for mitochondrial localization. While redundant with higher-quality annotations, it provides a valid automatic annotation that does not conflict with established knowledge. Supporting Evidence: PMID:25347204 The generation of [4Fe-4S] clusters in mitochondria critically depends, in both yeast and human cells, on two A-type ISC proteins (in mammals named ISCA1 and ISCA2) |
| GO:0016226 iron-sulfur cluster assembly | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation for iron-sulfur cluster assembly based on InterPro domain mapping. Reason: This IEA annotation is correct based on domain analysis (FeS_cluster_insertion domain IPR016092). Consistent with ISCA2's role in Fe-S biogenesis and the IBA annotation for the same term. Supporting Evidence: PMID:25347204 The generation of [4Fe-4S] clusters in mitochondria critically depends, in both yeast and human cells, on two A-type ISC proteins |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: IEA annotation for metal ion binding based on UniProt keyword mapping. Very general annotation subsumed by more specific iron and Fe-S cluster binding terms. Reason: While technically correct (ISCA2 binds iron as part of Fe-S clusters), this term is overly broad and uninformative given the more specific annotations for iron ion binding and Fe-S cluster binding that are already present. It adds little value beyond what is captured by more specific MF terms. |
| GO:0051536 iron-sulfur cluster binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for general iron-sulfur cluster binding based on combined IEA methods. Reason: This general Fe-S cluster binding annotation is correct and serves as a parent term encompassing both [2Fe-2S] and [4Fe-4S] cluster binding, which are both relevant to ISCA2 function. More specific child terms are also annotated. Supporting Evidence: PMID:25347204 ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a dimeric state |
| GO:0120510 mitochondrial [4Fe-4S] assembly complex | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation indicating ISCA2 is part of the mitochondrial [4Fe-4S] assembly complex, based on ARBA machine learning. Reason: This is an accurate annotation. ISCA2 is indeed a component of the mitochondrial [4Fe-4S] assembly complex (ISCA1:ISCA2 complex) as defined in GO. The GO term definition explicitly states "In humans it consists of ISCA1 and ISCA2." Supporting Evidence: PMID:25347204 We found that (i) ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a dimeric state, and (ii) two molecules of [2Fe-2S](2+) GRX5 donate their cluster to a heterodimeric ISCA1/ISCA2 complex |
| GO:0005515 protein binding | IPI PMID:25347204 Formation of [4Fe-4S] clusters in the mitochondrial iron-sul... | MODIFY | Summary: IPI annotation for protein binding based on ISCA2 interaction with ISCA1 (Q9BUE6) demonstrated in this study. Reason: The annotation captures a real interaction (ISCA2 with ISCA1), but "protein binding" is uninformative. ISCA2 forms a functional heterodimeric complex with ISCA1 that assembles [4Fe-4S] clusters. This is better captured by the complex membership annotation (GO:0120510) or the identical protein binding annotation for homodimerization. Proposed replacements: mitochondrial [4Fe-4S] assembly complex Supporting Evidence: PMID:25347204 We found that (i) ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a dimeric state, and (ii) two molecules of [2Fe-2S](2+) GRX5 donate their cluster to a heterodimeric ISCA1/ISCA2 complex |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: IPI annotation for protein binding based on high-throughput interactome mapping (interaction with RNF41/Q9H4P4). Reason: This annotation derives from high-throughput interactome mapping and captures an interaction with RNF41 (E3 ubiquitin ligase). While the interaction may be real, the generic "protein binding" term is uninformative and the biological relevance of ISCA2-RNF41 interaction to ISCA2's core Fe-S assembly function is unclear. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:31831856 Structural properties of [2Fe-2S] ISCA2-IBA57: a complex of ... | MODIFY | Summary: IPI annotation for protein binding based on ISCA2-IBA57 interaction demonstrated by structural and biophysical studies (Nasta et al., 2019). Reason: This captures the important ISCA2-IBA57 interaction, but "protein binding" is uninformative. ISCA2 forms a [2Fe-2S]-bridged heterocomplex with IBA57 that is structurally characterized and functionally important for late-stage Fe-S assembly. Proposed replacements: iron-sulfur cluster chaperone activity Supporting Evidence: PMID:31831856 The [2Fe-2S] cluster is out of the ISCA2 core while being shared with IBA57 in the dimer PMID:31831856 dimeric [2Fe-2S] ISCA2-IBA57 hetero-complex is a physiologically relevant species |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI annotation for multiple protein interactions from high-throughput binary interactome mapping. Reason: This is a high-throughput study identifying multiple interactors. The generic "protein binding" term is uninformative. Many of the reported interactors (e.g., SUOX, GEM, EIF3E) lack clear functional relevance to ISCA2's core Fe-S assembly function and may represent experimental artifacts or transient interactions. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: IPI annotation from interactome mapping in the context of neurodegenerative disease protein networks. Reason: This high-throughput interactome study reports multiple ISCA2 interactors, but the generic "protein binding" annotation is uninformative. The biological relevance of these interactions to ISCA2's core Fe-S assembly function is unclear. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IPI annotation from dual proteome-scale network studies showing ISCA2 interactions with IBA57, ISCA1, and RNF41. Reason: While this study confirms biologically relevant interactions (ISCA1, IBA57), the generic "protein binding" term is uninformative. The relevant functional interactions are better captured by complex membership (GO:0120510) and specific binding annotations. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:39408793 Defects in the Maturation of Mitochondrial Iron-Sulfur Prote... | ACCEPT | Summary: IPI annotation based on ISCA2-IBA57 interaction studies in context of MMDS3 pathogenic variant analysis. Reason: This study specifically characterizes the ISCA2-IBA57 interaction in the context of disease-causing IBA57 variants. While "protein binding" is generic, this annotation has clear functional relevance to understanding ISCA2's role in the late ISC pathway and disease mechanisms. Supporting Evidence: file:human/ISCA2/ISCA2-deep-research-falcon.md ISCA2 forms a dimer and assembles a [2Fe-2S] ISCA2-IBA57 heterocomplex that is oxidation-resistant and can reactivate apo-aconitase PMID:39408793 Defects in the Maturation of Mitochondrial Iron-Sulfur Proteins: Biophysical Investigation of the MMDS3 Causing Gly104Cys Variant of IBA57. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: IPI annotation from multimodal cell mapping study showing ISCA2 interactions. Reason: High-throughput study with generic "protein binding" annotation that is uninformative about ISCA2's specific molecular function. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics. |
| GO:0042802 identical protein binding | IPI PMID:25347204 Formation of [4Fe-4S] clusters in the mitochondrial iron-sul... | ACCEPT | Summary: ISCA2 forms homodimers, as demonstrated in structural and biochemical studies (PMID:25347204, PMID:31831856). Reason: ISCA2 homodimerization is well-documented and functionally relevant. The apo form of ISCA2 is dimeric, and this dimerization is important for its cluster binding and assembly function. Supporting Evidence: PMID:25347204 ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a dimeric state PMID:31831856 ISCA2-IBA57 complex with ISCA2 providing the homodimerization core interface |
| GO:0042802 identical protein binding | IPI PMID:31831856 Structural properties of [2Fe-2S] ISCA2-IBA57: a complex of ... | ACCEPT | Summary: Structural study (SAXS and modeling) confirming ISCA2 homodimerization as the core interface in the ISCA2-IBA57 complex. Reason: This study provides structural evidence for ISCA2 homodimerization. The ISCA2 dimer provides the core interface for complex formation with IBA57. Supporting Evidence: PMID:31831856 ISCA2-IBA57 complex with ISCA2 providing the homodimerization core interface |
| GO:0005739 mitochondrion | IDA PMID:22323289 The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are... | ACCEPT | Summary: Direct experimental evidence (IDA) for mitochondrial localization from the foundational study establishing ISCA2's role in [4Fe-4S] protein maturation. Reason: This is high-quality experimental evidence for mitochondrial localization from the key study by Sheftel et al. that established the function of human ISCA1, ISCA2, and IBA57 in [4Fe-4S] protein maturation. Supporting Evidence: file:human/ISCA2/ISCA2-deep-research-falcon.md ISCA2 functions in the mitochondrial matrix, evidenced by its role in mitochondrial [4Fe-4S] client maturation PMID:22323289 Feb 9. The human mitochondrial ISCA1, ISCA2, and IBA57 proteins are required for [4Fe-4S] protein maturation. |
| GO:0051604 protein maturation | IDA PMID:25347204 Formation of [4Fe-4S] clusters in the mitochondrial iron-sul... | ACCEPT | Summary: Direct experimental evidence that ISCA2 is involved in [4Fe-4S] protein maturation by assembling clusters for transfer to target apo-proteins. Reason: This annotation is based on biochemical reconstitution studies showing the ISCA1:ISCA2 complex assembles [4Fe-4S] clusters for transfer to target proteins. Supporting Evidence: PMID:25347204 These findings imply that such heterodimeric complex is the functional unit in mitochondria receiving [2Fe-2S] clusters from hGRX5 and assembling [4Fe-4S] clusters before their transfer to the final target apo proteins |
| GO:0051604 protein maturation | NAS PMID:31831856 Structural properties of [2Fe-2S] ISCA2-IBA57: a complex of ... | ACCEPT | Summary: Non-traceable author statement annotation for protein maturation function based on the ISCA2-IBA57 structural study. Reason: While NAS is a weaker evidence code, the annotation is consistent with the well-established role of ISCA2 in [4Fe-4S] protein maturation. The referenced paper provides structural context for understanding how ISCA2 contributes to this process. Supporting Evidence: PMID:31831856 dimeric [2Fe-2S] ISCA2-IBA57 hetero-complex is a physiologically relevant species |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput proteomics study confirming ISCA2 as part of the high-confidence mitochondrial proteome. Reason: This high-quality proteomics study provides additional support for mitochondrial localization, consistent with other experimental evidence. Supporting Evidence: PMID:34800366 Epub 2021 Nov 19. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. |
| GO:0120510 mitochondrial [4Fe-4S] assembly complex | IDA PMID:25347204 Formation of [4Fe-4S] clusters in the mitochondrial iron-sul... | ACCEPT | Summary: Direct experimental evidence that ISCA2 is part of the mitochondrial [4Fe-4S] assembly complex (ISCA1:ISCA2 heterodimer) that assembles [4Fe-4S] clusters. Reason: This is a key annotation capturing ISCA2's core function. The study demonstrates that the ISCA1:ISCA2 heterodimeric complex is the functional unit for [4Fe-4S] cluster assembly. Supporting Evidence: PMID:25347204 We found that (i) ISCA2 binds either [2Fe-2S] or [4Fe-4S] cluster in a dimeric state, and (ii) two molecules of [2Fe-2S](2+) GRX5 donate their cluster to a heterodimeric ISCA1/ISCA2 complex |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-8878815 | ACCEPT | Summary: Reactome pathway annotation indicating ISCA2 functions in the mitochondrial matrix, where [4Fe-4S] cluster formation occurs on the ISCA1:ISCA2 complex. Reason: The mitochondrial matrix localization is consistent with ISCA2's role in late-stage Fe-S cluster assembly, which occurs in the matrix compartment. Reactome provides curated pathway context. Supporting Evidence: Reactome:R-HSA-8878815 Formation of 4Fe-4S cluster on ISCA1:ISCA2 |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9854984 | ACCEPT | Summary: Reactome annotation for mitochondrial matrix localization in context of Fe-S cluster transfer to SDHB. Reason: Consistent with ISCA2's role in maturation of mitochondrial [4Fe-4S] proteins including succinate dehydrogenase complex subunits. Supporting Evidence: Reactome:R-HSA-9854984 Transfer of Fe-S clusters to SDHB |
| GO:0044572 [4Fe-4S] cluster assembly | IDA PMID:25347204 Formation of [4Fe-4S] clusters in the mitochondrial iron-sul... | NEW | Summary: NEW ANNOTATION: ISCA2 is involved in [4Fe-4S] cluster assembly as a biological process. The ISCA1:ISCA2 complex assembles [4Fe-4S] clusters from [2Fe-2S] precursors. Reason: The existing annotations include the general term GO:0016226 (iron-sulfur cluster assembly), but ISCA2's specific function is [4Fe-4S] cluster assembly, which is captured by the more precise child term GO:0044572. Supporting Evidence: PMID:25347204 This complex acts as an "assembler" of [4Fe-4S] clusters; i.e., the two GRX5-donated [2Fe-2S](2+) clusters generate a [4Fe-4S](2+) cluster |
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