NFS1 is the essential human cysteine desulfurase that serves as the central sulfur donor for iron-sulfur (Fe-S) cluster biosynthesis. This PLP-dependent enzyme catalyzes the desulfuration of L-cysteine to L-alanine, generating a protein-bound persulfide intermediate on the active-site cysteine (Cys381). The mitochondrial isoform functions as the catalytic heart of the core ISC (iron-sulfur cluster) assembly complex, forming a functional dimer that associates with LYRM4/ISD11 (for stabilization), acyl carrier protein NDUFAB1/ACP1 (regulatory), the scaffold protein ISCU2, frataxin (FXN, allosteric activator), and ferredoxin FDX2 (electron donor) to assemble [2Fe-2S] clusters de novo on ISCU2. These clusters are then transferred to recipient apoproteins via chaperones HSPA9/HSC20 and GLRX5. A cytoplasmic isoform (lacking the N-terminal 60 residues) serves as sulfur donor for molybdenum cofactor (Moco) biosynthesis via interaction with MOCS3 and may contribute to cytosolic tRNA thiolation. NFS1 also localizes to the nucleus and has been detected at centrosomes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: NFS1 is predominantly localized in mitochondria where it functions as the core cysteine desulfurase of the ISC machinery (PMID:16847322, PMID:29097656). The mitochondrial isoform contains an N-terminal transit peptide targeting it to the mitochondrial matrix. Reason: Mitochondrial localization is the primary site of NFS1 function, confirmed by multiple experimental studies and phylogenetic inference. Supporting Evidence: PMID:16847322 The protein is located predominantly in mitochondria, but small amounts are present in the cytosol/nucleus. PMID:9885568 different forms of NifS that localize either to mitochondria or to the cytosol and nucleus are synthesized from a single transcript |
| GO:0016226 iron-sulfur cluster assembly | IBA GO_REF:0000033 | ACCEPT | Summary: NFS1 is essential for iron-sulfur cluster assembly as the cysteine desulfurase that provides sulfur for the ISC machinery (PMID:16847322, PMID:29097656, PMID:38627381). This is its core function. Reason: Iron-sulfur cluster assembly is the central biological process of NFS1, conserved across species and supported by extensive experimental evidence. Supporting Evidence: PMID:16847322 huNfs1 performs an essential function in Fe/S protein biogenesis in human cells PMID:29097656 A critical initial step in Fe/S cluster synthesis is the supply of sulfur by the cysteine desulfurase NFS1 |
| GO:0031071 cysteine desulfurase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Cysteine desulfurase activity is the defining enzymatic function of NFS1 (EC 2.8.1.7). The enzyme converts L-cysteine to L-alanine and a persulfide intermediate (PMID:16527810, PMID:18650437, PMID:29097656). Reason: This is the core molecular function of NFS1, extensively characterized biochemically and structurally. Supporting Evidence: PMID:16527810 the cytosolic form of ISCS is an active cysteine desulfurase that covalently binds 35S acquired from desulfuration of radiolabeled cysteine PMID:29097656 The enzyme belongs to a subfamily of pyridoxal 5′-phosphate (PLP)-dependent transaminases that convert free l-cysteine to alanine and an enzyme-bound persulfide (-SSH) group9, 10 |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: A cytoplasmic isoform of NFS1 exists, generated by alternative initiation at the second AUG codon, lacking the mitochondrial targeting sequence (PMID:9885568, PMID:23593335). This isoform functions in Moco biosynthesis. Reason: Cytosolic localization is well-established for the shorter NFS1 isoform and is functionally important for molybdenum cofactor biosynthesis. Supporting Evidence: PMID:9885568 different forms of NifS that localize either to mitochondria or to the cytosol and nucleus are synthesized from a single transcript PMID:23593335 we were also able to detect NFS1 in the cytosolic fraction |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: NFS1 has been detected in the nucleus, though its function there is not well characterized (PMID:16847322, PMID:23593335). This may relate to tRNA modification or other sulfur-dependent nuclear processes. Reason: Nuclear localization is supported by multiple studies, though the functional significance is less clear than mitochondrial localization. Supporting Evidence: PMID:16847322 small amounts are present in the cytosol/nucleus PMID:23593335 NFS1-EYFP and EYFP-NFS1delta1-55 were showing a localization in the nucleus |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation for nuclear localization based on orthology to mouse NFS1. Reason: Consistent with IBA and experimental evidence supporting nuclear localization. Supporting Evidence: PMID:16847322 small amounts are present in the cytosol/nucleus |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation for mitochondrial localization consistent with known biology. Reason: Redundant with IBA annotation but consistent with extensive experimental evidence. Supporting Evidence: PMID:29097656 De novo Fe/S cluster synthesis occurs on the mitochondrial scaffold protein ISCU and requires cysteine desulfurase NFS1 |
| GO:0005813 centrosome | IEA GO_REF:0000044 | ACCEPT | Summary: Centrosome localization was identified in PMID:30817134 as a novel, MOCS3-independent localization site for NFS1. Function at centrosomes is unknown. Reason: Supported by experimental evidence (PMID:30817134), though biological significance remains unclear. Supporting Evidence: PMID:30817134 we identified a MOCS3-independent novel localization of NFS1 at the centrosome |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation for cytosolic localization, consistent with known isoform biology. Reason: Redundant with IBA annotation but consistent with experimental evidence. Supporting Evidence: PMID:23593335 we were also able to detect NFS1 in the cytosolic fraction |
| GO:0006777 Mo-molybdopterin cofactor biosynthetic process | IEA GO_REF:0000043 | ACCEPT | Summary: NFS1 serves as the sulfur donor for molybdenum cofactor (Moco) biosynthesis via transfer to MOCS3 in the cytosol (PMID:18650437, PMID:23593335). Reason: Well-established secondary function of cytosolic NFS1 isoform, supported by biochemical and cellular studies. Supporting Evidence: PMID:18650437 cytosolic Nfs1 has an important role in sulfur transfer for the biosynthesis of Moco PMID:23593335 NFS1 is the sulfur donor for Moco biosynthesis in eukaryotes in general |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | MODIFY | Summary: NFS1 has transferase activity as it transfers sulfur from cysteine to persulfide intermediates and then to acceptor proteins. Reason: This term is too broad. The specific function is cysteine desulfurase activity (GO:0031071), which better captures NFS1's enzymatic mechanism. Proposed replacements: cysteine desulfurase activity |
| GO:0030170 pyridoxal phosphate binding | IEA GO_REF:0000002 | ACCEPT | Summary: NFS1 is a PLP-dependent enzyme with pyridoxal 5'-phosphate covalently bound to Lys258 as an internal aldimine (PMID:29097656, PMID:31101807). Reason: PLP binding is essential for cysteine desulfurase catalytic mechanism and is confirmed by crystal structures. Supporting Evidence: PMID:29097656 The large domain of NFS1 (residues 71-315) harbors the PLP cofactor, which is covalently bound to Lys258 as an internal aldimine |
| GO:0031071 cysteine desulfurase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation for cysteine desulfurase activity consistent with experimental evidence. Reason: Redundant with IBA and IDA annotations but correct. Supporting Evidence: PMID:29097656 The enzyme belongs to a subfamily of pyridoxal 5′-phosphate (PLP)-dependent transaminases that convert free l-cysteine to alanine and an enzyme-bound persulfide (-SSH) group9, 10 |
| GO:0044571 [2Fe-2S] cluster assembly | IEA GO_REF:0000002 | ACCEPT | Summary: NFS1 is essential for [2Fe-2S] cluster assembly as the sulfur donor in the core ISC complex (PMID:38627381, PMID:29097656). The persulfide on Cys381 is transferred to ISCU2 Cys138 for cluster assembly. Reason: [2Fe-2S] cluster assembly is the primary product of NFS1's function in the ISC complex, well-characterized by cryo-EM and biochemistry. Supporting Evidence: PMID:38627381 The core ISC complex synthesizes [2Fe-2S] clusters de novo from Fe and a persulfide (SSH) bound at conserved cluster assembly site residues |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: NFS1 can bind metal ions including zinc, which coordinates at the interface with ISCU (PMID:29097656). However, this is a broad term. Reason: While NFS1 can bind metal ions (Zn at the NFS1-ISCU interface), metal ion binding is not a core molecular function - cysteine desulfurase activity is the defining function. Supporting Evidence: PMID:29097656 In (NIAU-Zn)2 a Zn ion occupies the expected Fe/S cluster synthesis site |
| GO:0051536 iron-sulfur cluster binding | IEA GO_REF:0000043 | REMOVE | Summary: NFS1 participates in iron-sulfur cluster assembly but does not itself permanently bind Fe-S clusters. The clusters are assembled on ISCU2, not held stably by NFS1. Reason: NFS1 is a sulfur donor enzyme, not an Fe-S cluster binding protein. The clusters are synthesized on the scaffold ISCU2, not retained by NFS1. Supporting Evidence: PMID:29097656 De novo Fe/S cluster synthesis occurs on the mitochondrial scaffold protein ISCU and requires cysteine desulfurase NFS1 |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000107 | ACCEPT | Summary: NFS1 functions in the mitochondrial matrix as part of the ISC machinery (PMID:16847322, deep research). Reason: More specific than GO:0005739 (mitochondrion) and accurate for the site of NFS1's Fe-S cluster assembly function. Supporting Evidence: PMID:16847322 huNfs1 is required inside mitochondria for efficient maturation of cellular Fe/S proteins |
| GO:0016226 iron-sulfur cluster assembly | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic annotation based on orthology, consistent with core function. Reason: Redundant with IBA and IDA annotations but correct. Supporting Evidence: PMID:16847322 huNfs1 performs an essential function in Fe/S protein biogenesis |
| GO:0044572 [4Fe-4S] cluster assembly | IEA GO_REF:0000120 | MODIFY | Summary: NFS1 contributes to [4Fe-4S] cluster assembly indirectly - it provides sulfur for [2Fe-2S] clusters on ISCU2, which are then converted to [4Fe-4S] clusters by late ISC factors (ISCA1/2, NFU1). Reason: NFS1 acts upstream of [4Fe-4S] cluster assembly. Its direct role is in [2Fe-2S] cluster assembly on ISCU2. The [4Fe-4S] conversion occurs via downstream factors. Proposed replacements: [2Fe-2S] cluster assembly Supporting Evidence: PMID:38627381 The core ISC complex synthesizes [2Fe-2S] clusters de novo |
| GO:0099128 mitochondrial [2Fe-2S] assembly complex | IEA GO_REF:0000120 | ACCEPT | Summary: NFS1 is a component of the mitochondrial [2Fe-2S] assembly complex (core ISC complex) containing NFS1-LYRM4-NDUFAB1-ISCU-FXN-FDX2. Reason: NFS1 is confirmed as an integral component of this complex by structural and biochemical studies. Supporting Evidence: PMID:29097656 Here, we report crystal and solution structures of human NFS1 in association with ISD11-ACP, ISCU, FDX2, and FXN, together forming the 'core ISC complex' PMID:31101807 Here the 3.2 Å resolution cryo-electron microscopy structure of the FXN-bound active human complex, containing two copies of the NFS1-ISD11-ACP-ISCU-FXN hetero-pentamer, delineates the interactions of FXN with other component proteins of the complex |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Nucleoplasm localization detected by HPA immunofluorescence, consistent with nuclear localization observed in other studies. Reason: Consistent with other evidence for nuclear NFS1 localization. Supporting Evidence: PMID:23593335 NFS1-EYFP and EYFP-NFS1delta1-55 were showing a localization in the nucleus |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosol localization detected by HPA immunofluorescence. Reason: Consistent with known cytosolic NFS1 isoform. Supporting Evidence: PMID:23593335 we were also able to detect NFS1 in the cytosolic fraction |
| GO:0016226 iron-sulfur cluster assembly | TAS Reactome:R-HSA-1362409 | ACCEPT | Summary: Reactome pathway annotation for mitochondrial iron-sulfur cluster biogenesis. Reason: Consistent with NFS1's established role in Fe-S cluster assembly. Supporting Evidence: PMID:29097656 A critical initial step in Fe/S cluster synthesis is the supply of sulfur by the cysteine desulfurase NFS1 |
| GO:0031071 cysteine desulfurase activity | EXP PMID:20873749 Human frataxin is an allosteric switch that activates the Fe... | ACCEPT | Summary: Experimental evidence from Tsai and Barondeau showing NFS1 cysteine desulfurase activity and activation by frataxin. Frataxin binding dramatically changes the K_M for cysteine from 0.59 to 0.011 mM. Reason: Direct experimental demonstration of NFS1 cysteine desulfurase activity and FXN-dependent regulation. Supporting Evidence: PMID:20873749 Frataxin binding dramatically changes the K(M) for cysteine from 0.59 to 0.011 mM |
| GO:0005739 mitochondrion | NAS PMID:27519411 Architecture of the Human Mitochondrial Iron-Sulfur Cluster ... | ACCEPT | Summary: Non-traceable author statement for mitochondrial localization from architectural study of the human mitochondrial Fe-S cluster assembly machinery. Reason: Consistent with extensive experimental evidence for mitochondrial localization. Supporting Evidence: PMID:29097656 De novo Fe/S cluster synthesis occurs on the mitochondrial scaffold protein ISCU and requires cysteine desulfurase NFS1 PMID:27519411 Epub 2016 Aug 12. 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: Author statement from Boniecki et al. Nature Communications 2017 structural study of the mitochondrial Fe/S cluster synthesis complex. Reason: This is a key structural study demonstrating NFS1's role in Fe-S cluster assembly, though the annotation type should ideally be experimental. Supporting Evidence: PMID:29097656 Our structural and complementary biochemical studies provide important functional insights into the molecular mechanisms of de novo [2Fe–2S] cluster synthesis on the ISCU scaffold protein and the dynamics of the core ISC complex during this process |
| GO:0005829 cytosol | IDA PMID:23593335 The L-cysteine desulfurase NFS1 is localized in the cytosol ... | ACCEPT | Summary: Direct immunodetection of NFS1 in cytosolic fractions of HeLa cells by Marelja et al., demonstrating cytosolic localization and interaction with MOCS3. Reason: Strong experimental evidence for cytosolic localization of the shorter NFS1 isoform. Supporting Evidence: PMID:23593335 we were also able to detect NFS1 in the cytosolic fraction |
| GO:0006777 Mo-molybdopterin cofactor biosynthetic process | IDA Q9Y697-2 PMID:18650437 A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a... | ACCEPT | Summary: Direct experimental evidence that NFS1 acts as sulfur donor for MOCS3 in molybdenum cofactor biosynthesis. Sulfur is transferred via persulfide intermediate from Cys381 to MOCS3-RLD Cys412. Reason: Strong biochemical evidence for NFS1's role in Moco biosynthesis via sulfur transfer to MOCS3. Supporting Evidence: PMID:18650437 sulfur is transferred from L-cysteine to MOCS3-RLD via an Nfs1-bound persulfide intermediate |
| GO:0031071 cysteine desulfurase activity | IDA PMID:28634302 Structure of human Fe-S assembly subcomplex reveals unexpect... | ACCEPT | Summary: Structural study revealing unexpected NFS1 architecture and interactions with acyl-ACP-ISD11, confirming cysteine desulfurase activity. Reason: Experimental structural biology study supporting cysteine desulfurase function. Supporting Evidence: PMID:29097656 The enzyme belongs to a subfamily of pyridoxal 5′-phosphate (PLP)-dependent transaminases that convert free l-cysteine to alanine and an enzyme-bound persulfide (-SSH) group9, 10 PMID:28634302 Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions. |
| GO:0031071 cysteine desulfurase activity | IDA PMID:38627381 Mechanism and structural dynamics of sulfur transfer during ... | ACCEPT | Summary: Schulz et al. 2024 Nature Communications provides detailed mechanism of persulfide transfer from NFS1 Cys381 to ISCU2 Cys138 via cryo-EM snapshots. Reason: State-of-the-art structural and biochemical study elucidating the cysteine desulfurase mechanism in atomic detail. Supporting Evidence: PMID:38627381 High-resolution cryo-EM structures obtained from anaerobically prepared samples provide snapshots that both visualize different stages of persulfide transfer from Cys381NFS1 to Cys138ISCU2 |
| GO:0044571 [2Fe-2S] cluster assembly | IDA PMID:38627381 Mechanism and structural dynamics of sulfur transfer during ... | ACCEPT | Summary: Direct experimental evidence from Schulz et al. 2024 showing NFS1's role in [2Fe-2S] cluster assembly through persulfide transfer mechanism. Reason: High-resolution mechanistic study of [2Fe-2S] cluster assembly process. Supporting Evidence: PMID:38627381 Maturation of iron-sulfur proteins in eukaryotes is initiated in mitochondria by the core iron-sulfur cluster assembly (ISC) complex |
| GO:0097163 sulfur carrier activity | IDA PMID:38627381 Mechanism and structural dynamics of sulfur transfer during ... | ACCEPT | Summary: NFS1 acts as a sulfur carrier by generating a persulfide on Cys381 that is then transferred to ISCU2. This sulfur carrier function is central to its role in Fe-S cluster assembly. Reason: Accurate description of NFS1's sulfur transfer mechanism, complementary to cysteine desulfurase activity annotation. Supporting Evidence: PMID:38627381 persulfide transfer from Cys381NFS1 to Cys138ISCU2 PMID:18650437 sulfur is transferred from L-cysteine to MOCS3-RLD via an Nfs1-bound persulfide intermediate |
| GO:0016226 iron-sulfur cluster assembly | IDA PMID:16847322 Role of human mitochondrial Nfs1 in cytosolic iron-sulfur pr... | ACCEPT | Summary: siRNA knockdown of NFS1 in HeLa cells demonstrates its essential role in iron-sulfur cluster assembly for both mitochondrial and cytosolic Fe-S proteins. Reason: Functional genetic evidence confirming NFS1 is essential for Fe-S protein biogenesis in human cells. Supporting Evidence: PMID:16847322 The activities of both mitochondrial and cytosolic Fe/S proteins were strongly impaired, demonstrating that huNfs1 performs an essential function in Fe/S protein biogenesis |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput proteomics study confirming NFS1 as a mitochondrial protein. Reason: Consistent with known mitochondrial localization, HTP evidence supports existing annotations. Supporting Evidence: PMID:29097656 De novo Fe/S cluster synthesis occurs on the mitochondrial scaffold protein ISCU and requires cysteine desulfurase NFS1 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: NFS1 binds to frataxin (FXN/Q16595) in the core ISC complex, as shown by cryo-EM structure at 3.2 A resolution. Reason: Protein binding is too generic. NFS1's interaction with FXN is specific and functionally important for allosteric activation of cysteine desulfurase activity. Proposed replacements: cysteine desulfurase activity Supporting Evidence: PMID:31101807 FXN binds at the interface of two NFS1 and one ISCU subunits PMID:20873749 Human frataxin is an allosteric switch that activates the Fe-S cluster biosynthetic complex. |
| GO:0005515 protein binding | IPI PMID:23593335 The L-cysteine desulfurase NFS1 is localized in the cytosol ... | KEEP AS NON CORE | Summary: NFS1 interacts with MOCS3 (O95396) in the cytosol for molybdenum cofactor biosynthesis, demonstrated by FRET and split-EGFP. Reason: This interaction is real but protein binding is too generic. The functional context (sulfur transfer to MOCS3) is captured in the Moco biosynthesis annotation. Supporting Evidence: PMID:23593335 Here, we present direct data to show the interaction of NFS1 and MOCS3 in the cytosol of human cells using Förster resonance energy transfer and a split-EGFP system |
| GO:0005634 nucleus | IDA PMID:23593335 The L-cysteine desulfurase NFS1 is localized in the cytosol ... | ACCEPT | Summary: Nuclear localization of NFS1 detected by immunofluorescence microscopy. Reason: Experimental evidence for nuclear localization, though nuclear function is less well characterized than mitochondrial function. Supporting Evidence: PMID:23593335 NFS1-EYFP and EYFP-NFS1delta1-55 were showing a localization in the nucleus |
| GO:0005739 mitochondrion | IDA PMID:23593335 The L-cysteine desulfurase NFS1 is localized in the cytosol ... | ACCEPT | Summary: Mitochondrial localization confirmed by immunofluorescence and co-localization with Mitotracker. Reason: Direct experimental evidence for the predominant mitochondrial localization. Supporting Evidence: PMID:23593335 the majority of NFS1-EYFP and ISD11-ECFP were targeted to the mitochondria |
| GO:0005739 mitochondrion | IDA PMID:30817134 Analysis of the Cellular Roles of MOCS3 Identifies a MOCS3-I... | ACCEPT | Summary: Mitochondrial localization confirmed by Neukranz et al. in the context of studying MOCS3-independent NFS1 localizations. Reason: Consistent with extensive evidence for mitochondrial localization. Supporting Evidence: PMID:30817134 the l-cysteine desulfurase NFS1 was shown to act as a sulfur donor for MOCS3 in the cytosol |
| GO:0005813 centrosome | IDA PMID:30817134 Analysis of the Cellular Roles of MOCS3 Identifies a MOCS3-I... | ACCEPT | Summary: Novel centrosome localization identified, independent of MOCS3 interaction. Reason: Experimental evidence for a novel NFS1 localization site, though functional significance is unclear. Supporting Evidence: PMID:30817134 we identified a MOCS3-independent novel localization of NFS1 at the centrosome |
| GO:0005829 cytosol | IDA PMID:30817134 Analysis of the Cellular Roles of MOCS3 Identifies a MOCS3-I... | ACCEPT | Summary: Cytosolic localization confirmed in the context of studying centrosome and MOCS3-dependent localization. Reason: Consistent with known cytosolic NFS1 isoform. Supporting Evidence: PMID:30817134 the l-cysteine desulfurase NFS1 was shown to act as a sulfur donor for MOCS3 in the cytosol |
| GO:0031071 cysteine desulfurase activity | IDA PMID:23593335 The L-cysteine desulfurase NFS1 is localized in the cytosol ... | ACCEPT | Summary: Cysteine desulfurase activity demonstrated biochemically, with sulfur mobilization from L-cysteine and persulfide formation on Cys381. Reason: Direct biochemical demonstration of NFS1 cysteine desulfurase activity. Supporting Evidence: PMID:23593335 the sulfur is mobilized from L-cysteine by NFS1 forming a persulfide group on its conserved Cys381 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-947514 | ACCEPT | Summary: Reactome pathway annotation for NFS1-MOCS3 sulfur transfer in cytosol. Reason: Consistent with known cytosolic function in Moco biosynthesis. Supporting Evidence: PMID:18650437 cytosolic Nfs1 has an important role in sulfur transfer for the biosynthesis of Moco |
| GO:0005515 protein binding | IPI PMID:31664822 Structure of the Human ACP-ISD11 Heterodimer. | KEEP AS NON CORE | Summary: NFS1 binds to NDUFAB1/ACP (O14561) and LYRM4/ISD11 (Q9HD34) in the cysteine desulfurase complex, shown by structural study of ACP-ISD11 heterodimer. Reason: These interactions are functionally important for NFS1 stability and activity but protein binding is too generic a term. Supporting Evidence: PMID:29097656 ISD11 binds to NFS1 distal from the desulfurase active site PMID:31664822 Epub 2019 Nov 8. Structure of the Human ACP-ISD11 Heterodimer. |
| GO:0031071 cysteine desulfurase activity | IDA PMID:31664822 Structure of the Human ACP-ISD11 Heterodimer. | ACCEPT | Summary: Cysteine desulfurase activity confirmed in the context of ACP-ISD11 complex structural studies. Reason: Experimental evidence supporting the core molecular function. Supporting Evidence: PMID:29097656 The enzyme belongs to a subfamily of pyridoxal 5′-phosphate (PLP)-dependent transaminases that convert free l-cysteine to alanine and an enzyme-bound persulfide (-SSH) group9, 10 PMID:31664822 Epub 2019 Nov 8. Structure of the Human ACP-ISD11 Heterodimer. |
| GO:0044571 [2Fe-2S] cluster assembly | IDA PMID:31664822 Structure of the Human ACP-ISD11 Heterodimer. | ACCEPT | Summary: [2Fe-2S] cluster assembly activity demonstrated with the reconstituted NFS1-ISD11-ACP complex. Reason: Experimental evidence for Fe-S cluster assembly activity. Supporting Evidence: PMID:29097656 Fe/S cluster synthesis rates and efficiencies were observed for both human and C. thermophilum ISC proteins PMID:31664822 Epub 2019 Nov 8. Structure of the Human ACP-ISD11 Heterodimer. |
| GO:0005515 protein binding | IPI PMID:18650437 A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a... | KEEP AS NON CORE | Summary: NFS1 binds to LYRM4/ISD11 (Q9HD34) for stabilization and activation of cysteine desulfurase activity. Reason: The NFS1-LYRM4 interaction is essential for NFS1 stability and function but protein binding is too generic. Supporting Evidence: PMID:18650437 A variant of Nfs1 was purified in conjunction with Isd11 |
| GO:0099128 mitochondrial [2Fe-2S] assembly complex | IDA PMID:31101807 Structure of the human frataxin-bound iron-sulfur cluster as... | ACCEPT | Summary: Cryo-EM structure at 3.2 A demonstrates NFS1 as part of the complete human mitochondrial ISC complex with FXN, ISCU, ISD11, and ACP. Reason: High-resolution structural evidence confirming NFS1 as integral to the mitochondrial [2Fe-2S] assembly complex. Supporting Evidence: PMID:31101807 Here the 3.2 Å resolution cryo-electron microscopy structure of the FXN-bound active human complex, containing two copies of the NFS1-ISD11-ACP-ISCU-FXN hetero-pentamer, delineates the interactions of FXN with other component proteins of the complex |
| GO:0005515 protein binding | IPI PMID:18650437 A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a... | KEEP AS NON CORE | Summary: NFS1 binds to MOCS3 (O95396) for sulfur transfer in molybdenum cofactor biosynthesis pathway. Reason: Functionally important interaction but protein binding is too generic. Supporting Evidence: PMID:18650437 Nfs1 interacted specifically with MOCS3-RLD |
| GO:0031071 cysteine desulfurase activity | IDA Q9Y697-2 PMID:18650437 A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a... | ACCEPT | Summary: Cysteine desulfurase activity characterized biochemically, including kinetic parameters for L-cysteine. Reason: Quantitative biochemical characterization of NFS1 cysteine desulfurase activity. Supporting Evidence: PMID:18650437 the kinetic parameters of the purified protein were determined |
| GO:0031071 cysteine desulfurase activity | IDA Q9Y697-2 PMID:16527810 Roles of the mammalian cytosolic cysteine desulfurase, ISCS,... | ACCEPT | Summary: Cytosolic NFS1 isoform demonstrated to be an active cysteine desulfurase that can support Fe-S cluster assembly on IRP1. Reason: Direct demonstration of cytosolic NFS1 cysteine desulfurase activity. Supporting Evidence: PMID:16527810 the cytosolic form of ISCS is an active cysteine desulfurase that covalently binds 35S acquired from desulfuration of radiolabeled cysteine |
| GO:0005515 protein binding | IPI PMID:28001042 Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FD... | KEEP AS NON CORE | Summary: NFS1 binds to ferredoxin-2 (FDX2/Q6P4F2), the electron donor in the ISC complex. Reason: Important functional interaction but protein binding is too generic. Supporting Evidence: PMID:29097656 crystal and solution structures of human NFS1 in association with ISD11-ACP, ISCU, FDX2, and FXN PMID:28001042 Epub 2017 Jan 11. Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both Bind Cysteine Desulfurase and Donate Electrons for Iron-Sulfur Cluster Biosynthesis. |
| GO:0005515 protein binding | IPI Q9Y697-2 PMID:29309586 Cytosolic HSC20 integrates de novo iron-sulfur cluster bioge... | KEEP AS NON CORE | Summary: Cytosolic NFS1 isoform interacts with CIAO1/CIA1 (Q8IWL3) for integrating de novo Fe-S cluster biogenesis with CIA-mediated transfer. Reason: Interaction documented but functional significance for NFS1 is secondary. Supporting Evidence: file:human/NFS1/NFS1-deep-research-falcon.md Cytosolic HSC20 integrates de novo iron-sulfur cluster biogenesis with the CIAO1-mediated transfer PMID:29309586 Cytosolic HSC20 integrates de novo iron-sulfur cluster biogenesis with the CIAO1-mediated transfer to recipients. |
| GO:0044572 [4Fe-4S] cluster assembly | IDA Q9Y697-2 PMID:16527810 Roles of the mammalian cytosolic cysteine desulfurase, ISCS,... | MODIFY | Summary: Cytosolic NFS1 and ISCU can support [4Fe-4S] cluster formation on IRP1 in vitro. Reason: Annotation uses acts_upstream_of qualifier. NFS1 contributes sulfur for initial [2Fe-2S] cluster formation; [4Fe-4S] assembly is a downstream event. Proposed replacements: [2Fe-2S] cluster assembly Supporting Evidence: PMID:16527810 the cytosolic forms of ISCS and ISCU facilitated efficient formation of a [4Fe-4S] cluster on IRP1 |
| GO:0044571 [2Fe-2S] cluster assembly | IDA PMID:24971490 Human frataxin activates Fe-S cluster biosynthesis by facili... | ACCEPT | Summary: Bridwell-Rabb et al. show frataxin accelerates sulfur accumulation on ISCU2 for [2Fe-2S] cluster synthesis via the NFS1-containing assembly complex. Reason: Mechanistic study of [2Fe-2S] cluster assembly by the NFS1-containing complex. Supporting Evidence: file:human/NFS1/NFS1-deep-research-falcon.md FXN accelerates the accumulation of sulfur on ISCU2 and that the resulting persulfide species is viable in the subsequent synthesis of Fe-S clusters PMID:24971490 Human frataxin activates Fe-S cluster biosynthesis by facilitating sulfur transfer chemistry. |
| GO:0042803 protein homodimerization activity | IDA PMID:34824239 N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synth... | ACCEPT | Summary: NFS1 functions as a homodimer, with dimerization important for complex assembly and [2Fe-2S] cluster synthesis. Reason: Homodimerization is a consistent structural feature of NFS1 demonstrated in multiple crystal structures. Supporting Evidence: PMID:29097656 The three structures with a central NFS1 dimer PMID:16527810 Human cytosolic ISCS dimerized as efficiently as bacterial ISCS 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: NFS1 dimer interacts with ISCU (Q9H1K1) and LYRM4 (Q9HD34) in the core ISC complex, as shown by crystal structures. Reason: These interactions are essential but protein binding is too generic. Supporting Evidence: PMID:29097656 crystal structures of three different NFS1-ISD11-ACP complexes with and without ISCU |
| GO:0031071 cysteine desulfurase activity | IDA PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S ... | ACCEPT | Summary: Boniecki et al. 2017 Nature Communications provides crystal structures and biochemical characterization of NFS1 cysteine desulfurase activity. Reason: Comprehensive structural and biochemical study of NFS1 desulfurase function. Supporting Evidence: PMID:29097656 The enzyme belongs to a subfamily of pyridoxal 5′-phosphate (PLP)-dependent transaminases that convert free l-cysteine to alanine and an enzyme-bound persulfide (-SSH) group9, 10 |
| GO:0042803 protein homodimerization activity | IDA PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S ... | ACCEPT | Summary: NFS1 homodimer structure determined by X-ray crystallography. Reason: Structural confirmation of NFS1 homodimerization. Supporting Evidence: PMID:29097656 The three structures with a central NFS1 dimer |
| GO:0005515 protein binding | IPI PMID:23940031 Human mitochondrial chaperone (mtHSP70) and cysteine desulfu... | KEEP AS NON CORE | Summary: NFS1 binds preferentially to disordered ISCU (Q9H1K1), while chaperone HSC20 binds structured ISCU. Reason: Important mechanistic insight but protein binding is too generic. Supporting Evidence: file:human/NFS1/NFS1-deep-research-falcon.md NFS1 preferentially binds disordered ISCU conformation PMID:23940031 2013 Aug 12. 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:21298097 Mammalian frataxin - an essential function for cellular viab... | ACCEPT | Summary: Schmucker et al. demonstrate frataxin interacts with preformed ISCU/NFS1/ISD11 complex. Reason: Experimental evidence for NFS1 as part of the core Fe-S assembly complex. Supporting Evidence: file:human/NFS1/NFS1-deep-research-falcon.md mammalian frataxin interacts with the preformed core complex 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: NFS1 interacts with ISCU (Q9H1K1), demonstrated by immunoprecipitation in early study of distinct mitochondrial and cytosolic Fe-S assembly complexes. Reason: Important early evidence for NFS1-ISCU interaction but protein binding is too generic. Supporting Evidence: file:human/NFS1/NFS1-deep-research-falcon.md Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells PMID:11060020 Distinct iron-sulfur cluster assembly complexes exist in the cytosol and mitochondria of human cells. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-1362408 | ACCEPT | Summary: Reactome pathway annotation for NFS1 function in [2Fe-2S] cluster assembly in mitochondrial matrix. Reason: Consistent with known mitochondrial matrix localization for Fe-S assembly. Supporting Evidence: PMID:16847322 huNfs1 is required inside mitochondria for efficient maturation of cellular Fe/S proteins |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-1362416 | ACCEPT | Summary: Reactome pathway annotation for frataxin iron binding in mitochondrial matrix context with NFS1. Reason: Consistent with mitochondrial matrix localization. Supporting Evidence: PMID:29097656 De novo Fe/S cluster synthesis occurs on the mitochondrial scaffold protein ISCU and requires cysteine desulfurase NFS1 |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9854984 | ACCEPT | Summary: Reactome pathway for transfer of Fe-S clusters to SDHB in mitochondrial matrix. Reason: NFS1 provides sulfur for Fe-S cluster assembly in mitochondrial matrix. Supporting Evidence: PMID:16847322 The activities of both mitochondrial and cytosolic Fe/S proteins were strongly impaired |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9866272 | ACCEPT | Summary: Reactome pathway for [2Fe-2S] insertion into UQCRFS1 in mitochondrial matrix. Reason: Downstream of NFS1's sulfur provision role in Fe-S cluster assembly. Supporting Evidence: PMID:29097656 De novo Fe/S cluster synthesis occurs on the mitochondrial scaffold protein ISCU |
| GO:0005515 protein binding | IPI PMID:26702583 Mitochondrial Hspa9/Mortalin regulates erythroid differentia... | KEEP AS NON CORE | Summary: NFS1 interacts with HSPA9/mortalin (P38646), the mitochondrial Hsp70 chaperone involved in Fe-S cluster handoff. Reason: Functionally relevant interaction but protein binding is too generic. Supporting Evidence: file:human/NFS1/NFS1-deep-research-falcon.md HSPA9 (Hsp70) and HSC20 (J-domain cochaperone) recognize LYR-like motifs to mediate cluster transfer PMID:26702583 Dec 17. 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: Mitochondrial localization confirmed in context of HSPA9 interaction studies. Reason: Consistent with known mitochondrial localization. Supporting Evidence: PMID:16847322 The protein is located predominantly in mitochondria PMID:26702583 Dec 17. Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-sulfur cluster assembly. |
| GO:0005515 protein binding | IPI PMID:16527810 Roles of the mammalian cytosolic cysteine desulfurase, ISCS,... | KEEP AS NON CORE | Summary: NFS1 binds to ISCU (Q9H1K1) for Fe-S cluster assembly. Reason: Essential interaction but protein binding is too generic. Supporting Evidence: PMID:16527810 formed a complex in vitro with overexpressed cytosolic human ISCU |
| GO:0005634 nucleus | IDA PMID:16847322 Role of human mitochondrial Nfs1 in cytosolic iron-sulfur pr... | ACCEPT | Summary: Nuclear localization detected by siRNA knockdown studies. Reason: Experimental evidence for nuclear NFS1. Supporting Evidence: PMID:16847322 small amounts are present in the cytosol/nucleus |
| GO:0005759 mitochondrial matrix | IDA PMID:16847322 Role of human mitochondrial Nfs1 in cytosolic iron-sulfur pr... | ACCEPT | Summary: Mitochondrial matrix localization determined by subcellular fractionation and functional studies. Reason: Direct experimental evidence for mitochondrial matrix localization. Supporting Evidence: PMID:16847322 huNfs1 is required inside mitochondria for efficient maturation of cellular Fe/S proteins |
| GO:0005829 cytosol | IDA PMID:16527810 Roles of the mammalian cytosolic cysteine desulfurase, ISCS,... | ACCEPT | Summary: Cytosolic localization of shorter NFS1 isoform demonstrated. Reason: Experimental evidence for cytosolic isoform. Supporting Evidence: PMID:16527810 the other less abundant form is cytosolic and nuclear |
| GO:0042803 protein homodimerization activity | IDA PMID:16527810 Roles of the mammalian cytosolic cysteine desulfurase, ISCS,... | ACCEPT | Summary: Human cytosolic NFS1 dimerizes as efficiently as bacterial IscS. Reason: Experimental demonstration of NFS1 homodimerization. Supporting Evidence: PMID:16527810 Human cytosolic ISCS dimerized as efficiently as bacterial ISCS |
| GO:0005634 nucleus | TAS PMID:9885568 Targeting of a human iron-sulfur cluster assembly enzyme, ni... | ACCEPT | Summary: Original description of NFS1 subcellular targeting via alternative AUG utilization, including nuclear localization. Reason: Foundational study establishing NFS1 targeting to multiple compartments. Supporting Evidence: PMID:9885568 different forms of NifS that localize either to mitochondria or to the cytosol and nucleus are synthesized from a single transcript |
| GO:0005739 mitochondrion | TAS PMID:9885568 Targeting of a human iron-sulfur cluster assembly enzyme, ni... | ACCEPT | Summary: Original characterization of NFS1 mitochondrial targeting. Reason: Foundational study establishing NFS1 subcellular localization. Supporting Evidence: PMID:9885568 different forms of NifS that localize either to mitochondria or to the cytosol and nucleus are synthesized from a single transcript |
| GO:0005829 cytosol | TAS PMID:9885568 Targeting of a human iron-sulfur cluster assembly enzyme, ni... | ACCEPT | Summary: Original characterization of cytosolic NFS1 isoform. Reason: Foundational study establishing alternative NFS1 isoforms. Supporting Evidence: PMID:9885568 different forms of NifS that localize either to mitochondria or to the cytosol and nucleus are synthesized from a single transcript |
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