id: Q9Y697
gene_symbol: NFS1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      reason: Mitochondrial localization is the primary site of NFS1 function, 
        confirmed by multiple experimental studies and phylogenetic inference.
      supported_by:
        - reference_id: PMID:16847322
          supporting_text: The protein is located predominantly in mitochondria,
            but small amounts are present in the cytosol/nucleus.
        - reference_id: PMID:9885568
          supporting_text: different forms of NifS that localize either to 
            mitochondria or to the cytosol and nucleus are synthesized from a 
            single transcript
  - term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      reason: Iron-sulfur cluster assembly is the central biological process of 
        NFS1, conserved across species and supported by extensive experimental 
        evidence.
      supported_by:
        - reference_id: PMID:16847322
          supporting_text: huNfs1 performs an essential function in Fe/S protein
            biogenesis in human cells
        - reference_id: PMID:29097656
          supporting_text: A critical initial step in Fe/S cluster synthesis is 
            the supply of sulfur by the cysteine desulfurase NFS1
  - term:
      id: GO:0031071
      label: cysteine desulfurase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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).
      action: ACCEPT
      reason: This is the core molecular function of NFS1, extensively 
        characterized biochemically and structurally.
      supported_by:
        - reference_id: PMID:16527810
          supporting_text: the cytosolic form of ISCS is an active cysteine 
            desulfurase that covalently binds 35S acquired from desulfuration of
            radiolabeled cysteine
        - reference_id: PMID:29097656
          supporting_text: 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
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      reason: Cytosolic localization is well-established for the shorter NFS1 
        isoform and is functionally important for molybdenum cofactor 
        biosynthesis.
      supported_by:
        - reference_id: PMID:9885568
          supporting_text: different forms of NifS that localize either to 
            mitochondria or to the cytosol and nucleus are synthesized from a 
            single transcript
        - reference_id: PMID:23593335
          supporting_text: we were also able to detect NFS1 in the cytosolic 
            fraction
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      reason: Nuclear localization is supported by multiple studies, though the 
        functional significance is less clear than mitochondrial localization.
      supported_by:
        - reference_id: PMID:16847322
          supporting_text: small amounts are present in the cytosol/nucleus
        - reference_id: PMID:23593335
          supporting_text: NFS1-EYFP and EYFP-NFS1delta1-55 were showing a 
            localization in the nucleus
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Electronic annotation for nuclear localization based on orthology
        to mouse NFS1.
      action: ACCEPT
      reason: Consistent with IBA and experimental evidence supporting nuclear 
        localization.
      supported_by:
        - reference_id: PMID:16847322
          supporting_text: small amounts are present in the cytosol/nucleus
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Electronic annotation for mitochondrial localization consistent 
        with known biology.
      action: ACCEPT
      reason: Redundant with IBA annotation but consistent with extensive 
        experimental evidence.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: De novo Fe/S cluster synthesis occurs on the 
            mitochondrial scaffold protein ISCU and requires cysteine 
            desulfurase NFS1
  - term:
      id: GO:0005813
      label: centrosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Centrosome localization was identified in PMID:30817134 as a 
        novel, MOCS3-independent localization site for NFS1. Function at 
        centrosomes is unknown.
      action: ACCEPT
      reason: Supported by experimental evidence (PMID:30817134), though 
        biological significance remains unclear.
      supported_by:
        - reference_id: PMID:30817134
          supporting_text: we identified a MOCS3-independent novel localization 
            of NFS1 at the centrosome
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Electronic annotation for cytosolic localization, consistent with
        known isoform biology.
      action: ACCEPT
      reason: Redundant with IBA annotation but consistent with experimental 
        evidence.
      supported_by:
        - reference_id: PMID:23593335
          supporting_text: we were also able to detect NFS1 in the cytosolic 
            fraction
  - term:
      id: GO:0006777
      label: Mo-molybdopterin cofactor biosynthetic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: NFS1 serves as the sulfur donor for molybdenum cofactor (Moco) 
        biosynthesis via transfer to MOCS3 in the cytosol (PMID:18650437, 
        PMID:23593335).
      action: ACCEPT
      reason: Well-established secondary function of cytosolic NFS1 isoform, 
        supported by biochemical and cellular studies.
      supported_by:
        - reference_id: PMID:18650437
          supporting_text: cytosolic Nfs1 has an important role in sulfur 
            transfer for the biosynthesis of Moco
        - reference_id: PMID:23593335
          supporting_text: NFS1 is the sulfur donor for Moco biosynthesis in 
            eukaryotes in general
  - term:
      id: GO:0016740
      label: transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: NFS1 has transferase activity as it transfers sulfur from 
        cysteine to persulfide intermediates and then to acceptor proteins.
      action: MODIFY
      reason: This term is too broad. The specific function is cysteine 
        desulfurase activity (GO:0031071), which better captures NFS1's 
        enzymatic mechanism.
      proposed_replacement_terms:
        - id: GO:0031071
          label: cysteine desulfurase activity
  - term:
      id: GO:0030170
      label: pyridoxal phosphate binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: NFS1 is a PLP-dependent enzyme with pyridoxal 5'-phosphate 
        covalently bound to Lys258 as an internal aldimine (PMID:29097656, 
        PMID:31101807).
      action: ACCEPT
      reason: PLP binding is essential for cysteine desulfurase catalytic 
        mechanism and is confirmed by crystal structures.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: The large domain of NFS1 (residues 71-315) harbors 
            the PLP cofactor, which is covalently bound to Lys258 as an internal
            aldimine
  - term:
      id: GO:0031071
      label: cysteine desulfurase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Electronic annotation for cysteine desulfurase activity 
        consistent with experimental evidence.
      action: ACCEPT
      reason: Redundant with IBA and IDA annotations but correct.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: 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
  - term:
      id: GO:0044571
      label: '[2Fe-2S] cluster assembly'
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      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.
      action: ACCEPT
      reason: '[2Fe-2S] cluster assembly is the primary product of NFS1''s function
        in the ISC complex, well-characterized by cryo-EM and biochemistry.'
      supported_by:
        - reference_id: PMID:38627381
          supporting_text: The core ISC complex synthesizes [2Fe-2S] clusters de
            novo from Fe and a persulfide (SSH) bound at conserved cluster 
            assembly site residues
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: NFS1 can bind metal ions including zinc, which coordinates at the
        interface with ISCU (PMID:29097656). However, this is a broad term.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: In (NIAU-Zn)2 a Zn ion occupies the expected Fe/S 
            cluster synthesis site
  - term:
      id: GO:0051536
      label: iron-sulfur cluster binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      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.
      action: REMOVE
      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.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: De novo Fe/S cluster synthesis occurs on the 
            mitochondrial scaffold protein ISCU and requires cysteine 
            desulfurase NFS1
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: NFS1 functions in the mitochondrial matrix as part of the ISC 
        machinery (PMID:16847322, deep research).
      action: ACCEPT
      reason: More specific than GO:0005739 (mitochondrion) and accurate for the
        site of NFS1's Fe-S cluster assembly function.
      supported_by:
        - reference_id: PMID:16847322
          supporting_text: huNfs1 is required inside mitochondria for efficient 
            maturation of cellular Fe/S proteins
  - term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Electronic annotation based on orthology, consistent with core 
        function.
      action: ACCEPT
      reason: Redundant with IBA and IDA annotations but correct.
      supported_by:
        - reference_id: PMID:16847322
          supporting_text: huNfs1 performs an essential function in Fe/S protein
            biogenesis
  - term:
      id: GO:0044572
      label: '[4Fe-4S] cluster assembly'
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      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).
      action: MODIFY
      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_replacement_terms:
        - id: GO:0044571
          label: '[2Fe-2S] cluster assembly'
      supported_by:
        - reference_id: PMID:38627381
          supporting_text: The core ISC complex synthesizes [2Fe-2S] clusters de
            novo
  - term:
      id: GO:0099128
      label: mitochondrial [2Fe-2S] assembly complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: NFS1 is a component of the mitochondrial [2Fe-2S] assembly 
        complex (core ISC complex) containing NFS1-LYRM4-NDUFAB1-ISCU-FXN-FDX2.
      action: ACCEPT
      reason: NFS1 is confirmed as an integral component of this complex by 
        structural and biochemical studies.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: 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'
        - reference_id: PMID:31101807
          supporting_text: 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
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: Nucleoplasm localization detected by HPA immunofluorescence, 
        consistent with nuclear localization observed in other studies.
      action: ACCEPT
      reason: Consistent with other evidence for nuclear NFS1 localization.
      supported_by:
        - reference_id: PMID:23593335
          supporting_text: NFS1-EYFP and EYFP-NFS1delta1-55 were showing a 
            localization in the nucleus
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: Cytosol localization detected by HPA immunofluorescence.
      action: ACCEPT
      reason: Consistent with known cytosolic NFS1 isoform.
      supported_by:
        - reference_id: PMID:23593335
          supporting_text: we were also able to detect NFS1 in the cytosolic 
            fraction
  - term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1362409
    review:
      summary: Reactome pathway annotation for mitochondrial iron-sulfur cluster
        biogenesis.
      action: ACCEPT
      reason: Consistent with NFS1's established role in Fe-S cluster assembly.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: A critical initial step in Fe/S cluster synthesis is 
            the supply of sulfur by the cysteine desulfurase NFS1
  - term:
      id: GO:0031071
      label: cysteine desulfurase activity
    evidence_type: EXP
    original_reference_id: PMID:20873749
    review:
      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.
      action: ACCEPT
      reason: Direct experimental demonstration of NFS1 cysteine desulfurase 
        activity and FXN-dependent regulation.
      supported_by:
        - reference_id: PMID:20873749
          supporting_text: Frataxin binding dramatically changes the K(M) for 
            cysteine from 0.59 to 0.011 mM
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: NAS
    original_reference_id: PMID:27519411
    review:
      summary: Non-traceable author statement for mitochondrial localization 
        from architectural study of the human mitochondrial Fe-S cluster 
        assembly machinery.
      action: ACCEPT
      reason: Consistent with extensive experimental evidence for mitochondrial 
        localization.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: De novo Fe/S cluster synthesis occurs on the 
            mitochondrial scaffold protein ISCU and requires cysteine 
            desulfurase NFS1
        - reference_id: PMID:27519411
          supporting_text: Epub 2016 Aug 12. Architecture of the Human 
            Mitochondrial Iron-Sulfur Cluster Assembly Machinery.
  - term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    evidence_type: NAS
    original_reference_id: PMID:29097656
    review:
      summary: Author statement from Boniecki et al. Nature Communications 2017 
        structural study of the mitochondrial Fe/S cluster synthesis complex.
      action: ACCEPT
      reason: This is a key structural study demonstrating NFS1's role in Fe-S 
        cluster assembly, though the annotation type should ideally be 
        experimental.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: 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
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: PMID:23593335
    review:
      summary: Direct immunodetection of NFS1 in cytosolic fractions of HeLa 
        cells by Marelja et al., demonstrating cytosolic localization and 
        interaction with MOCS3.
      action: ACCEPT
      reason: Strong experimental evidence for cytosolic localization of the 
        shorter NFS1 isoform.
      supported_by:
        - reference_id: PMID:23593335
          supporting_text: we were also able to detect NFS1 in the cytosolic 
            fraction
  - term:
      id: GO:0006777
      label: Mo-molybdopterin cofactor biosynthetic process
    evidence_type: IDA
    original_reference_id: PMID:18650437
    review:
      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.
      action: ACCEPT
      reason: Strong biochemical evidence for NFS1's role in Moco biosynthesis 
        via sulfur transfer to MOCS3.
      supported_by:
        - reference_id: PMID:18650437
          supporting_text: sulfur is transferred from L-cysteine to MOCS3-RLD 
            via an Nfs1-bound persulfide intermediate
    isoform: Q9Y697-2
  - term:
      id: GO:0031071
      label: cysteine desulfurase activity
    evidence_type: IDA
    original_reference_id: PMID:28634302
    review:
      summary: Structural study revealing unexpected NFS1 architecture and 
        interactions with acyl-ACP-ISD11, confirming cysteine desulfurase 
        activity.
      action: ACCEPT
      reason: Experimental structural biology study supporting cysteine 
        desulfurase function.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: 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
        - reference_id: PMID:28634302
          supporting_text: Structure of human Fe-S assembly subcomplex reveals 
            unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 
            interactions.
  - term:
      id: GO:0031071
      label: cysteine desulfurase activity
    evidence_type: IDA
    original_reference_id: PMID:38627381
    review:
      summary: Schulz et al. 2024 Nature Communications provides detailed 
        mechanism of persulfide transfer from NFS1 Cys381 to ISCU2 Cys138 via 
        cryo-EM snapshots.
      action: ACCEPT
      reason: State-of-the-art structural and biochemical study elucidating the 
        cysteine desulfurase mechanism in atomic detail.
      supported_by:
        - reference_id: PMID:38627381
          supporting_text: High-resolution cryo-EM structures obtained from 
            anaerobically prepared samples provide snapshots that both visualize
            different stages of persulfide transfer from Cys381NFS1 to 
            Cys138ISCU2
  - term:
      id: GO:0044571
      label: '[2Fe-2S] cluster assembly'
    evidence_type: IDA
    original_reference_id: PMID:38627381
    review:
      summary: Direct experimental evidence from Schulz et al. 2024 showing 
        NFS1's role in [2Fe-2S] cluster assembly through persulfide transfer 
        mechanism.
      action: ACCEPT
      reason: High-resolution mechanistic study of [2Fe-2S] cluster assembly 
        process.
      supported_by:
        - reference_id: PMID:38627381
          supporting_text: Maturation of iron-sulfur proteins in eukaryotes is 
            initiated in mitochondria by the core iron-sulfur cluster assembly 
            (ISC) complex
  - term:
      id: GO:0097163
      label: sulfur carrier activity
    evidence_type: IDA
    original_reference_id: PMID:38627381
    review:
      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.
      action: ACCEPT
      reason: Accurate description of NFS1's sulfur transfer mechanism, 
        complementary to cysteine desulfurase activity annotation.
      supported_by:
        - reference_id: PMID:38627381
          supporting_text: persulfide transfer from Cys381NFS1 to Cys138ISCU2
        - reference_id: PMID:18650437
          supporting_text: sulfur is transferred from L-cysteine to MOCS3-RLD 
            via an Nfs1-bound persulfide intermediate
  - term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    evidence_type: IDA
    original_reference_id: PMID:16847322
    review:
      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.
      action: ACCEPT
      reason: Functional genetic evidence confirming NFS1 is essential for Fe-S 
        protein biogenesis in human cells.
      supported_by:
        - reference_id: PMID:16847322
          supporting_text: 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
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HTP
    original_reference_id: PMID:34800366
    review:
      summary: High-throughput proteomics study confirming NFS1 as a 
        mitochondrial protein.
      action: ACCEPT
      reason: Consistent with known mitochondrial localization, HTP evidence 
        supports existing annotations.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: De novo Fe/S cluster synthesis occurs on the 
            mitochondrial scaffold protein ISCU and requires cysteine 
            desulfurase NFS1
        - reference_id: PMID:34800366
          supporting_text: Epub 2021 Nov 19. Quantitative high-confidence human 
            mitochondrial proteome and its dynamics in cellular context.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31101807
    review:
      summary: NFS1 binds to frataxin (FXN/Q16595) in the core ISC complex, as 
        shown by cryo-EM structure at 3.2 A resolution.
      action: MODIFY
      reason: Protein binding is too generic. NFS1's interaction with FXN is 
        specific and functionally important for allosteric activation of 
        cysteine desulfurase activity.
      proposed_replacement_terms:
        - id: GO:0031071
          label: cysteine desulfurase activity
      additional_reference_ids:
        - PMID:20873749
      supported_by:
        - reference_id: PMID:31101807
          supporting_text: FXN binds at the interface of two NFS1 and one ISCU 
            subunits
        - reference_id: PMID:20873749
          supporting_text: Human frataxin is an allosteric switch that activates
            the Fe-S cluster biosynthetic complex.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23593335
    review:
      summary: NFS1 interacts with MOCS3 (O95396) in the cytosol for molybdenum 
        cofactor biosynthesis, demonstrated by FRET and split-EGFP.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:23593335
          supporting_text: 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
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:23593335
    review:
      summary: Nuclear localization of NFS1 detected by immunofluorescence 
        microscopy.
      action: ACCEPT
      reason: Experimental evidence for nuclear localization, though nuclear 
        function is less well characterized than mitochondrial function.
      supported_by:
        - reference_id: PMID:23593335
          supporting_text: NFS1-EYFP and EYFP-NFS1delta1-55 were showing a 
            localization in the nucleus
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:23593335
    review:
      summary: Mitochondrial localization confirmed by immunofluorescence and 
        co-localization with Mitotracker.
      action: ACCEPT
      reason: Direct experimental evidence for the predominant mitochondrial 
        localization.
      supported_by:
        - reference_id: PMID:23593335
          supporting_text: the majority of NFS1-EYFP and ISD11-ECFP were 
            targeted to the mitochondria
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:30817134
    review:
      summary: Mitochondrial localization confirmed by Neukranz et al. in the 
        context of studying MOCS3-independent NFS1 localizations.
      action: ACCEPT
      reason: Consistent with extensive evidence for mitochondrial localization.
      supported_by:
        - reference_id: PMID:30817134
          supporting_text: the l-cysteine desulfurase NFS1 was shown to act as a
            sulfur donor for MOCS3 in the cytosol
  - term:
      id: GO:0005813
      label: centrosome
    evidence_type: IDA
    original_reference_id: PMID:30817134
    review:
      summary: Novel centrosome localization identified, independent of MOCS3 
        interaction.
      action: ACCEPT
      reason: Experimental evidence for a novel NFS1 localization site, though 
        functional significance is unclear.
      supported_by:
        - reference_id: PMID:30817134
          supporting_text: we identified a MOCS3-independent novel localization 
            of NFS1 at the centrosome
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: PMID:30817134
    review:
      summary: Cytosolic localization confirmed in the context of studying 
        centrosome and MOCS3-dependent localization.
      action: ACCEPT
      reason: Consistent with known cytosolic NFS1 isoform.
      supported_by:
        - reference_id: PMID:30817134
          supporting_text: the l-cysteine desulfurase NFS1 was shown to act as a
            sulfur donor for MOCS3 in the cytosol
  - term:
      id: GO:0031071
      label: cysteine desulfurase activity
    evidence_type: IDA
    original_reference_id: PMID:23593335
    review:
      summary: Cysteine desulfurase activity demonstrated biochemically, with 
        sulfur mobilization from L-cysteine and persulfide formation on Cys381.
      action: ACCEPT
      reason: Direct biochemical demonstration of NFS1 cysteine desulfurase 
        activity.
      supported_by:
        - reference_id: PMID:23593335
          supporting_text: the sulfur is mobilized from L-cysteine by NFS1 
            forming a persulfide group on its conserved Cys381
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-947514
    review:
      summary: Reactome pathway annotation for NFS1-MOCS3 sulfur transfer in 
        cytosol.
      action: ACCEPT
      reason: Consistent with known cytosolic function in Moco biosynthesis.
      supported_by:
        - reference_id: PMID:18650437
          supporting_text: cytosolic Nfs1 has an important role in sulfur 
            transfer for the biosynthesis of Moco
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31664822
    review:
      summary: NFS1 binds to NDUFAB1/ACP (O14561) and LYRM4/ISD11 (Q9HD34) in 
        the cysteine desulfurase complex, shown by structural study of ACP-ISD11
        heterodimer.
      action: KEEP_AS_NON_CORE
      reason: These interactions are functionally important for NFS1 stability 
        and activity but protein binding is too generic a term.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: ISD11 binds to NFS1 distal from the desulfurase 
            active site
        - reference_id: PMID:31664822
          supporting_text: Epub 2019 Nov 8. Structure of the Human ACP-ISD11 
            Heterodimer.
  - term:
      id: GO:0031071
      label: cysteine desulfurase activity
    evidence_type: IDA
    original_reference_id: PMID:31664822
    review:
      summary: Cysteine desulfurase activity confirmed in the context of 
        ACP-ISD11 complex structural studies.
      action: ACCEPT
      reason: Experimental evidence supporting the core molecular function.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: 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
        - reference_id: PMID:31664822
          supporting_text: Epub 2019 Nov 8. Structure of the Human ACP-ISD11 
            Heterodimer.
  - term:
      id: GO:0044571
      label: '[2Fe-2S] cluster assembly'
    evidence_type: IDA
    original_reference_id: PMID:31664822
    review:
      summary: '[2Fe-2S] cluster assembly activity demonstrated with the reconstituted
        NFS1-ISD11-ACP complex.'
      action: ACCEPT
      reason: Experimental evidence for Fe-S cluster assembly activity.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: Fe/S cluster synthesis rates and efficiencies were 
            observed for both human and C. thermophilum ISC proteins
        - reference_id: PMID:31664822
          supporting_text: Epub 2019 Nov 8. Structure of the Human ACP-ISD11 
            Heterodimer.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18650437
    review:
      summary: NFS1 binds to LYRM4/ISD11 (Q9HD34) for stabilization and 
        activation of cysteine desulfurase activity.
      action: KEEP_AS_NON_CORE
      reason: The NFS1-LYRM4 interaction is essential for NFS1 stability and 
        function but protein binding is too generic.
      supported_by:
        - reference_id: PMID:18650437
          supporting_text: A variant of Nfs1 was purified in conjunction with 
            Isd11
  - term:
      id: GO:0099128
      label: mitochondrial [2Fe-2S] assembly complex
    evidence_type: IDA
    original_reference_id: PMID:31101807
    review:
      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.
      action: ACCEPT
      reason: High-resolution structural evidence confirming NFS1 as integral to
        the mitochondrial [2Fe-2S] assembly complex.
      supported_by:
        - reference_id: PMID:31101807
          supporting_text: 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
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18650437
    review:
      summary: NFS1 binds to MOCS3 (O95396) for sulfur transfer in molybdenum 
        cofactor biosynthesis pathway.
      action: KEEP_AS_NON_CORE
      reason: Functionally important interaction but protein binding is too 
        generic.
      supported_by:
        - reference_id: PMID:18650437
          supporting_text: Nfs1 interacted specifically with MOCS3-RLD
  - term:
      id: GO:0031071
      label: cysteine desulfurase activity
    evidence_type: IDA
    original_reference_id: PMID:18650437
    review:
      summary: Cysteine desulfurase activity characterized biochemically, 
        including kinetic parameters for L-cysteine.
      action: ACCEPT
      reason: Quantitative biochemical characterization of NFS1 cysteine 
        desulfurase activity.
      supported_by:
        - reference_id: PMID:18650437
          supporting_text: the kinetic parameters of the purified protein were 
            determined
    isoform: Q9Y697-2
  - term:
      id: GO:0031071
      label: cysteine desulfurase activity
    evidence_type: IDA
    original_reference_id: PMID:16527810
    review:
      summary: Cytosolic NFS1 isoform demonstrated to be an active cysteine 
        desulfurase that can support Fe-S cluster assembly on IRP1.
      action: ACCEPT
      reason: Direct demonstration of cytosolic NFS1 cysteine desulfurase 
        activity.
      supported_by:
        - reference_id: PMID:16527810
          supporting_text: the cytosolic form of ISCS is an active cysteine 
            desulfurase that covalently binds 35S acquired from desulfuration of
            radiolabeled cysteine
    isoform: Q9Y697-2
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28001042
    review:
      summary: NFS1 binds to ferredoxin-2 (FDX2/Q6P4F2), the electron donor in 
        the ISC complex.
      action: KEEP_AS_NON_CORE
      reason: Important functional interaction but protein binding is too 
        generic.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: crystal and solution structures of human NFS1 in 
            association with ISD11-ACP, ISCU, FDX2, and FXN
        - reference_id: PMID:28001042
          supporting_text: 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.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29309586
    review:
      summary: Cytosolic NFS1 isoform interacts with CIAO1/CIA1 (Q8IWL3) for 
        integrating de novo Fe-S cluster biogenesis with CIA-mediated transfer.
      action: KEEP_AS_NON_CORE
      reason: Interaction documented but functional significance for NFS1 is 
        secondary.
      supported_by:
        - reference_id: file:human/NFS1/NFS1-deep-research-falcon.md
          supporting_text: Cytosolic HSC20 integrates de novo iron-sulfur 
            cluster biogenesis with the CIAO1-mediated transfer
        - reference_id: PMID:29309586
          supporting_text: Cytosolic HSC20 integrates de novo iron-sulfur 
            cluster biogenesis with the CIAO1-mediated transfer to recipients.
    isoform: Q9Y697-2
  - term:
      id: GO:0044572
      label: '[4Fe-4S] cluster assembly'
    evidence_type: IDA
    original_reference_id: PMID:16527810
    review:
      summary: Cytosolic NFS1 and ISCU can support [4Fe-4S] cluster formation on
        IRP1 in vitro.
      action: MODIFY
      reason: Annotation uses acts_upstream_of qualifier. NFS1 contributes 
        sulfur for initial [2Fe-2S] cluster formation; [4Fe-4S] assembly is a 
        downstream event.
      proposed_replacement_terms:
        - id: GO:0044571
          label: '[2Fe-2S] cluster assembly'
      supported_by:
        - reference_id: PMID:16527810
          supporting_text: the cytosolic forms of ISCS and ISCU facilitated 
            efficient formation of a [4Fe-4S] cluster on IRP1
    isoform: Q9Y697-2
  - term:
      id: GO:0044571
      label: '[2Fe-2S] cluster assembly'
    evidence_type: IDA
    original_reference_id: PMID:24971490
    review:
      summary: Bridwell-Rabb et al. show frataxin accelerates sulfur 
        accumulation on ISCU2 for [2Fe-2S] cluster synthesis via the 
        NFS1-containing assembly complex.
      action: ACCEPT
      reason: Mechanistic study of [2Fe-2S] cluster assembly by the 
        NFS1-containing complex.
      supported_by:
        - reference_id: file:human/NFS1/NFS1-deep-research-falcon.md
          supporting_text: FXN accelerates the accumulation of sulfur on ISCU2 
            and that the resulting persulfide species is viable in the 
            subsequent synthesis of Fe-S clusters
        - reference_id: PMID:24971490
          supporting_text: Human frataxin activates Fe-S cluster biosynthesis by
            facilitating sulfur transfer chemistry.
  - term:
      id: GO:0042803
      label: protein homodimerization activity
    evidence_type: IDA
    original_reference_id: PMID:34824239
    review:
      summary: NFS1 functions as a homodimer, with dimerization important for 
        complex assembly and [2Fe-2S] cluster synthesis.
      action: ACCEPT
      reason: Homodimerization is a consistent structural feature of NFS1 
        demonstrated in multiple crystal structures.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: The three structures with a central NFS1 dimer
        - reference_id: PMID:16527810
          supporting_text: Human cytosolic ISCS dimerized as efficiently as 
            bacterial ISCS
        - reference_id: PMID:34824239
          supporting_text: N-terminal tyrosine of ISCU2 triggers [2Fe-2S] 
            cluster synthesis by ISCU2 dimerization.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29097656
    review:
      summary: NFS1 dimer interacts with ISCU (Q9H1K1) and LYRM4 (Q9HD34) in the
        core ISC complex, as shown by crystal structures.
      action: KEEP_AS_NON_CORE
      reason: These interactions are essential but protein binding is too 
        generic.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: crystal structures of three different NFS1-ISD11-ACP 
            complexes with and without ISCU
  - term:
      id: GO:0031071
      label: cysteine desulfurase activity
    evidence_type: IDA
    original_reference_id: PMID:29097656
    review:
      summary: Boniecki et al. 2017 Nature Communications provides crystal 
        structures and biochemical characterization of NFS1 cysteine desulfurase
        activity.
      action: ACCEPT
      reason: Comprehensive structural and biochemical study of NFS1 desulfurase
        function.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: 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
  - term:
      id: GO:0042803
      label: protein homodimerization activity
    evidence_type: IDA
    original_reference_id: PMID:29097656
    review:
      summary: NFS1 homodimer structure determined by X-ray crystallography.
      action: ACCEPT
      reason: Structural confirmation of NFS1 homodimerization.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: The three structures with a central NFS1 dimer
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23940031
    review:
      summary: NFS1 binds preferentially to disordered ISCU (Q9H1K1), while 
        chaperone HSC20 binds structured ISCU.
      action: KEEP_AS_NON_CORE
      reason: Important mechanistic insight but protein binding is too generic.
      supported_by:
        - reference_id: file:human/NFS1/NFS1-deep-research-falcon.md
          supporting_text: NFS1 preferentially binds disordered ISCU 
            conformation
        - reference_id: PMID:23940031
          supporting_text: 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).
  - term:
      id: GO:0099128
      label: mitochondrial [2Fe-2S] assembly complex
    evidence_type: IDA
    original_reference_id: PMID:21298097
    review:
      summary: Schmucker et al. demonstrate frataxin interacts with preformed 
        ISCU/NFS1/ISD11 complex.
      action: ACCEPT
      reason: Experimental evidence for NFS1 as part of the core Fe-S assembly 
        complex.
      supported_by:
        - reference_id: file:human/NFS1/NFS1-deep-research-falcon.md
          supporting_text: mammalian frataxin interacts with the preformed core 
            complex
        - reference_id: PMID:21298097
          supporting_text: 'Mammalian frataxin: an essential function for cellular
            viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur
            assembly complex.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11060020
    review:
      summary: NFS1 interacts with ISCU (Q9H1K1), demonstrated by 
        immunoprecipitation in early study of distinct mitochondrial and 
        cytosolic Fe-S assembly complexes.
      action: KEEP_AS_NON_CORE
      reason: Important early evidence for NFS1-ISCU interaction but protein 
        binding is too generic.
      supported_by:
        - reference_id: file:human/NFS1/NFS1-deep-research-falcon.md
          supporting_text: Distinct iron-sulfur cluster assembly complexes exist
            in the cytosol and mitochondria of human cells
        - reference_id: PMID:11060020
          supporting_text: Distinct iron-sulfur cluster assembly complexes exist
            in the cytosol and mitochondria of human cells.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1362408
    review:
      summary: Reactome pathway annotation for NFS1 function in [2Fe-2S] cluster
        assembly in mitochondrial matrix.
      action: ACCEPT
      reason: Consistent with known mitochondrial matrix localization for Fe-S 
        assembly.
      supported_by:
        - reference_id: PMID:16847322
          supporting_text: huNfs1 is required inside mitochondria for efficient 
            maturation of cellular Fe/S proteins
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1362416
    review:
      summary: Reactome pathway annotation for frataxin iron binding in 
        mitochondrial matrix context with NFS1.
      action: ACCEPT
      reason: Consistent with mitochondrial matrix localization.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: De novo Fe/S cluster synthesis occurs on the 
            mitochondrial scaffold protein ISCU and requires cysteine 
            desulfurase NFS1
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9854984
    review:
      summary: Reactome pathway for transfer of Fe-S clusters to SDHB in 
        mitochondrial matrix.
      action: ACCEPT
      reason: NFS1 provides sulfur for Fe-S cluster assembly in mitochondrial 
        matrix.
      supported_by:
        - reference_id: PMID:16847322
          supporting_text: The activities of both mitochondrial and cytosolic 
            Fe/S proteins were strongly impaired
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9866272
    review:
      summary: Reactome pathway for [2Fe-2S] insertion into UQCRFS1 in 
        mitochondrial matrix.
      action: ACCEPT
      reason: Downstream of NFS1's sulfur provision role in Fe-S cluster 
        assembly.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: De novo Fe/S cluster synthesis occurs on the 
            mitochondrial scaffold protein ISCU
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26702583
    review:
      summary: NFS1 interacts with HSPA9/mortalin (P38646), the mitochondrial 
        Hsp70 chaperone involved in Fe-S cluster handoff.
      action: KEEP_AS_NON_CORE
      reason: Functionally relevant interaction but protein binding is too 
        generic.
      supported_by:
        - reference_id: file:human/NFS1/NFS1-deep-research-falcon.md
          supporting_text: HSPA9 (Hsp70) and HSC20 (J-domain cochaperone) 
            recognize LYR-like motifs to mediate cluster transfer
        - reference_id: PMID:26702583
          supporting_text: Dec 17. Mitochondrial Hspa9/Mortalin regulates 
            erythroid differentiation via iron-sulfur cluster assembly.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:26702583
    review:
      summary: Mitochondrial localization confirmed in context of HSPA9 
        interaction studies.
      action: ACCEPT
      reason: Consistent with known mitochondrial localization.
      supported_by:
        - reference_id: PMID:16847322
          supporting_text: The protein is located predominantly in mitochondria
        - reference_id: PMID:26702583
          supporting_text: Dec 17. Mitochondrial Hspa9/Mortalin regulates 
            erythroid differentiation via iron-sulfur cluster assembly.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16527810
    review:
      summary: NFS1 binds to ISCU (Q9H1K1) for Fe-S cluster assembly.
      action: KEEP_AS_NON_CORE
      reason: Essential interaction but protein binding is too generic.
      supported_by:
        - reference_id: PMID:16527810
          supporting_text: formed a complex in vitro with overexpressed 
            cytosolic human ISCU
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:16847322
    review:
      summary: Nuclear localization detected by siRNA knockdown studies.
      action: ACCEPT
      reason: Experimental evidence for nuclear NFS1.
      supported_by:
        - reference_id: PMID:16847322
          supporting_text: small amounts are present in the cytosol/nucleus
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: IDA
    original_reference_id: PMID:16847322
    review:
      summary: Mitochondrial matrix localization determined by subcellular 
        fractionation and functional studies.
      action: ACCEPT
      reason: Direct experimental evidence for mitochondrial matrix 
        localization.
      supported_by:
        - reference_id: PMID:16847322
          supporting_text: huNfs1 is required inside mitochondria for efficient 
            maturation of cellular Fe/S proteins
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: PMID:16527810
    review:
      summary: Cytosolic localization of shorter NFS1 isoform demonstrated.
      action: ACCEPT
      reason: Experimental evidence for cytosolic isoform.
      supported_by:
        - reference_id: PMID:16527810
          supporting_text: the other less abundant form is cytosolic and nuclear
  - term:
      id: GO:0042803
      label: protein homodimerization activity
    evidence_type: IDA
    original_reference_id: PMID:16527810
    review:
      summary: Human cytosolic NFS1 dimerizes as efficiently as bacterial IscS.
      action: ACCEPT
      reason: Experimental demonstration of NFS1 homodimerization.
      supported_by:
        - reference_id: PMID:16527810
          supporting_text: Human cytosolic ISCS dimerized as efficiently as 
            bacterial ISCS
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: TAS
    original_reference_id: PMID:9885568
    review:
      summary: Original description of NFS1 subcellular targeting via 
        alternative AUG utilization, including nuclear localization.
      action: ACCEPT
      reason: Foundational study establishing NFS1 targeting to multiple 
        compartments.
      supported_by:
        - reference_id: PMID:9885568
          supporting_text: different forms of NifS that localize either to 
            mitochondria or to the cytosol and nucleus are synthesized from a 
            single transcript
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: TAS
    original_reference_id: PMID:9885568
    review:
      summary: Original characterization of NFS1 mitochondrial targeting.
      action: ACCEPT
      reason: Foundational study establishing NFS1 subcellular localization.
      supported_by:
        - reference_id: PMID:9885568
          supporting_text: different forms of NifS that localize either to 
            mitochondria or to the cytosol and nucleus are synthesized from a 
            single transcript
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: PMID:9885568
    review:
      summary: Original characterization of cytosolic NFS1 isoform.
      action: ACCEPT
      reason: Foundational study establishing alternative NFS1 isoforms.
      supported_by:
        - reference_id: PMID:9885568
          supporting_text: different forms of NifS that localize either to 
            mitochondria or to the cytosol and nucleus are synthesized from a 
            single transcript
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:9885568
    title: Targeting of a human iron-sulfur cluster assembly enzyme, nifs, to 
      different subcellular compartments is regulated through alternative AUG 
      utilization.
    findings:
      - statement: Alternative AUG usage generates mitochondrial and 
          cytosolic/nuclear NFS1 isoforms
        supporting_text: different forms of NifS that localize either to 
          mitochondria or to the cytosol and nucleus are synthesized from a 
          single transcript
  - id: PMID:11060020
    title: Distinct iron-sulfur cluster assembly complexes exist in the cytosol 
      and mitochondria of human cells.
    findings:
      - statement: NFS1 interacts with ISCU in Fe-S assembly complexes
  - id: PMID:16527810
    title: Roles of the mammalian cytosolic cysteine desulfurase, ISCS, and 
      scaffold protein, ISCU, in iron-sulfur cluster assembly.
    findings:
      - statement: Cytosolic NFS1 is an active cysteine desulfurase
        supporting_text: the cytosolic form of ISCS is an active cysteine 
          desulfurase that covalently binds 35S acquired from desulfuration of 
          radiolabeled cysteine
      - statement: NFS1 homodimerizes and forms complex with ISCU
        supporting_text: Human cytosolic ISCS dimerized as efficiently as 
          bacterial ISCS
      - statement: Can support [4Fe-4S] cluster formation on IRP1
        supporting_text: the cytosolic forms of ISCS and ISCU facilitated 
          efficient formation of a [4Fe-4S] cluster on IRP1
  - id: PMID:16847322
    title: Role of human mitochondrial Nfs1 in cytosolic iron-sulfur protein 
      biogenesis and iron regulation.
    findings:
      - statement: NFS1 is essential for both mitochondrial and cytosolic Fe-S 
          protein biogenesis
        supporting_text: huNfs1 performs an essential function in Fe/S protein 
          biogenesis in human cells
      - statement: Mitochondrial localization is required for function
        supporting_text: huNfs1 is required inside mitochondria for efficient 
          maturation of cellular Fe/S proteins
  - id: PMID:18650437
    title: 'A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a sulfur donor
      for MOCS3, a protein involved in molybdenum cofactor biosynthesis.'
    findings:
      - statement: NFS1 interacts with LYRM4/ISD11 for activity
        supporting_text: A variant of Nfs1 was purified in conjunction with 
          Isd11
      - statement: NFS1 transfers sulfur to MOCS3 for Moco biosynthesis
        supporting_text: sulfur is transferred from L-cysteine to MOCS3-RLD via 
          an Nfs1-bound persulfide intermediate
  - id: PMID:20873749
    title: Human frataxin is an allosteric switch that activates the Fe-S 
      cluster biosynthetic complex.
    findings:
      - statement: Frataxin binding dramatically increases NFS1 catalytic 
          efficiency
        supporting_text: Frataxin binding dramatically changes the K(M) for 
          cysteine from 0.59 to 0.011 mM
  - id: PMID:21298097
    title: Mammalian frataxin - an essential function for cellular viability 
      through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur 
      assembly complex.
    findings:
      - statement: NFS1 forms stable quaternary complex with ISCU, ISD11, and 
          frataxin
  - id: PMID:23593335
    title: The L-cysteine desulfurase NFS1 is localized in the cytosol where it 
      provides the sulfur for molybdenum cofactor biosynthesis in humans.
    findings:
      - statement: NFS1 detected in cytosol, mitochondria, and nucleus
        supporting_text: we were also able to detect NFS1 in the cytosolic 
          fraction
      - statement: NFS1 interacts with MOCS3 in cytosol by FRET
        supporting_text: 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
  - id: PMID:23940031
    title: 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).
    findings:
      - statement: NFS1 preferentially binds disordered ISCU conformation
        supporting_text: isolated NFS1 binds to the D-state of ISCU
  - id: PMID:24971490
    title: Human frataxin activates Fe-S cluster biosynthesis by facilitating 
      sulfur transfer chemistry.
    findings:
      - statement: FXN accelerates sulfur accumulation on ISCU2
      - statement: Persulfide species viable for Fe-S cluster synthesis
  - id: PMID:26702583
    title: Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via 
      iron-sulfur cluster assembly.
    findings:
      - statement: NFS1 interacts with HSPA9 chaperone
  - id: PMID:27519411
    title: Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly 
      Machinery.
    findings: []
  - id: PMID:28001042
    title: Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both 
      Bind Cysteine Desulfurase.
    findings:
      - statement: NFS1 binds FDX2 for electron donation
  - id: PMID:28634302
    title: Structure of human Fe-S assembly subcomplex reveals unexpected 
      cysteine desulfurase architecture.
    findings:
      - statement: Acyl-ACP-ISD11 interaction with NFS1 revealed
  - id: PMID:29097656
    title: Structure and functional dynamics of the mitochondrial Fe/S cluster 
      synthesis complex.
    findings:
      - statement: Crystal structures of NFS1-ISD11-ACP with and without ISCU
        supporting_text: crystal structures of three different NFS1-ISD11-ACP 
          complexes with and without ISCU
      - statement: NFS1 functions as homodimer
        supporting_text: The three structures with a central NFS1 dimer
      - statement: ISD11 stabilizes NFS1 but does not directly participate in 
          catalysis
        supporting_text: ISD11 binds to NFS1 distal from the desulfurase active 
          site and does not directly participate in catalysis
      - statement: PLP bound to Lys258
        supporting_text: The large domain of NFS1 (residues 71-315) harbors the 
          PLP cofactor, which is covalently bound to Lys258 as an internal 
          aldimine
  - id: PMID:29309586
    title: Cytosolic HSC20 integrates de novo iron-sulfur cluster biogenesis 
      with the CIAO1-mediated transfer.
    findings:
      - statement: Cytosolic NFS1 isoform interacts with CIAO1
  - id: PMID:30817134
    title: Analysis of the Cellular Roles of MOCS3 Identifies a 
      MOCS3-Independent Localization of NFS1 at the Tips of the Centrosome.
    findings:
      - statement: Novel centrosome localization of NFS1 discovered
        supporting_text: we identified a MOCS3-independent novel localization of
          NFS1 at the centrosome
  - id: PMID:31101807
    title: Structure of the human frataxin-bound iron-sulfur cluster assembly 
      complex provides insight into its activation mechanism.
    findings:
      - statement: 3.2 A cryo-EM structure of FXN-bound ISC complex
        supporting_text: 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
      - statement: FXN binds at interface of two NFS1 and one ISCU
        supporting_text: FXN binds at the interface of two NFS1 and one ISCU 
          subunits
  - id: PMID:31664822
    title: Structure of the Human ACP-ISD11 Heterodimer.
    findings:
      - statement: NFS1 forms cysteine desulfurase complex with LYRM4 and 
          NDUFAB1
  - id: PMID:34800366
    title: Quantitative high-confidence human mitochondrial proteome.
    findings:
      - statement: HTP confirmation of NFS1 as mitochondrial protein
  - id: PMID:34824239
    title: N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by 
      ISCU2 dimerization.
    findings:
      - statement: Crystal structures of NFS1 with ISCU
      - statement: NFS1 homodimerization confirmed
  - id: PMID:38627381
    title: Mechanism and structural dynamics of sulfur transfer during de novo 
      [2Fe-2S] cluster assembly on ISCU2.
    findings:
      - statement: Cryo-EM snapshots of persulfide transfer from NFS1 Cys381 to 
          ISCU2 Cys138
        supporting_text: High-resolution cryo-EM structures obtained from 
          anaerobically prepared samples provide snapshots that both visualize 
          different stages of persulfide transfer from Cys381NFS1 to Cys138ISCU2
      - statement: Clarifies molecular role of frataxin
        supporting_text: clarify the molecular role of frataxin in optimally 
          positioning assembly site residues for fast sulfur transfer
  - id: Reactome:R-HSA-1362408
    title: FXN:NFS1:ISD11:ISCU assembles 2Fe-2S iron-sulfur cluster
    findings: []
  - id: Reactome:R-HSA-1362409
    title: Mitochondrial iron-sulfur cluster biogenesis
    findings: []
  - id: Reactome:R-HSA-1362416
    title: Frataxin binds iron
    findings: []
  - id: Reactome:R-HSA-947514
    title: PXLP-K198-NFS1 transfers sulfur from cysteine onto MOCS3
    findings: []
  - id: Reactome:R-HSA-9854984
    title: Transfer of Fe-S clusters to SDHB
    findings: []
  - id: Reactome:R-HSA-9866272
    title: 2Fe-2S is inserted in UQCRFS1
    findings: []
  - id: file:human/NFS1/NFS1-deep-research-falcon.md
    title: Deep research on NFS1 function and mechanism
    findings:
      - statement: NFS1 is the central cysteine desulfurase in the mitochondrial
          ISC machinery
core_functions:
  - molecular_function:
      id: GO:0031071
      label: cysteine desulfurase activity
    description: 'Primary enzymatic function: PLP-dependent desulfuration of L-cysteine
      to L-alanine, generating a persulfide on active-site Cys381. This is the defining
      molecular function of NFS1.'
  - molecular_function:
      id: GO:0097163
      label: sulfur carrier activity
    description: NFS1 carries sulfur from cysteine substrate to acceptor 
      proteins (ISCU2 for Fe-S clusters, MOCS3 for Moco biosynthesis) via a 
      persulfide intermediate.
  - molecular_function:
      id: GO:0031071
      label: cysteine desulfurase activity
    directly_involved_in:
      - id: GO:0044571
        label: '[2Fe-2S] cluster assembly'
    locations:
      - id: GO:0005759
        label: mitochondrial matrix
    in_complex:
      id: GO:0099128
      label: mitochondrial [2Fe-2S] assembly complex
    description: Essential for de novo [2Fe-2S] cluster assembly as the sulfur 
      donor in the core mitochondrial ISC complex. The persulfide is transferred
      from Cys381 to ISCU2 Cys138, with frataxin enhancing transfer efficiency.
  - molecular_function:
      id: GO:0031071
      label: cysteine desulfurase activity
    directly_involved_in:
      - id: GO:0006777
        label: Mo-molybdopterin cofactor biosynthetic process
    locations:
      - id: GO:0005829
        label: cytosol
    description: 'Secondary function of cytosolic NFS1 isoform: sulfur donor for MOCS3
      in molybdenum cofactor biosynthesis pathway.'
tags:
  - iron-sulfur-cluster-biogenesis