id: A6NFY7
gene_symbol: SDHAF1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SDHAF1 (succinate dehydrogenase assembly factor 1) is a small (115 aa) LYR-motif protein
  of the mitochondrial matrix that acts as an assembly factor for succinate dehydrogenase
  (SDH, respiratory Complex II), the enzyme that couples oxidation of succinate to fumarate
  with reduction of ubiquinone and links the TCA cycle to the electron transport chain.
  SDHAF1 is not a structural subunit of the mature complex and is not itself catalytic.
  It promotes maturation of the iron-sulfur (Fe-S) subunit SDHB: through an N-terminal LYR
  motif it binds the DnaJ/Hsp40-type co-chaperone HSC20 (HSCB), recruiting the HSC20-HSPA9
  chaperone system and the ISCU scaffold, while an arginine-rich C-terminal region binds
  SDHB, thereby positioning the Fe-S transfer machinery to insert iron-sulfur clusters into
  SDHB and protecting SDHB from oxidative damage. It is a member of the complex I LYR family,
  SDHAF1 subfamily. Biallelic loss-of-function variants cause an autosomal-recessive,
  riboflavin-responsive mitochondrial complex II deficiency presenting as infantile
  leukoencephalopathy with succinate accumulation.
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) localization of SDHAF1 to mitochondrion. Correct but non-specific;
      the protein is more precisely in the mitochondrial matrix. Kept as non-core because
      the specific matrix localization and the assembly BP better capture the biology.
    action: KEEP_AS_NON_CORE
    reason: >-
      UniProt states subcellular location is mitochondrion matrix, consistent with this
      broader mitochondrion term. Retained but subsumed by the more specific matrix term.
    supported_by:
    - reference_id: file:human/SDHAF1/SDHAF1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0034553
    label: mitochondrial respiratory chain complex II assembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic (IBA) assignment of the core biological process. This is exactly the
      process SDHAF1 performs and is consistent with the experimental IMP annotation and
      with UniProt. Accepted as a core function.
    action: ACCEPT
    reason: >-
      SDHAF1 is a bona fide SDH (Complex II) assembly factor; the IBA agrees with the
      experimental IMP annotation (PMID:19465911) and UniProt.
    supported_by:
    - reference_id: PMID:19465911
      supporting_text: "SDHAF1 is the first bona fide SDH assembly factor reported in any organism."
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      InterPro2GO (IEA) mitochondrial localization. Correct but non-specific relative to
      the matrix localization. Kept as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the curated mitochondrion/matrix localization; less specific than the
      matrix term.
    supported_by:
    - reference_id: file:human/SDHAF1/SDHAF1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      UniProt subcellular-location mapping (IEA) to mitochondrial matrix. This is the
      correct, specific compartment for SDHAF1 and is supported by the curated UniProt
      location. Accepted.
    action: ACCEPT
    reason: >-
      Matches the experimentally supported UniProt subcellular location (matrix).
    supported_by:
    - reference_id: file:human/SDHAF1/SDHAF1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0034553
    label: mitochondrial respiratory chain complex II assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO (IEA) assignment of the core biological process from the SDHAF1-specific
      InterPro signature. Correct and consistent with the experimental and phylogenetic
      annotations. Accepted.
    action: ACCEPT
    reason: >-
      The InterPro family (IPR045295, Complex1_LYR_SDHAF1_LYRM8) is SDHAF1-specific and the
      inferred assembly process matches the experimental IMP annotation.
    supported_by:
    - reference_id: PMID:19465911
      supporting_text: "SDHAF1 is the first bona fide SDH assembly factor reported in any organism."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24606901
  qualifier: enables
  review:
    summary: >-
      IPI "protein binding" from IntAct curation of the HSC20/LYR-motif study; the recorded
      partners are SDHB (P21912, substrate) and HSCB/HSC20 (Q8IWL3, co-chaperone). These are
      the functionally central interactions, but the bare "protein binding" term is
      uninformative. Kept as non-core; the specific molecular function is captured by
      protein-folding chaperone binding (GO:0051087) in core_functions.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real, physiologically meaningful interactions (co-chaperone HSC20 and substrate SDHB),
      but GO:0005515 is too general; superseded in core_functions by the chaperone-binding MF.
    supported_by:
    - reference_id: PMID:24606901
      supporting_text: >-
        members of the LYR motif family which assist assembly of complexes II or III, SDHAF1
        and LYRM7, respectively, are HSC20 binding partners.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26749241
  qualifier: enables
  review:
    summary: >-
      IPI "protein binding" from IntAct curation of the disease-mechanism paper; partners are
      SDHB (P21912) and HSCB/HSC20 (Q8IWL3). Functionally meaningful but uninformative as a
      bare term. Kept as non-core; specific MF captured as protein-folding chaperone binding.
    action: KEEP_AS_NON_CORE
    reason: >-
      Meaningful SDHB and HSC20 interactions underpinning Fe-S transfer, but GO:0005515 is
      too general; superseded by GO:0051087 in core_functions.
    supported_by:
    - reference_id: PMID:26749241
      supporting_text: >-
        SDHAF1 transiently binds to aromatic peptides of SDHB through an arginine-rich region
        in its C terminus and specifically engages a Fe-S donor complex, consisting of the
        scaffold, holo-ISCU, and the co-chaperone-chaperone pair, HSC20-HSPA9, through an LYR
        motif near its N-terminal domain.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28380382
  qualifier: enables
  review:
    summary: >-
      IPI "protein binding" from IntAct curation; recorded partner is HSCB/HSC20 (Q8IWL3).
      This HSC20-centered study places SDHAF1 in the LYR-family Fe-S delivery network.
      Meaningful interaction but uninformative as a bare term; kept as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Genuine co-chaperone (HSC20) interaction, but GO:0005515 is too general; superseded by
      GO:0051087 protein-folding chaperone binding in core_functions.
    supported_by:
    - reference_id: PMID:28380382
      supporting_text: >-
        Binding of HSC20 to the LYR motif of LYRM7 in a pre-assembled UQCRFS1-LYRM7 intermediate
        in the mitochondrial matrix facilitates Fe-S cluster transfer to UQCRFS1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      IPI "protein binding" from the HuRI large-scale binary (Y2H) interactome; recorded
      partners are KRT27 (Q7Z3Y8, a keratin) and CIDEB (Q9UHD4). Neither is a plausible
      physiological partner for a mitochondrial-matrix assembly factor; these are likely
      high-throughput screen artifacts. Marked as over-annotated: the bare "protein binding"
      term adds no functional information and the partners are not biologically relevant.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Large-scale Y2H hits (keratin KRT27, CIDEB) are non-physiological for a matrix protein;
      GO:0005515 is uninformative and not supported by any functional role.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        With approximately 53,000 protein-protein interactions, HuRI has approximately four
        times as many such interactions as there are high-quality curated interactions from
        small-scale studies.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      IPI "protein binding" from the BioPlex 3.0 AP-MS interactome; recorded partner is SDHB
      (P21912), the physiological substrate of SDHAF1. Consistent with the curated
      SDHAF1-SDHB interaction. Kept as non-core because GO:0005515 is uninformative; the
      specific activity is captured elsewhere.
    action: KEEP_AS_NON_CORE
    reason: >-
      Real SDHB interaction (consistent with UniProt SUBUNIT), but GO:0005515 is too general.
    supported_by:
    - reference_id: file:human/SDHAF1/SDHAF1-uniprot.txt
      supporting_text: "Interacts with SDHB within an SDHA-SDHB subcomplex"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct (IDA) immunofluorescence localization to mitochondrion (Human Protein Atlas).
      Correct but non-specific; the protein resides in the matrix. Kept as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Consistent with the curated matrix localization; less specific than the matrix term.
    supported_by:
    - reference_id: file:human/SDHAF1/SDHAF1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput (HTP) detection of SDHAF1 in the high-confidence human mitochondrial
      proteome, confirming mitochondrial localization. Correct but non-specific relative to
      the matrix. Kept as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supports mitochondrial residence via a quantitative mito-proteome dataset; subsumed by
      the more specific matrix term.
    supported_by:
    - reference_id: file:human/SDHAF1/SDHAF1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9854984
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) matrix localization within the SDH assembly pathway (Transfer of Fe-S
      clusters to SDHB). Matches the curated UniProt matrix location. Accepted.
    action: ACCEPT
    reason: >-
      Correct, specific compartment consistent with UniProt and with SDHAF1's role in the
      matrix-localized Fe-S transfer step.
    supported_by:
    - reference_id: file:human/SDHAF1/SDHAF1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9855212
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) matrix localization (SDHA binds to SDHB reaction). Correct, specific
      compartment consistent with UniProt. Accepted.
    action: ACCEPT
    reason: >-
      Matches the curated matrix localization.
    supported_by:
    - reference_id: file:human/SDHAF1/SDHAF1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9855252
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) matrix localization (SDHA:SDHB binds to SDHC:SDHD reaction). Correct,
      specific compartment consistent with UniProt. Accepted.
    action: ACCEPT
    reason: >-
      Matches the curated matrix localization.
    supported_by:
    - reference_id: file:human/SDHAF1/SDHAF1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:19465911
  qualifier: located_in
  review:
    summary: >-
      Direct (IDA) localization of SDHAF1 to mitochondrion in the founding paper. Correct but
      non-specific; the curated location is the matrix. Kept as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimental mitochondrial localization; subsumed by the more specific matrix term.
    supported_by:
    - reference_id: file:human/SDHAF1/SDHAF1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0034553
    label: mitochondrial respiratory chain complex II assembly
  evidence_type: IMP
  original_reference_id: PMID:19465911
  qualifier: involved_in
  review:
    summary: >-
      Experimental (IMP) assignment of the core biological process from the founding SDHAF1
      paper: SDHAF1 mutations cause SDH (Complex II) deficiency, and SDH activity/amount are
      restored proportionally with re-expression of the wild-type gene. This is the defining
      function of SDHAF1. Accepted as the primary core annotation.
    action: ACCEPT
    reason: >-
      Directly supported experimental annotation establishing SDHAF1 as a Complex II
      assembly factor; consistent with UniProt FUNCTION.
    supported_by:
    - reference_id: PMID:19465911
      supporting_text: >-
        SDH activity and amount were restored in mutant fibroblasts proportionally with
        re-expression of the wild-type gene.
core_functions:
- description: >-
    Assembly factor mediating maturation and iron-sulfur cluster acquisition of the SDHB
    subunit during assembly of mitochondrial respiratory Complex II (succinate
    dehydrogenase). SDHAF1 binds the DnaJ/Hsp40-type co-chaperone HSC20 (HSCB) via its
    N-terminal LYR motif to recruit the HSC20-HSPA9 chaperone system and the ISCU scaffold,
    and binds SDHB via its C-terminal arginine-rich region, positioning the Fe-S transfer
    machinery to deliver clusters to SDHB. Loss of function causes SDH deficiency that is
    rescued by wild-type re-expression.
  molecular_function:
    id: GO:0051087
    label: protein-folding chaperone binding
  directly_involved_in:
  - id: GO:0034553
    label: mitochondrial respiratory chain complex II assembly
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:24606901
    supporting_text: >-
      members of the LYR motif family which assist assembly of complexes II or III, SDHAF1
      and LYRM7, respectively, are HSC20 binding partners.
  - reference_id: PMID:26749241
    supporting_text: >-
      SDHAF1 transiently binds to aromatic peptides of SDHB through an arginine-rich region
      in its C terminus and specifically engages a Fe-S donor complex, consisting of the
      scaffold, holo-ISCU, and the co-chaperone-chaperone pair, HSC20-HSPA9, through an LYR
      motif near its N-terminal domain.
  - reference_id: PMID:19465911
    supporting_text: >-
      SDHAF1 is the first bona fide SDH assembly factor reported in any organism.
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:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:19465911
  title: SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in
    SDH-defective infantile leukoencephalopathy.
  findings:
  - statement: >-
      Founding paper identifying SDHAF1 as the first bona fide SDH (Complex II) assembly
      factor; biallelic mutations cause SDH-defective infantile leukoencephalopathy, and
      wild-type re-expression restores SDH activity and amount.
    reference_section_type: ABSTRACT
    supporting_text: >-
      SDH activity and amount were restored in mutant fibroblasts proportionally with
      re-expression of the wild-type gene.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified founding paper; source of the experimental IMP for GO:0034553 and the
      IDA mitochondrial localization. Abstract-only in cache.
- id: PMID:24606901
  title: Cochaperone binding to LYR motifs confers specificity of iron sulfur cluster
    delivery.
  findings:
  - statement: >-
      SDHAF1 (LYRM8) is an HSC20 binding partner; LYR-motif proteins engage the
      ISCU-HSC20-HSPA9 Fe-S transfer complex, and SDHAF1 associates with SDHB via a non-LYR
      site while positioning the Fe-S transfer complex through its own LYR motif.
    reference_section_type: DISCUSSION
    supporting_text: >-
      members of the LYR motif family which assist assembly of complexes II or III, SDHAF1
      and LYRM7, respectively, are HSC20 binding partners.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full text available and read; directly supports the protein-folding chaperone binding
      MF (SDHAF1-HSC20) and the SDHB-recruitment adaptor role.
- id: PMID:26749241
  title: Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clusters to SDHB.
  findings:
  - statement: >-
      SDHAF1 contributes to Fe-S cluster incorporation into SDHB by binding SDHB (C-terminal
      arginine-rich region) and engaging the HSC20-HSPA9 co-chaperone/chaperone pair with
      the ISCU scaffold via its N-terminal LYR motif; disease mutations abrogate SDHB
      binding, leading to LONP1-mediated SDHB degradation, and riboflavin ameliorates the
      phenotype.
    reference_section_type: ABSTRACT
    supporting_text: >-
      SDHAF1 transiently binds to aromatic peptides of SDHB through an arginine-rich region
      in its C terminus and specifically engages a Fe-S donor complex, consisting of the
      scaffold, holo-ISCU, and the co-chaperone-chaperone pair, HSC20-HSPA9, through an LYR
      motif near its N-terminal domain.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified; central mechanism/disease paper. Abstract-only in cache but abstract
      fully supports the mechanism cited.
- id: PMID:28380382
  title: A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent Iron-Sulfur
    Clusters to Mammalian Respiratory Chain Complexes I-III.
  findings:
  - statement: >-
      The HSC20-HSPA9-ISCU Fe-S transfer complex delivers clusters to LYR-motif-associated
      respiratory chain assembly intermediates (complexes I-III), the general framework in
      which SDHAF1 acts for Complex II.
    reference_section_type: ABSTRACT
    supporting_text: >-
      Binding of HSC20 to the LYR motif of LYRM7 in a pre-assembled UQCRFS1-LYRM7 intermediate
      in the mitochondrial matrix facilitates Fe-S cluster transfer to UQCRFS1.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Contextual (LYRM7/Complex III focus) but corroborates the HSC20-LYR Fe-S delivery
      mechanism shared by SDHAF1; source of an IntAct HSCB interaction annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: >-
      Large-scale binary (Y2H) interactome (HuRI); source of high-throughput SDHAF1
      interactions with KRT27 and CIDEB that are not physiologically meaningful for a matrix
      assembly factor.
    reference_section_type: ABSTRACT
    supporting_text: >-
      With approximately 53,000 protein-protein interactions, HuRI has approximately four
      times as many such interactions as there are high-quality curated interactions from
      small-scale studies.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Systematic interactome; the SDHAF1 hits (KRT27, CIDEB) are likely screen artifacts and
      support only the over-annotated bare protein-binding annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings:
  - statement: >-
      BioPlex 3.0 AP-MS interactome; recovers the SDHAF1-SDHB interaction consistent with
      SDHAF1's role as an SDHB-binding assembly factor.
    reference_section_type: ABSTRACT
    supporting_text: >-
      Comparison across cell lines validates thousands of interactions and reveals extensive
      customization.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale AP-MS; the SDHAF1-SDHB hit is consistent with curated biology but the
      annotation itself is bare protein binding.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings:
  - statement: >-
      High-confidence quantitative human mitochondrial proteome; supports SDHAF1
      mitochondrial localization (source of the HTP localization annotation).
    reference_section_type: ABSTRACT
    supporting_text: >-
      Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular
      context.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale mito localization dataset; corroborates mitochondrial residence only.
- id: Reactome:R-HSA-9854984
  title: Transfer of Fe-S clusters to SDHB
  findings: []
- id: Reactome:R-HSA-9855212
  title: SDHA binds to SDHB
  findings: []
- id: Reactome:R-HSA-9855252
  title: SDHA:SDHB binds to SDHC:SDHD
  findings: []