id: Q9NX18
gene_symbol: SDHAF2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SDHAF2 (also known as SDH5, PGL2, C11orf79) is a soluble mitochondrial-matrix assembly
  factor for succinate dehydrogenase (SDH), the respiratory chain Complex II that links the
  tricarboxylic acid cycle and the electron transport chain. SDHAF2 is not a subunit of the
  mature enzyme and has no succinate dehydrogenase catalytic activity of its own. Its defining
  role is to bind the flavoprotein subunit SDHA and, acting as a chaperone/assembly factor
  together with a dicarboxylate cofactor, to remodel and orient the flavin and capping domains
  of SDHA so that covalent attachment of the FAD cofactor (flavinylation) can occur. This
  covalent flavinylation is required for SDH assembly and activity. Germline loss-of-function
  mutations in SDHAF2 cause hereditary pheochromocytoma/paraganglioma (PPGL2); the G78R variant
  abolishes both SDHA binding and SDHA flavinylation.
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetically-inferred mitochondrial localization. Consistent with the
      experimentally established mitochondrial-matrix localization of SDHAF2; a more specific
      matrix term is available and captured by other annotations, but this general term is
      correct.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/SDHAF2/SDHAF2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0006121
    label: mitochondrial electron transport, succinate to ubiquinone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      This term describes the catalytic electron-transport activity of the mature Complex II,
      not the function of the assembly factor. SDHAF2 is required for SDH assembly/activity but
      does not itself carry out succinate-to-ubiquinone electron transport. Over-annotation
      propagated by IBA from the catalytic SDH subunits in the shared PANTHER family; the
      honest role is captured by the Complex II assembly and protein-FAD linkage terms.
    action: MARK_AS_OVER_ANNOTATED
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - ROLE_CONFLATION
    supported_by:
    - reference_id: file:human/SDHAF2/SDHAF2-uniprot.txt
      supporting_text: "Plays an essential role in the assembly of succinate"
- 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: >-
      Correct and core. SDHAF2 is a dedicated assembly factor for respiratory Complex II
      (SDH). Phylogenetic inference here agrees with direct experimental evidence
      (PMID:32887801, PMID:19628817).
    action: ACCEPT
    supported_by:
    - reference_id: file:human/SDHAF2/SDHAF2-uniprot.txt
      supporting_text: "Plays an essential role in the assembly of succinate"
- term:
    id: GO:0006099
    label: tricarboxylic acid cycle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      SDH (Complex II) is a TCA-cycle enzyme, but SDHAF2 is an assembly factor and does not
      itself carry out TCA-cycle chemistry. This is an over-annotation transferred by IBA from
      the catalytic subunits; SDHAF2 acts upstream by enabling SDHA maturation rather than
      participating in the cycle.
    action: MARK_AS_OVER_ANNOTATED
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - ROLE_CONFLATION
    supported_by:
    - reference_id: file:human/SDHAF2/SDHAF2-uniprot.txt
      supporting_text: "Required for flavinylation (covalent"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: >-
      InterPro2GO electronic annotation of mitochondrial localization. Correct and supported
      by experimental data; general term subsumed by the more specific mitochondrial matrix
      annotation.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/SDHAF2/SDHAF2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic (UniRule/SubCell) annotation of mitochondrial-matrix localization. This is
      the correct, specific subcellular location, corroborated experimentally
      (PMID:19628817, EXP).
    action: ACCEPT
    supported_by:
    - reference_id: file:human/SDHAF2/SDHAF2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0006121
    label: mitochondrial electron transport, succinate to ubiquinone
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  qualifier: involved_in
  review:
    summary: >-
      Electronic UniRule annotation of the mature-enzyme catalytic process. As with the IBA
      version, this is an over-annotation for an assembly factor that does not itself perform
      electron transport. Marked as over-annotated rather than removed since SDHAF2 is
      genuinely required for this activity to occur.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: file:human/SDHAF2/SDHAF2-uniprot.txt
      supporting_text: "Plays an essential role in the assembly of succinate"
- term:
    id: GO:0010719
    label: negative regulation of epithelial to mesenchymal transition
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA machine-learning electronic annotation echoing the cancer-context moonlighting role
      reported for SDH5 (PMID:23983127). This is a disease/cancer-associated regulatory
      phenotype, indirect and cell-type dependent, not the core mitochondrial assembly
      function. Kept as non-core; the underlying experimental MGI annotation is retained
      separately.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:23983127
      supporting_text: >-
        loss of succinate dehydrogenase 5 (SDH5) expression initiates
        epithelial-mesenchymal transition (EMT)
- term:
    id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation reflecting the SDH5–GSK-3β–β-catenin (Wnt) axis reported in
      lung cancer (PMID:23983127). A moonlighting/regulatory role, indirect and context
      dependent, not part of the core assembly-factor function. Kept as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:23983127
      supporting_text: >-
        SDH5 functions as a negative regulator of Wnt-β-catenin signaling
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19628817
  qualifier: enables
  review:
    summary: >-
      Experimental IPI documenting the physical interaction between SDHAF2 (SDH5) and the SDH
      catalytic subunit SDHA (P31040) — the biologically central interaction of this protein.
      Retained, but "protein binding" (GO:0005515) is uninformative as a molecular function;
      the informative activity is captured in core_functions as protein-folding chaperone
      activity toward SDHA. Marked as over-annotated per policy (experimental IPI is not
      removed).
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:19628817
      supporting_text: >-
        Both yeast and human Sdh5 interact with the catalytic subunit of the succinate
        dehydrogenase (SDH) complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: >-
      High-throughput quantitative-interactome IPI (with SDHA, P31040). Corroborates the
      SDHAF2–SDHA interaction but "protein binding" is an uninformative MF. Over-annotated per
      policy.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      High-throughput interactome (BioPlex) IPI, WITH/FROM SDHA (P31040). Consistent with the
      known SDHAF2–SDHA interaction; "protein binding" is uninformative as an MF.
      Over-annotated per policy.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Binary (Y2H) high-throughput interactome IPI, WITH/FROM CYP4F2 (P78329) and SEC22A
      (Q96IW7). These are isolated high-throughput pairs with no biological follow-up and are
      not part of the known SDHAF2 biology; "protein binding" is uninformative as an MF.
      Over-annotated per policy.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      High-throughput interactome (BioPlex 3.0) IPI, WITH/FROM SDHA (P31040). Corroborates the
      SDHAF2–SDHA interaction; "protein binding" is uninformative as an MF. Over-annotated per
      policy.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence-based (HPA) IDA localizing SDHAF2 to the mitochondrion. Correct;
      subsumed by the more specific mitochondrial-matrix location.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/SDHAF2/SDHAF2-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 mitochondrial-proteome study placing SDHAF2 in the mitochondrion.
      Consistent with all other localization evidence.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/SDHAF2/SDHAF2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: EXP
  original_reference_id: PMID:19628817
  qualifier: located_in
  review:
    summary: >-
      Experimental (EXP) evidence for mitochondrial-matrix localization from the founding SDH5
      study. This is the correct, specific subcellular location and is a core location.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/SDHAF2/SDHAF2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0034553
    label: mitochondrial respiratory chain complex II assembly
  evidence_type: IDA
  original_reference_id: PMID:32887801
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental evidence (X-ray structure of the human SDHA–SDHAF2 complex, PDB
      6VAX) for SDHAF2's role in Complex II assembly, showing it works with a dicarboxylate to
      orient the SDHA flavin and capping domains to support covalent FAD attachment. This is a
      core function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:32887801
      supporting_text: >-
        works in synergy with SDHAF2 to properly orient the flavin and capping domains of
        SDHA
- term:
    id: GO:0006470
    label: protein dephosphorylation
  evidence_type: IGI
  original_reference_id: PMID:23983127
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      MGI IGI (acts_upstream_of_or_within) based on the report that SDH5 interaction with
      GSK-3β facilitates its activation through Ser-9 dephosphorylation. SDHAF2 is not itself a
      phosphatase; the dephosphorylation is a downstream consequence of the SDH5–GSK-3β
      interaction in a cancer context. Retained but non-core (moonlighting/regulatory role,
      not the mitochondrial assembly function).
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:23983127
      supporting_text: >-
        The physical interaction between SDH5 and GSK-3β facilitates GSK-3β activation through
        Ser-9 dephosphorylation
- term:
    id: GO:0010719
    label: negative regulation of epithelial to mesenchymal transition
  evidence_type: IMP
  original_reference_id: PMID:23983127
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      Experimental MGI IMP: loss of SDH5 initiates EMT in lung-cancer models. A genuine
      cancer-context regulatory phenotype, but indirect and cell-type dependent, and distinct
      from the core mitochondrial assembly-factor function. Kept as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:23983127
      supporting_text: >-
        loss of succinate dehydrogenase 5 (SDH5) expression initiates
        epithelial-mesenchymal transition (EMT)
- term:
    id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  evidence_type: IGI
  original_reference_id: PMID:23983127
  qualifier: acts_upstream_of_or_within
  review:
    summary: >-
      MGI IGI (with β-catenin, P35222) for SDH5 acting as a negative regulator of
      Wnt/β-catenin signaling via GSK-3β. A moonlighting/regulatory role in a cancer context,
      indirect and not the core function. Kept as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:23983127
      supporting_text: >-
        SDH5 functions as a negative regulator of Wnt-β-catenin signaling
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:19628817
  qualifier: located_in
  review:
    summary: >-
      IDA mitochondrial localization from the founding SDH5 study. Correct; subsumed by the
      more specific mitochondrial-matrix location also annotated from this paper.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/SDHAF2/SDHAF2-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion matrix"
- term:
    id: GO:0018293
    label: protein-FAD linkage
  evidence_type: IMP
  original_reference_id: PMID:19628817
  qualifier: involved_in
  review:
    summary: >-
      Core function. Experimental IMP: SDH5 is required for the flavination (covalent
      incorporation of FAD) of the SDH flavoprotein subunit. GO:0018293 "protein-FAD linkage"
      (a child of GO:0017013 protein flavinylation) is the precise term for the covalent
      FAD-attachment step that SDHAF2 promotes/enables.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:19628817
      supporting_text: >-
        Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation
        of the flavin adenine dinucleotide cofactor)
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IDA
  original_reference_id: PMID:32887801
  qualifier: enables
  review:
    summary: >-
      Proposed molecular function (NEW). SDHAF2 has no catalytic activity of its own and does
      not bind FAD directly; it is a dedicated chaperone/assembly factor (UniProt keyword
      "Chaperone") that binds SDHA and, with a dicarboxylate cofactor, remodels/orients its
      flavin and capping domains to license covalent flavinylation. GO:0044183 "protein
      folding chaperone" (MF) captures this activity far more informatively than the existing
      "protein binding" IPIs. Supported by the SDHA–SDHAF2 structure (PMID:32887801) and the
      requirement of SDHAF2 for SDHA flavinylation (PMID:19628817).
    action: NEW
    supported_by:
    - reference_id: PMID:32887801
      supporting_text: >-
        works in synergy with SDHAF2 to properly orient the flavin and capping domains of
        SDHA
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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000104
  title: Electronic Gene Ontology annotations created by transferring manual GO annotations
    between related proteins based on shared sequence features
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:19628817
  title: SDH5, a gene required for flavination of succinate dehydrogenase, is mutated
    in paraganglioma.
  findings:
  - statement: >-
      Both yeast and human Sdh5 (SDHAF2) interact with the SDH catalytic subunit and are
      required for SDH-dependent respiration and for flavination (covalent FAD incorporation)
      of the SDHA/Sdh1 flavoprotein subunit; germline loss-of-function mutations cause
      hereditary paraganglioma.
    supporting_text: >-
      Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation
      of the flavin adenine dinucleotide cofactor)
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Founding paper establishing SDHAF2/SDH5 as the SDH assembly factor required for SDHA
      flavinylation and as the PPGL2 paraganglioma gene. Cached entry is abstract-only.
- id: PMID:23983127
  title: Succinate dehydrogenase 5 (SDH5) regulates glycogen synthase kinase 3β-β-catenin-mediated
    lung cancer metastasis.
  findings:
  - statement: >-
      Loss of SDH5 initiates EMT and lung-cancer metastasis; SDH5 interacts with GSK-3β,
      facilitating its Ser-9 dephosphorylation/activation and thereby negatively regulating
      Wnt/β-catenin signaling.
    supporting_text: >-
      The physical interaction between SDH5 and GSK-3β facilitates GSK-3β activation through
      Ser-9 dephosphorylation
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Full text available. Basis for the MGI regulatory annotations (EMT, Wnt, protein
      dephosphorylation). Describes a cancer-context moonlighting role, not the core
      mitochondrial assembly function.
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale quantitative interactome; supports the SDHAF2–SDHA protein-binding IPI
      but does not discuss SDHAF2 biology specifically.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex-type high-throughput interactome supporting the SDHAF2–SDHA protein-binding IPI.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI binary (Y2H) interactome; source of the isolated CYP4F2 and SEC22A binding hits,
      which lack biological follow-up.
- id: PMID:32887801
  title: The roles of SDHAF2 and dicarboxylate in covalent flavinylation of SDHA,
    the human complex II flavoprotein.
  findings:
  - statement: >-
      X-ray structure of the human SDHA–SDHAF2 complex; SDHAF2 works with a small-molecule
      dicarboxylate to orient the flavin and capping domains of SDHA, adjusting the active
      site so that covalent FAD attachment is supported — establishing SDHAF2 as a
      chaperone/assembly factor rather than a catalyst.
    supporting_text: >-
      works in synergy with SDHAF2 to properly orient the flavin and capping domains of SDHA
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Structural/mechanistic paper (PDB 6VAX). Cached entry is abstract-only. Directly
      supports the Complex II assembly and flavinylation core functions.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex 3.0 interactome supporting the SDHAF2–SDHA protein-binding IPI.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput mitochondrial-proteome study; supports mitochondrial localization.
core_functions:
- description: >-
    Acts as a dedicated chaperone/assembly factor for succinate dehydrogenase (respiratory
    Complex II): binds the flavoprotein subunit SDHA and, together with a dicarboxylate
    cofactor, remodels and orients its flavin and capping domains to license covalent
    attachment of FAD (flavinylation) to SDHA. This maturation of SDHA is required for
    assembly of a functional Complex II. SDHAF2 has no catalytic activity of its own and is
    not a subunit of the mature enzyme.
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  directly_involved_in:
  - id: GO:0018293
    label: protein-FAD linkage
  - id: GO:0034553
    label: mitochondrial respiratory chain complex II assembly
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:19628817
    supporting_text: >-
      Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation
      of the flavin adenine dinucleotide cofactor)
  - reference_id: PMID:32887801
    supporting_text: >-
      works in synergy with SDHAF2 to properly orient the flavin and capping domains of SDHA