SDHB

---
id: P21912
gene_symbol: SDHB
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SDHB encodes the iron-sulfur protein (Ip) subunit of succinate dehydrogenase (SDH,
  Complex II),
  a heterotetrameric enzyme (SDHA/SDHB/SDHC/SDHD) embedded in the mitochondrial inner
  membrane.
  SDHB contains three iron-sulfur clusters ([2Fe-2S], [4Fe-4S], [3Fe-4S]) organized
  in a
  butterfly-like two-domain structure that relays electrons from the FAD cofactor
  in SDHA to
  ubiquinone bound at the SDHC/SDHD membrane interface. SDHB also directly contacts
  the
  ubiquinone binding site via residues Pro197, Trp201, and Ile246. Complex II is unique
  among
  OXPHOS complexes in that it does NOT pump protons across the inner membrane. SDHB
  functions
  as a tumor suppressor; heterozygous loss-of-function mutations cause paraganglioma/
  pheochromocytoma (PPGL4) via succinate accumulation and pseudohypoxic HIF stabilization.
  Biallelic mutations cause mitochondrial complex II deficiency type 4 (MC2DN4) with
  leukoencephalopathy.
existing_annotations:
# ============================================================
# IBA ANNOTATIONS (phylogenetic inference from GO_Central)
# ============================================================
  - term:
      id: GO:0009060
      label: aerobic respiration
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for aerobic respiration. SDHB is a core subunit of Complex
        II which links
        the TCA cycle to the electron transport chain during aerobic respiration.
        The IBA is
        phylogenetically well-supported with evidence from orthologous SDH iron-sulfur
        subunits
        across multiple species. This is confirmed by the cDNA cloning study (PMID:2302193)
        establishing SDHB as part of the succinate-ubiquinone oxidoreductase system,
        and by the
        cryo-EM structure (PMID:37098072) showing SDHB as an integral component of
        the functioning
        human Complex II.
      action: ACCEPT
      reason: >-
        Aerobic respiration is a core biological process for SDHB as part of Complex
        II.
        The IBA is phylogenetically sound and well-supported by biochemical and structural
        evidence.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            Human complex II is a key protein complex that links two essential
            energy-producing processes: the tricarboxylic acid cycle and oxidative
            phosphorylation
        - reference_id: PMID:2302193
          supporting_text: >-
            Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme
            complex
            of both the tricarboxylic acid cycle and of the aerobic respiratory chains
            of
            mitochondria in eukaryotic cell and prokaryotic organisms
  - term:
      id: GO:0022904
      label: respiratory electron transport chain
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for respiratory electron transport chain. SDHB provides the
        electron
        relay pathway between SDHA (FAD) and ubiquinone via its three Fe-S clusters.
        The
        cryo-EM structure (PMID:37098072) confirmed the electron transfer pathway
        through
        SDHB: FAD -> [2Fe-2S] -> [4Fe-4S] -> [3Fe-4S] -> ubiquinone, with edge-to-edge
        distances less than 14 angstroms between redox centers, sufficient for efficient
        electron transfer.
      action: ACCEPT
      reason: >-
        Core biological process for SDHB. The iron-sulfur clusters in SDHB constitute
        the
        electron relay chain within Complex II. Well-supported by IBA phylogenetic
        inference
        and the cryo-EM structure.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            The edge-to-edge distance between these redox-active prosthetic groups
            is less than
            14 Å (Fig. 3), a distance range that can efficiently support the delivery
            of electrons
            between these redox centers (22)
  - term:
      id: GO:0031966
      label: mitochondrial membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for mitochondrial membrane localization. SDHB is part of Complex
        II
        which is embedded in the mitochondrial inner membrane. SDHB itself is a peripheral
        membrane protein on the matrix side, contacting the membrane-spanning SDHC/SDHD
        subunits. The qualifier in the GOA is 'is_active_in' which is appropriate.
        This
        is a correct but less specific term than 'mitochondrial inner membrane' (GO:0005743)
        which is also annotated.
      action: ACCEPT
      reason: >-
        Correct localization. The IBA is phylogenetically sound. While less specific
        than
        GO:0005743 (mitochondrial inner membrane), it is acceptable for an IBA to
        annotate
        at this level. The more specific term is also present from other evidence
        codes.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            The hydrophilic head of human CII consists of the flavin adenine dinucleotide
            (FAD)-binding protein (SDHA) and the iron-sulfur protein (SDHB)

# ============================================================
# IEA ANNOTATIONS (electronic/computational)
# ============================================================
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation based on combined automated methods including ortholog transfer
        from
        rat (UniProtKB:P21913) and UniProt subcellular location mapping. SDHB is a
        peripheral
        membrane protein on the matrix side of the inner mitochondrial membrane as
        part of
        Complex II. Confirmed by the cryo-EM structure (PMID:37098072) which shows
        SDHB in
        the hydrophilic head region facing the matrix.
      action: ACCEPT
      reason: >-
        Correct localization. SDHB is part of Complex II which is anchored in the
        inner
        mitochondrial membrane. Consistent with experimental evidence from cryo-EM.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            The entire hydrophobic domain contains two membrane-anchored subunits:
            SDHC and SDHD
  - term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for TCA cycle involvement from combined automated methods.
        Complex II
        is the only membrane-bound member of the TCA cycle, where it catalyzes the
        oxidation
        of succinate to fumarate. SDHB is essential for coupling this reaction to
        ubiquinone
        reduction by providing the electron relay from FAD to ubiquinone.
      action: ACCEPT
      reason: >-
        TCA cycle involvement is a core function of SDHB as part of Complex II. This
        is
        well-established biochemistry.
      supported_by:
        - reference_id: PMID:26925370
          supporting_text: >-
            cII, or succinate-ubiquinone oxidoreductase (E.C. 1.3.5.1), is the only
            membrane-bound
            member of the tricarboxylic acid cycle, where it functions as a succinate
            dehydrogenase (SDH)
  - term:
      id: GO:0008177
      label: succinate dehydrogenase (quinone) activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for the overall SDH quinone activity from combined automated
        methods
        (EC 1.3.5.1, ortholog transfer). GO:0008177 represents the overall reaction
        of the
        entire SDH complex (succinate + quinone -> fumarate + quinol). For SDHB, the
        qualifier
        should ideally be 'contributes_to' rather than 'enables' since SDHB alone
        cannot
        catalyze this reaction. SDHB provides the electron relay but does not contain
        the
        succinate binding site (in SDHA) or the full quinone binding site (shared
        with
        SDHC/SDHD). However, the IEA mapping is not incorrect per se.
      action: ACCEPT
      reason: >-
        SDHB contributes to the overall SDH quinone activity by providing the electron
        relay
        from FAD to ubiquinone. Consistent with IMP annotations for the same term
        from
        PMID:26925370 and PMID:27604842. The IEA is a broader mapping that is acceptable.
  - term:
      id: GO:0009055
      label: electron transfer activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        IEA annotation for electron transfer activity from InterPro (IPR025192,
        Succ_DH/fum_Rdtase_N). SDHB is the iron-sulfur protein subunit that relays
        electrons
        from the FAD in SDHA through its three Fe-S clusters to ubiquinone. This is
        the
        primary subunit-specific molecular function of SDHB.
      action: ACCEPT
      reason: >-
        Electron transfer activity is the core subunit-specific molecular function
        of SDHB.
        Its three iron-sulfur clusters ([2Fe-2S], [4Fe-4S], [3Fe-4S]) form the electron
        relay
        pathway in Complex II. This is well-established from structural and biochemical
        data.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            SDHB contains two domains: the N-terminal domain (residues A35 to A142)
            and the
            C-terminal domain (residues A143 to A273)
        - reference_id: PMID:37098072
          supporting_text: >-
            The edge-to-edge distance between these redox-active prosthetic groups
            is less than
            14 Å (Fig. 3), a distance range that can efficiently support the delivery
            of electrons
            between these redox centers
  - term:
      id: GO:0016491
      label: oxidoreductase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for general oxidoreductase activity. Complex II is classified
        as
        EC 1.3.5.1, an oxidoreductase. SDHB contributes to this activity as part of
        the
        complex. This is a correct but very broad parent term. The more specific child
        terms (GO:0008177, GO:0009055) are also annotated.
      action: ACCEPT
      reason: >-
        Correct but general. It is acceptable for IEA annotations to be broader than
        experimental annotations. The more specific GO:0008177 and GO:0009055 are
        also present.
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation from UniProt keyword (KW-0479 Metal-binding) mapping. SDHB
        binds
        iron as part of its three iron-sulfur clusters. This is correct but very general.
        The more specific iron-sulfur cluster binding terms are also annotated.
      action: ACCEPT
      reason: >-
        Correct but general. SDHB binds iron ions as part of its Fe-S clusters. The
        more
        specific child terms (GO:0051536, GO:0051537, GO:0051538, GO:0051539) are
        also
        annotated and provide more informative descriptions.
  - term:
      id: GO:0051536
      label: iron-sulfur cluster binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for iron-sulfur cluster binding from combined automated methods
        (InterPro domains IPR001041, IPR009051, IPR025192, IPR036010 and UniProt keyword).
        SDHB contains three distinct iron-sulfur clusters confirmed by cryo-EM
        (PMID:37098072) and EPR spectroscopy.
      action: ACCEPT
      reason: >-
        Correct. SDHB binds three distinct iron-sulfur clusters. This is a general
        parent
        term; the more specific cluster-type-specific terms are also annotated.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            Electron paramagnetic resonance (EPR) spectra revealed the presence of
            redox centers
  - term:
      id: GO:0051537
      label: 2 iron, 2 sulfur cluster binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for [2Fe-2S] cluster binding from combined automated methods
        (InterPro
        IPR006058 and UniProt keyword KW-0001). SDHB binds one [2Fe-2S] cluster coordinated
        by Cys93, Cys98, Cys101, and Cys113 in the N-terminal domain, as confirmed
        by
        cryo-EM structure (PMID:37098072, PDB:8GS8).
      action: ACCEPT
      reason: >-
        Correct. The [2Fe-2S] cluster in the N-terminal domain of SDHB is the first
        electron acceptor from FAD in the electron relay chain.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            SDHB contains two domains: the N-terminal domain (residues A35 to A142)
            and the
            C-terminal domain (residues A143 to A273)
  - term:
      id: GO:0051538
      label: 3 iron, 4 sulfur cluster binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation for [3Fe-4S] cluster binding from UniProt keyword (KW-0003)
        mapping. SDHB binds one [3Fe-4S] cluster coordinated by Cys196, Cys243, and
        Cys249
        in the C-terminal domain, as confirmed by cryo-EM (PMID:37098072, PDB:8GS8).
      action: ACCEPT
      reason: >-
        Correct. The [3Fe-4S] cluster in SDHB is the terminal electron donor to ubiquinone
        in the electron relay chain.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            SDHB contains two domains: the N-terminal domain (residues A35 to A142)
            and the
            C-terminal domain (residues A143 to A273)
  - term:
      id: GO:0051539
      label: 4 iron, 4 sulfur cluster binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: >-
        IEA annotation for [4Fe-4S] cluster binding from UniProt keyword (KW-0004)
        mapping.
        SDHB binds one [4Fe-4S] cluster coordinated by Cys186, Cys189, Cys192, and
        Cys253
        in the C-terminal domain, as confirmed by cryo-EM (PMID:37098072, PDB:8GS8).
      action: ACCEPT
      reason: >-
        Correct. The [4Fe-4S] cluster in SDHB is the intermediate electron carrier
        between
        the [2Fe-2S] and [3Fe-4S] clusters in the electron relay chain.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            SDHB contains two domains: the N-terminal domain (residues A35 to A142)
            and the
            C-terminal domain (residues A143 to A273)

# ============================================================
# IPI ANNOTATIONS (protein-protein interaction)
# ============================================================
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19688755
    review:
      summary: >-
        IPI annotation for interaction with SDHA (P31040) from LC-MS/MS analysis of
        blue
        native PAGE-separated complexes. This confirms the well-established SDHB-SDHA
        interaction as part of Complex II assembly. The SDHA-SDHB subcomplex is a
        recognized
        assembly intermediate (PMID:24606901).
      action: KEEP_AS_NON_CORE
      reason: >-
        The SDHB-SDHA interaction is a core biochemical feature of Complex II, but
        this is
        already captured by the CC annotation GO:0045273 (part_of respiratory chain
        complex II).
        The generic 'protein binding' annotation is uninformative.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24606901
    review:
      summary: >-
        IPI annotation for interactions with SDHAF1 (A6NFY7), SDHA (P31040), HSCB/HSC20
        (Q8IWL3), and ISCU (Q9H1K1) from a study on cochaperone binding to LYR motifs
        for
        iron-sulfur cluster delivery (Maio et al. 2014). This study discovered that
        SDHB
        contains two LYR motifs that engage the HSC20-HSPA9-ISCU complex for Fe-S
        cluster
        incorporation. These are biologically meaningful interactions essential for
        Complex II
        assembly.
      action: KEEP_AS_NON_CORE
      reason: >-
        These interactions are biologically important for Fe-S cluster assembly into
        SDHB,
        but 'protein binding' is uninformative. The actual biology is Fe-S cluster
        transfer
        during Complex II assembly, which is better captured by other annotations.
        Multiple
        GOA entries exist for this PMID with different WITH/FROM interactors.
      supported_by:
        - reference_id: PMID:24606901
          supporting_text: >-
            In succinate dehydrogenase B, two LYR motifs engage the ISCU-HSC20-HSPA9
            complex
            to aid incorporation of three Fe-S clusters within the final structure
            of complex II
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26749241
    review:
      summary: >-
        IPI annotation for interactions with SDHAF1 (A6NFY7), SDHA (P31040), HSCB/HSC20
        (Q8IWL3), and ISCU (Q9H1K1) from Maio et al. (2016) on SDHAF1 mutations impairing
        Fe-S cluster transfer to SDHB. This study demonstrated that SDHAF1 transiently
        binds
        to SDHB through an arginine-rich region and engages the Fe-S donor complex
        for cluster
        incorporation. Pathogenic SDHAF1 mutations abrogate binding to SDHB.
      action: KEEP_AS_NON_CORE
      reason: >-
        Biologically significant interactions for Complex II assembly, but 'protein
        binding'
        is uninformative. The SDHAF1-SDHB interaction is specifically required for
        Fe-S
        cluster incorporation.
      supported_by:
        - reference_id: PMID:26749241
          supporting_text: >-
            SDHAF1 contributes to iron-sulfur (Fe-S) cluster incorporation into the
            Fe-S subunit
            of CII, SDHB. SDHAF1 transiently binds to aromatic peptides of SDHB through
            an
            arginine-rich region in its C terminus
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28380382
    review:
      summary: >-
        IPI annotation for interaction with HSCB/HSC20 (Q8IWL3) from Maio et al. (2017)
        on Fe-S cluster delivery to respiratory chain complexes. This paper directly
        studies HSC20 binding to LYRM7 and transfer to UQCRFS1; its SDHB-HSC20
        statement is background from prior SDHB work rather than direct evidence for
        this SDHB row.
      action: REMOVE
      reason: >-
        Do not retain this as an SDHB-HSC20 binding annotation from PMID:28380382.
        The direct SDHB-HSC20 evidence is already represented by the PMID:24606901
        protein-binding row; PMID:28380382 supports the LYRM7/UQCRFS1 Complex III
        Fe-S transfer pathway.
      supported_by:
        - reference_id: PMID:28380382
          supporting_text: >-
            Recent studies have shown that the co-chaperone HSC20, essential for Fe-S
            cluster
            biogenesis of SDHB, directly binds LYRM7
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: >-
        IPI annotation for interaction with SDHA (P31040) from the architecture of
        the
        human interactome study (Huttlin et al. 2017). Confirms the well-known SDHA-SDHB
        subunit interaction within Complex II.
      action: KEEP_AS_NON_CORE
      reason: >-
        Another confirmation of the SDHA-SDHB interaction. Already well established
        and
        captured by the CC annotation for Complex II membership.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: >-
        IPI annotation for interactions with SDHAF1 (A6NFY7) and SDHA (P31040) from
        dual
        proteome-scale network study (Huttlin et al. 2021). Confirms the known Complex
        II
        subunit interactions.
      action: KEEP_AS_NON_CORE
      reason: >-
        Confirms SDHB-SDHA and SDHB-SDHAF1 interactions. Well established and captured
        by
        other annotations.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35512704
    review:
      summary: >-
        IPI annotation for interaction with SMAD4 (Q13485) from Mo et al. (2022) on
        systematic discovery of mutation-directed neo-protein-protein interactions
        in cancer. This study identified variant-enabled neo-interactions, not a
        normal physiological wild-type SDHB interaction.
      action: REMOVE
      reason: >-
        The SDHB-SMAD4 hit came from a mutation-directed neoPPI screen comparing
        wild-type and mutant alleles. Without variant-specific GO annotation support,
        this should not be retained as a normal SDHB gene-product annotation.
      supported_by:
        - reference_id: PMID:35512704
          supporting_text: >-
            The screening of 17,792 interactions with 2,172,864 data points revealed
            a landscape of gain of interactions encompassing both oncogenic and tumor
            suppressor mutations

# ============================================================
# IEA LOCALIZATION ANNOTATIONS
# ============================================================
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation for mitochondrial localization via Ensembl Compara ortholog
        transfer
        from mouse (UniProtKB:Q9CQA3). SDHB has a mitochondrial transit peptide (residues
        1-28, cleaved after Gly28 per PMID:25944712) and is localized to the mitochondrial
        matrix as part of Complex II.
      action: ACCEPT
      reason: >-
        Correct localization, well supported by multiple lines of evidence including
        the
        transit peptide and IDA evidence from HPA immunofluorescence.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation for mitochondrial matrix localization via Ensembl Compara ortholog
        transfer from mouse (UniProtKB:Q9CQA3). SDHB faces the matrix side of the
        inner
        membrane as a peripheral membrane protein. The qualifier in GOA is 'is_active_in'
        which is appropriate since the SDHB electron relay chain functions in the
        matrix.
      action: ACCEPT
      reason: >-
        Correct. SDHB is on the matrix side of the inner mitochondrial membrane, confirmed
        by cryo-EM structure (PMID:37098072) showing SDHB in the hydrophilic head
        of
        Complex II facing the matrix.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            The hydrophilic head of human CII consists of the flavin adenine dinucleotide
            (FAD)-binding protein (SDHA) and the iron-sulfur protein (SDHB)
  - term:
      id: GO:0006105
      label: succinate metabolic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation for succinate metabolic process via Ensembl Compara ortholog
        transfer
        from rat (UniProtKB:P21913). Complex II catalyzes the oxidation of succinate
        to
        fumarate. SDHB is essential for coupling succinate oxidation to ubiquinone
        reduction.
      action: ACCEPT
      reason: >-
        Correct. SDHB is essential for the complete succinate dehydrogenase (quinone)
        reaction
        which metabolizes succinate. Loss of SDHB leads to succinate accumulation,
        as
        demonstrated in SDHB-deficient tumors and mitochondrial disease.
  - term:
      id: GO:0022904
      label: respiratory electron transport chain
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation for respiratory electron transport chain from Ensembl Compara
        ortholog
        transfer from rat (UniProtKB:P21913). Redundant with the IBA annotation for
        the same
        term but from a different evidence source.
      action: ACCEPT
      reason: >-
        Correct and consistent with IBA annotation for the same term. Duplicates are
        expected
        when multiple evidence sources converge.
  - term:
      id: GO:0045273
      label: respiratory chain complex II (succinate dehydrogenase)
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation for Complex II membership via Ensembl Compara ortholog transfer
        from
        mouse (UniProtKB:Q9CQA3). Consistent with ISS, IDA, and other annotations
        for this
        term.
      action: ACCEPT
      reason: >-
        Correct and consistent with experimental evidence from cryo-EM (PMID:37098072).

# ============================================================
# EXPERIMENTAL AND CURATED ANNOTATIONS (IDA, IMP, NAS, TAS, ISS, HTP)
# ============================================================
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        IDA annotation for mitochondrial localization from HPA immunofluorescence
        data.
        Direct experimental evidence of SDHB mitochondrial localization.
      action: ACCEPT
      reason: >-
        Direct experimental evidence of mitochondrial localization by immunofluorescence.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: NAS
    original_reference_id: PMID:30030361
    review:
      summary: >-
        NAS annotation from ComplexPortal based on review by Signes and Fernandez-Vizarra
        (2018) on assembly of OXPHOS complexes. SDHB is part of Complex II which is
        embedded
        in the inner mitochondrial membrane.
      action: ACCEPT
      reason: >-
        Correct localization. Complex II spans the inner membrane via SDHC/SDHD subunits,
        with
        SDHB on the matrix side as a peripheral membrane protein.
  - term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    evidence_type: NAS
    original_reference_id: PMID:30030361
    review:
      summary: >-
        NAS annotation from ComplexPortal for TCA cycle involvement. SDHB is a structural
        subunit of Complex II which catalyzes the succinate to fumarate step of the
        TCA cycle.
      action: ACCEPT
      reason: >-
        Correct and consistent with IEA and TAS annotations for the same term.
  - term:
      id: GO:0006121
      label: mitochondrial electron transport, succinate to ubiquinone
    evidence_type: NAS
    original_reference_id: PMID:30030361
    review:
      summary: >-
        NAS annotation from ComplexPortal for the specific electron transport process
        from
        succinate to ubiquinone. This is the defining biological process for Complex
        II/SDH
        in the mitochondrial electron transport chain. SDHB provides the electron
        relay
        pathway through its three Fe-S clusters that connects FAD-mediated succinate
        oxidation in SDHA to ubiquinone reduction at the SDHC/SDHD interface.
      action: ACCEPT
      reason: >-
        This is a core biological process annotation for SDHB. The electron relay
        from SDHA
        through SDHB to ubiquinone is the defining function of SDHB within Complex
        II.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            we propose that the human CII succinate- and ubiquinone-binding sites
            are likely to be
            connected by a similar chain of redox centers
  - term:
      id: GO:0042776
      label: proton motive force-driven mitochondrial ATP synthesis
    evidence_type: NAS
    original_reference_id: PMID:30030361
    review:
      summary: >-
        NAS annotation from ComplexPortal suggesting SDHB is involved in proton motive
        force-driven mitochondrial ATP synthesis. This annotation is problematic because
        Complex II does NOT pump protons across the inner mitochondrial membrane.
        Unlike
        Complexes I, III, and IV which translocate protons to generate the proton
        motive force,
        Complex II transfers electrons from succinate to ubiquinone without any proton
        pumping.
        Complex II contributes to ATP synthesis only indirectly by feeding reduced
        ubiquinol
        into the Q pool, which is then oxidized by Complex III (which does pump protons).
      action: REMOVE
      reason: >-
        Complex II is the only OXPHOS complex that does NOT pump protons. The proton
        motive
        force is generated by Complexes I, III, and IV. Complex II feeds electrons
        into the
        ubiquinone pool but does not directly contribute to the proton gradient. This
        annotation
        is misleading. The correct process annotation for SDHB is GO:0006121 (mitochondrial
        electron transport, succinate to ubiquinone).
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            The respiratory chain (also called electron transport chain) consists
            of complexes I-IV.
            It oxidizes the reducing equivalents in nicotinamide adenine dinucleotide
            (NADH) and
            succinate using molecular oxygen and couples the translocation of protons
            from the
            mitochondrial matrix into the intermembrane space
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HTP
    original_reference_id: PMID:34800366
    review:
      summary: >-
        HTP annotation for mitochondrial localization from a quantitative high-confidence
        human
        mitochondrial proteome study (Morgenstern et al. 2021). SDHB was identified
        in the
        mitochondrial proteome.
      action: ACCEPT
      reason: >-
        Correct. SDHB is a well-established mitochondrial protein confirmed by proteomics.
  - term:
      id: GO:0045273
      label: respiratory chain complex II (succinate dehydrogenase)
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation for Complex II membership by manual transfer from ortholog
        (UniProtKB:Q007T0, bovine). Consistent with all other annotations for this
        term.
      action: ACCEPT
      reason: >-
        Correct. Transfer from the well-characterized bovine SDH complex. SDHB is
        unambiguously a subunit of Complex II.
  - term:
      id: GO:0045273
      label: respiratory chain complex II (succinate dehydrogenase)
    evidence_type: IDA
    original_reference_id: PMID:37098072
    review:
      summary: >-
        IDA annotation for Complex II membership from the cryo-EM structure study
        (Du et al.
        2023). This study resolved the human Complex II structure at 2.86 angstroms
        showing all
        four subunits. SDHB was directly identified in the complex by cryo-EM, SDS-PAGE,
        and
        mass spectrometry.
      action: ACCEPT
      reason: >-
        Direct experimental evidence from cryo-EM structure of human Complex II showing
        SDHB
        as a subunit. This is the strongest evidence for Complex II membership.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            We observed all four subunits in a monomeric assembly (Fig. 1A). This
            arrangement
            is similar to that in W. succinogenes QFR
        - reference_id: PMID:37098072
          supporting_text: >-
            All the four subunits (SDHA, SDHB, SDHC, and SDHD) were detected by SDS-PAGE
            (SI Appendix, Fig. S1D) and mass spectrometry (MS) (SI Appendix, Table
            S1)
        - reference_id: file:human/SDHB/SDHB-deep-research-falcon.md
          supporting_text: >-
            SDHB encodes the iron-sulfur subunit of succinate dehydrogenase (SDH;
            mitochondrial complex II)
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9854984
    review:
      summary: >-
        TAS annotation from Reactome for mitochondrial matrix localization. The Reactome
        entry
        R-HSA-9854984 describes the transfer of Fe-S clusters to SDHB, which occurs
        in the
        mitochondrial matrix.
      action: ACCEPT
      reason: >-
        Correct. Fe-S cluster transfer to SDHB occurs in the mitochondrial matrix
        during
        Complex II assembly.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9855212
    review:
      summary: >-
        TAS annotation from Reactome for matrix localization, associated with SDHA
        binding
        to SDHB. The SDHA-SDHB subcomplex formation occurs in the matrix.
      action: ACCEPT
      reason: >-
        Correct. SDHA-SDHB subcomplex formation occurs in the mitochondrial matrix.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9855252
    review:
      summary: >-
        TAS from Reactome for matrix localization, associated with SDHA:SDHB binding
        to
        SDHC:SDHD. The final assembly step of Complex II.
      action: ACCEPT
      reason: >-
        Correct. The SDHA:SDHB subcomplex joins the SDHC:SDHD membrane subcomplex
        at
        the inner membrane, with the hydrophilic head (containing SDHB) facing the
        matrix.
  - term:
      id: GO:0008177
      label: succinate dehydrogenase (quinone) activity
    evidence_type: IMP
    original_reference_id: PMID:26925370
    review:
      summary: >-
        IMP annotation for SDH quinone activity from Ardissone et al. (2015). This
        study
        reported two sisters with homozygous SDHB p.Asp48Val mutation, one presenting
        with
        leukoencephalopathy and complex II deficiency. Spectrophotometric assays showed
        reduction of cII (succinate-ubiquinone reductase) and SDH activities in both
        muscle
        tissue and skin fibroblasts. The IMP logic is that mutation in SDHB impairs
        SDH
        quinone activity, therefore SDHB contributes to this activity.
      action: ACCEPT
      reason: >-
        Valid IMP evidence. The homozygous SDHB D48V mutation causes decreased succinate
        dehydrogenase (ubiquinone) activity, directly demonstrating SDHB's contribution
        to
        the overall complex activity.
      supported_by:
        - reference_id: PMID:26925370
          supporting_text: >-
            Reduction of cII (succinate-ubiquinone reductase) and SDH activities were
            documented
            both on muscle tissue and skin fibroblasts
        - reference_id: PMID:26925370
          supporting_text: >-
            immunoblot analysis on proband's fibroblasts showed strongly decreased
            levels of SDHB,
            suggesting a deleterious effect of the identified SDHB variant on protein
            stability
  - term:
      id: GO:0008177
      label: succinate dehydrogenase (quinone) activity
    evidence_type: IMP
    original_reference_id: PMID:27604842
    review:
      summary: >-
        IMP annotation for SDH quinone activity from Gronborg et al. (2017). This
        study
        described two additional patients with respiratory chain deficiency due to
        bi-allelic
        SDHB mutations, confirming the specific neuroradiological presentation of
        complex II
        deficiency. One novel SDHB mutation and one previously described mutation
        (associated
        with familial paraganglioma in heterozygous form) were identified.
      action: ACCEPT
      reason: >-
        Valid IMP evidence. Bi-allelic SDHB mutations cause complex II deficiency,
        confirming SDHB's contribution to SDH quinone activity.
      supported_by:
        - reference_id: PMID:27604842
          supporting_text: >-
            two additional patients with respiratory chain deficiency due to bi-allelic
            SDHB
            mutations
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-70994
    review:
      summary: >-
        TAS annotation from Reactome for inner membrane localization. Reactome entry
        R-HSA-70994 describes the SDH complex dehydrogenation of succinate, placing
        SDHB
        at the inner mitochondrial membrane.
      action: ACCEPT
      reason: >-
        Correct. SDHB is part of Complex II which resides in the inner mitochondrial
        membrane.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9855252
    review:
      summary: >-
        TAS annotation from Reactome for inner membrane localization. Reactome entry
        R-HSA-9855252 describes SDHA:SDHB binding to SDHC:SDHD at the inner membrane.
      action: ACCEPT
      reason: >-
        Correct. The SDHA:SDHB subcomplex assembles with SDHC:SDHD at the inner membrane.
  - term:
      id: GO:0005743
      label: mitochondrial inner membrane
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation for inner membrane localization by transfer from bovine ortholog
        (UniProtKB:Q007T0). Consistent with other annotations and cryo-EM evidence.
      action: ACCEPT
      reason: >-
        Correct. Transfer from well-characterized bovine SDH complex. Confirmed by
        cryo-EM (PMID:37098072).
  - term:
      id: GO:0048039
      label: ubiquinone binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation for ubiquinone binding by transfer from bovine ortholog
        (UniProtKB:Q007T0). The cryo-EM structure (PMID:37098072) confirms that SDHB
        directly contacts ubiquinone via residues Pro197, Trp201, and Ile246 at the
        ubiquinone binding pocket formed at the interface of SDHB C-terminal segment,
        SDHC, and SDHD.
      action: ACCEPT
      reason: >-
        Correct. SDHB directly participates in ubiquinone binding, confirmed by the
        cryo-EM
        structure showing specific SDHB residues (Pro197, Trp201, Ile246) contacting
        ubiquinone.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            UQ is also observed to bind at the entrance of the pocket formed by the
            transmembrane
            helix I of SDHC, transmembrane helix II of SDHD, and the C-terminal segment
            of SDHB.
            It interacts with Pro-SDHB197, Trp-SDHB201, Ile-SDHB246
  - term:
      id: GO:0051537
      label: 2 iron, 2 sulfur cluster binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation for [2Fe-2S] cluster binding by transfer from bovine ortholog
        (UniProtKB:Q007T0). Confirmed by human cryo-EM structure (PMID:37098072) and
        EPR spectroscopy.
      action: ACCEPT
      reason: >-
        Correct. The [2Fe-2S] cluster is bound in the N-terminal domain of SDHB, confirmed
        by human cryo-EM structure at 2.86 angstroms.
      supported_by:
        - reference_id: PMID:37098072
          supporting_text: >-
            SDHB contains two domains: the N-terminal domain (residues A35 to A142)
            and the
            C-terminal domain (residues A143 to A273)
  - term:
      id: GO:0051538
      label: 3 iron, 4 sulfur cluster binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation for [3Fe-4S] cluster binding by transfer from bovine ortholog
        (UniProtKB:Q007T0). Confirmed by human cryo-EM structure (PMID:37098072) and
        EPR spectroscopy.
      action: ACCEPT
      reason: >-
        Correct. The [3Fe-4S] cluster is bound in the C-terminal domain of SDHB.
  - term:
      id: GO:0051539
      label: 4 iron, 4 sulfur cluster binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        ISS annotation for [4Fe-4S] cluster binding by transfer from bovine ortholog
        (UniProtKB:Q007T0). Confirmed by human cryo-EM structure (PMID:37098072) and
        EPR spectroscopy.
      action: ACCEPT
      reason: >-
        Correct. The [4Fe-4S] cluster is bound in the C-terminal domain of SDHB.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15961414
    review:
      summary: >-
        IPI annotation for interaction with frataxin (Q16595) from Gonzalez-Cabo et
        al.
        (2005). This study demonstrated physical interaction between yeast frataxin
        (Yfh1p)
        and succinate dehydrogenase subunits Sdh1p and Sdh2p, and also showed physical
        interaction between human frataxin and human SDH complex subunits. Frataxin
        is
        involved in iron-sulfur cluster biogenesis, and this interaction may relate
        to
        Fe-S cluster delivery to SDHB.
      action: KEEP_AS_NON_CORE
      reason: >-
        The SDHB-frataxin interaction is biologically interesting given frataxin's
        role in
        Fe-S cluster biogenesis and Friedreich ataxia pathogenesis. However, 'protein
        binding'
        is uninformative and this represents a regulatory/assembly interaction rather
        than a
        core SDHB function.
      supported_by:
        - reference_id: PMID:15961414
          supporting_text: >-
            We also demonstrate a physical interaction between human frataxin and
            human succinate
            dehydrogenase complex subunits, suggesting also a key role of frataxin
            in the
            mitochondrial electron transport chain in humans
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: TAS
    original_reference_id: PMID:2302193
    review:
      summary: >-
        TAS annotation for mitochondrial localization from the original cDNA cloning
        study
        of human SDHB (Kita et al. 1990). The study cloned the iron-sulfur subunit
        cDNA
        from human liver mitochondria.
      action: ACCEPT
      reason: >-
        Correct. The original study isolated the SDHB cDNA from liver mitochondria,
        establishing mitochondrial localization.
      supported_by:
        - reference_id: PMID:2302193
          supporting_text: >-
            the amino acid sequence of iron sulfur-subunit in human liver mitochondria
            was
            deduced from cDNA
  - term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    evidence_type: TAS
    original_reference_id: PMID:2302193
    review:
      summary: >-
        TAS annotation for TCA cycle involvement from Kita et al. (1990). The study
        describes Complex II as an important enzyme of the tricarboxylic acid cycle.
      action: ACCEPT
      reason: >-
        Correct. Complex II is a canonical TCA cycle enzyme.
      supported_by:
        - reference_id: PMID:2302193
          supporting_text: >-
            Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme
            complex
            of both the tricarboxylic acid cycle and of the aerobic respiratory chains
  - term:
      id: GO:0009060
      label: aerobic respiration
    evidence_type: TAS
    original_reference_id: PMID:2302193
    review:
      summary: >-
        TAS annotation for aerobic respiration from Kita et al. (1990). The study
        describes
        Complex II as part of the aerobic respiratory chains.
      action: ACCEPT
      reason: >-
        Correct. Consistent with IBA annotation for the same term.
      supported_by:
        - reference_id: PMID:2302193
          supporting_text: >-
            Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme
            complex
            of both the tricarboxylic acid cycle and of the aerobic respiratory chains
            of
            mitochondria in eukaryotic cell and prokaryotic organisms
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with GO
      terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data to
      orthologs by curator judgment of sequence similarity
    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: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:15961414
    title: Frataxin interacts functionally with mitochondrial electron transport chain
      proteins.
    findings:
      - statement: >-
          Human frataxin physically interacts with human succinate dehydrogenase complex
          subunits including SDHB, suggesting a key role of frataxin in the mitochondrial
          electron transport chain.
        supporting_text: >-
          We also demonstrate a physical interaction between human frataxin and human
          succinate
          dehydrogenase complex subunits, suggesting also a key role of frataxin in
          the
          mitochondrial electron transport chain in humans
  - id: PMID:19688755
    title: LC-MS/MS as an alternative for SDS-PAGE in blue native analysis of protein
      complexes.
    findings: []
  - id: PMID:2302193
    title: 'Human complex II (succinate-ubiquinone oxidoreductase): cDNA cloning of
      iron sulfur (Ip) subunit of liver mitochondria.'
    findings:
      - statement: >-
          First cDNA cloning of the human iron-sulfur subunit (SDHB) of Complex II
          from liver
          mitochondria. The mature protein is 252 amino acids with striking conservation
          of
          three cysteine-rich clusters comprising the iron-sulfur centers.
        supporting_text: >-
          Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme
          complex
          of both the tricarboxylic acid cycle and of the aerobic respiratory chains
          of
          mitochondria in eukaryotic cell and prokaryotic organisms
  - id: PMID:24606901
    title: Cochaperone binding to LYR motifs confers specificity of iron sulfur cluster
      delivery.
    findings:
      - statement: >-
          SDHB contains two LYR motifs that engage the ISCU-HSC20-HSPA9 Fe-S transfer
          complex
          to aid incorporation of its three Fe-S clusters. Assembly factor SDHAF1
          also
          associates with SDHB and uses its own LYR motif to position an additional
          Fe-S
          transfer complex near SDHB.
        supporting_text: >-
          In succinate dehydrogenase B, two LYR motifs engage the ISCU-HSC20-HSPA9
          complex
          to aid incorporation of three Fe-S clusters within the final structure of
          complex II
  - 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 transiently
          binding
          to SDHB through an arginine-rich region and engaging the Fe-S donor complex.
          Disease-
          causing SDHAF1 mutations abrogate binding to SDHB, impairing holo-SDHB biogenesis.
        supporting_text: >-
          SDHAF1 contributes to iron-sulfur (Fe-S) cluster incorporation into the
          Fe-S subunit
          of CII, SDHB. SDHAF1 transiently binds to aromatic peptides of SDHB through
          an
          arginine-rich region in its C terminus
  - id: PMID:26925370
    title: Mitochondrial leukoencephalopathy and complex II deficiency associated
      with a recessive SDHB mutation with reduced penetrance.
    findings:
      - statement: >-
          Homozygous SDHB p.Asp48Val mutation causes mitochondrial leukoencephalopathy
          with
          complex II deficiency. Spectrophotometric assays showed reduced succinate-ubiquinone
          reductase and SDH activities in muscle and fibroblasts. Immunoblot showed
          strongly
          decreased SDHB protein levels.
        supporting_text: >-
          Reduction of cII (succinate-ubiquinone reductase) and SDH activities were
          documented
          both on muscle tissue and skin fibroblasts
  - id: PMID:27604842
    title: 'Leukoencephalopathy due to Complex II Deficiency and Bi-Allelic SDHB Mutations:
      Further Cases and Implications for Genetic Counselling.'
    findings:
      - statement: >-
          Two additional patients with respiratory chain deficiency due to bi-allelic
          SDHB
          mutations, confirming the specific neuroradiological presentation of complex
          II
          deficiency. One SDHB mutation was previously described in heterozygous form
          in
          paraganglioma/pheochromocytoma patients.
        supporting_text: >-
          Isolated complex II deficiency is a rare cause of mitochondrial disease
          and
          bi-allelic mutations in SDHB have been identified in only a few patients
          with
          complex II deficiency and a progressive neurological phenotype with onset
          in
          infancy
  - 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 cochaperone HSC20 is essential for Fe-S cluster biogenesis of SDHB and
          also
          delivers Fe-S clusters to Complex I and Complex III subunits, highlighting
          the
          crucial role of the cochaperone-scaffold complex in respiratory chain assembly.
        supporting_text: >-
          Recent studies have shown that the co-chaperone HSC20, essential for Fe-S
          cluster
          biogenesis of SDHB, directly binds LYRM7
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and disease
      networks.
    findings: []
  - id: PMID:30030361
    title: Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.
    findings:
      - statement: >-
          Review of OXPHOS complex assembly. Complex II comprises SDHA, SDHB, SDHC,
          SDHD.
          Assembly involves FAD insertion into SDHA by SDHAF2, Fe-S cluster incorporation
          into SDHB, then SDHA-SDHB dimerization and insertion into the membrane via
          SDHC-SDHD.
        supporting_text: >-
          The assembly of the five oxidative phosphorylation system (OXPHOS) complexes
          in
          the inner mitochondrial membrane is an intricate process
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the human
      interactome.
    findings: []
  - id: PMID:34800366
    title: Quantitative high-confidence human mitochondrial proteome and its dynamics
      in cellular context.
    findings: []
  - id: PMID:35512704
    title: Systematic discovery of mutation-directed neo-protein-protein interactions
      in cancer.
    findings: []
  - id: PMID:37098072
    title: Structure of the human respiratory complex II.
    findings:
      - statement: >-
          Cryo-EM structure of human Complex II at 2.86 angstroms resolution showing
          all four
          subunits (SDHA, SDHB, SDHC, SDHD) with FAD, three Fe-S clusters, heme b,
          and
          ubiquinone. SDHB is a small iron-sulfur protein harboring [2Fe-2S], [4Fe-4S],
          and
          [3Fe-4S] clusters organized into two domains in a butterfly-like shape.
          The electron
          transfer pathway from FAD through Fe-S clusters to ubiquinone is proposed.
          SDHB
          residues Pro197, Trp201, and Ile246 directly contact ubiquinone.
        supporting_text: >-
          SDHB contains two domains: the N-terminal domain (residues A35 to A142)
          and the
          C-terminal domain (residues A143 to A273)
  - id: Reactome:R-HSA-70994
    title: SDH complex dehydrogenates succinate
    findings: []
  - 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: []
  - id: file:human/SDHB/SDHB-deep-research-falcon.md
    title: Deep research review of SDHB gene function (Falcon provider)
    findings:
      - statement: >-
          SDHB encodes the iron-sulfur subunit of Complex II. Loss of SDHB protein
          expression
          by IHC is used as a surrogate for SDH deficiency in pheochromocytoma and
          paraganglioma.
          SDH-deficient tumors are linked to a pseudohypoxic program featuring HIF-alpha
          activation.
core_functions:
  - molecular_function:
      id: GO:0009055
      label: electron transfer activity
    contributes_to_molecular_function:
      id: GO:0008177
      label: succinate dehydrogenase (quinone) activity
    directly_involved_in:
      - id: GO:0006121
        label: mitochondrial electron transport, succinate to ubiquinone
      - id: GO:0006099
        label: tricarboxylic acid cycle
    locations:
      - id: GO:0005759
        label: mitochondrial matrix
    in_complex:
      id: GO:0045273
      label: respiratory chain complex II (succinate dehydrogenase)
    description: >-
      SDHB is the iron-sulfur protein (Ip) subunit of succinate dehydrogenase (Complex
      II).
      It contains three iron-sulfur clusters ([2Fe-2S], [4Fe-4S], [3Fe-4S]) organized
      in a
      butterfly-like two-domain structure that relays electrons from the FAD cofactor
      in SDHA
      to ubiquinone at the SDHC/SDHD membrane interface. The primary subunit-specific
      molecular
      function of SDHB is electron transfer activity (GO:0009055), while it contributes
      to the
      overall succinate dehydrogenase (quinone) activity (GO:0008177) of the Complex
      II
      heterotetramer. SDHB also directly contacts the ubiquinone binding site via
      residues
      Pro197, Trp201, and Ile246 (GO:0048039 ubiquinone binding). The complex resides
      in the
      inner mitochondrial membrane with SDHB facing the matrix. SDHB is essential
      for coupling
      the TCA cycle (succinate oxidation) to the electron transport chain (ubiquinone
      reduction),
      the defining biological process GO:0006121.
    supported_by:
      - reference_id: PMID:37098072
        supporting_text: >-
          SDHB contains two domains: the N-terminal domain (residues A35 to A142)
          and the
          C-terminal domain (residues A143 to A273)
      - reference_id: PMID:37098072
        supporting_text: >-
          The edge-to-edge distance between these redox-active prosthetic groups is
          less than
          14 Å (Fig. 3), a distance range that can efficiently support the delivery
          of electrons
          between these redox centers (22)
      - reference_id: PMID:37098072
        supporting_text: >-
          UQ is also observed to bind at the entrance of the pocket formed by the
          transmembrane
          helix I of SDHC, transmembrane helix II of SDHD, and the C-terminal segment
          of SDHB.
          It interacts with Pro-SDHB197, Trp-SDHB201, Ile-SDHB246