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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0009060 aerobic respiration | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:37098072 Human complex II is a key protein complex that links two essential energy-producing processes: the tricarboxylic acid cycle and oxidative phosphorylation PMID:2302193 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 |
| GO:0022904 respiratory electron transport chain | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:37098072 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) |
| GO:0031966 mitochondrial membrane | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:37098072 The hydrophilic head of human CII consists of the flavin adenine dinucleotide (FAD)-binding protein (SDHA) and the iron-sulfur protein (SDHB) |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | ACCEPT | 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. Reason: Correct localization. SDHB is part of Complex II which is anchored in the inner mitochondrial membrane. Consistent with experimental evidence from cryo-EM. Supporting Evidence: PMID:37098072 The entire hydrophobic domain contains two membrane-anchored subunits: SDHC and SDHD |
| GO:0006099 tricarboxylic acid cycle | IEA GO_REF:0000120 | ACCEPT | 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. Reason: TCA cycle involvement is a core function of SDHB as part of Complex II. This is well-established biochemistry. Supporting Evidence: PMID:26925370 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) |
| GO:0008177 succinate dehydrogenase (quinone) activity | IEA GO_REF:0000120 | MODIFY | 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. Reason: SDHB contributes to the overall SDH quinone activity by providing the electron relay from FAD to ubiquinone, but does not enable it alone. Relation-only correction (go-annotation#6414): GO:0008177 is the whole-complex succinate:quinone reaction, which no single subunit carries out, so the GOA 'enables' relation should become 'contributes_to'. The term is kept; the intended contributes_to assertion is recorded as the paired NEW row below, pending the upstream GOA change. Proposed replacements: succinate dehydrogenase (quinone) activity |
| GO:0009055 electron transfer activity | IEA GO_REF:0000002 | ACCEPT | 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. 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. Supporting Evidence: PMID:37098072 SDHB contains two domains: the N-terminal domain (residues A35 to A142) and the C-terminal domain (residues A143 to A273) PMID:37098072 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 |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000120 | ACCEPT | 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. 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. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | 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. 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. |
| GO:0051536 iron-sulfur cluster binding | IEA GO_REF:0000120 | ACCEPT | 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. 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. Supporting Evidence: PMID:37098072 Electron paramagnetic resonance (EPR) spectra revealed the presence of redox centers |
| GO:0051537 2 iron, 2 sulfur cluster binding | IEA GO_REF:0000120 | ACCEPT | 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). 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. Supporting Evidence: PMID:37098072 SDHB contains two domains: the N-terminal domain (residues A35 to A142) and the C-terminal domain (residues A143 to A273) |
| GO:0051538 3 iron, 4 sulfur cluster binding | IEA GO_REF:0000043 | ACCEPT | 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). Reason: Correct. The [3Fe-4S] cluster in SDHB is the terminal electron donor to ubiquinone in the electron relay chain. Supporting Evidence: PMID:37098072 SDHB contains two domains: the N-terminal domain (residues A35 to A142) and the C-terminal domain (residues A143 to A273) |
| GO:0051539 4 iron, 4 sulfur cluster binding | IEA GO_REF:0000043 | ACCEPT | 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). 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. Supporting Evidence: PMID:37098072 SDHB contains two domains: the N-terminal domain (residues A35 to A142) and the C-terminal domain (residues A143 to A273) |
| GO:0005515 protein binding | IPI PMID:19688755 LC-MS/MS as an alternative for SDS-PAGE in blue native analy... | KEEP AS NON CORE | 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). 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. |
| GO:0005515 protein binding | IPI PMID:24606901 Cochaperone binding to LYR motifs confers specificity of iro... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:24606901 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 |
| GO:0005515 protein binding | IPI PMID:26749241 Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clu... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:26749241 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 |
| GO:0005515 protein binding | IPI PMID:28380382 A Single Adaptable Cochaperone-Scaffold Complex Delivers Nas... | REMOVE | 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. 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. Supporting Evidence: PMID:28380382 Recent studies have shown that the co-chaperone HSC20, essential for Fe-S cluster biogenesis of SDHB, directly binds LYRM7 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | 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. Reason: Another confirmation of the SDHA-SDHB interaction. Already well established and captured by the CC annotation for Complex II membership. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | 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. Reason: Confirms SDHB-SDHA and SDHB-SDHAF1 interactions. Well established and captured by other annotations. |
| GO:0005515 protein binding | IPI PMID:35512704 Systematic discovery of mutation-directed neo-protein-protei... | REMOVE | 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. 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. Supporting Evidence: PMID:35512704 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 |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | ACCEPT | 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. Reason: Correct localization, well supported by multiple lines of evidence including the transit peptide and IDA evidence from HPA immunofluorescence. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000107 | ACCEPT | 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. 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. Supporting Evidence: PMID:37098072 The hydrophilic head of human CII consists of the flavin adenine dinucleotide (FAD)-binding protein (SDHA) and the iron-sulfur protein (SDHB) |
| GO:0006105 succinate metabolic process | IEA GO_REF:0000107 | ACCEPT | 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. 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. |
| GO:0022904 respiratory electron transport chain | IEA GO_REF:0000107 | ACCEPT | 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. Reason: Correct and consistent with IBA annotation for the same term. Duplicates are expected when multiple evidence sources converge. |
| GO:0045273 respiratory chain complex II (succinate dehydrogenase) | IEA GO_REF:0000107 | ACCEPT | 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. Reason: Correct and consistent with experimental evidence from cryo-EM (PMID:37098072). |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: IDA annotation for mitochondrial localization from HPA immunofluorescence data. Direct experimental evidence of SDHB mitochondrial localization. Reason: Direct experimental evidence of mitochondrial localization by immunofluorescence. |
| GO:0005743 mitochondrial inner membrane | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | ACCEPT | 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. Reason: Correct localization. Complex II spans the inner membrane via SDHC/SDHD subunits, with SDHB on the matrix side as a peripheral membrane protein. |
| GO:0006099 tricarboxylic acid cycle | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | ACCEPT | 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. Reason: Correct and consistent with IEA and TAS annotations for the same term. |
| GO:0006121 mitochondrial electron transport, succinate to ubiquinone | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | ACCEPT | 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. 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. Supporting Evidence: PMID:37098072 we propose that the human CII succinate- and ubiquinone-binding sites are likely to be connected by a similar chain of redox centers |
| GO:0042776 proton motive force-driven mitochondrial ATP synthesis | NAS PMID:30030361 Assembly of mammalian oxidative phosphorylation complexes I-... | REMOVE | 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). 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). Supporting Evidence: PMID:37098072 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 |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | 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. Reason: Correct. SDHB is a well-established mitochondrial protein confirmed by proteomics. |
| GO:0045273 respiratory chain complex II (succinate dehydrogenase) | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for Complex II membership by manual transfer from ortholog (UniProtKB:Q007T0, bovine). Consistent with all other annotations for this term. Reason: Correct. Transfer from the well-characterized bovine SDH complex. SDHB is unambiguously a subunit of Complex II. |
| GO:0045273 respiratory chain complex II (succinate dehydrogenase) | IDA PMID:37098072 Structure of the human respiratory complex II. | ACCEPT | 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. 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. Supporting Evidence: PMID:37098072 We observed all four subunits in a monomeric assembly (Fig. 1A). This arrangement is similar to that in W. succinogenes QFR PMID:37098072 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) file:human/SDHB/SDHB-deep-research-falcon.md SDHB encodes the iron-sulfur subunit of succinate dehydrogenase (SDH; mitochondrial complex II) |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9854984 | ACCEPT | 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. Reason: Correct. Fe-S cluster transfer to SDHB occurs in the mitochondrial matrix during Complex II assembly. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9855212 | ACCEPT | Summary: TAS annotation from Reactome for matrix localization, associated with SDHA binding to SDHB. The SDHA-SDHB subcomplex formation occurs in the matrix. Reason: Correct. SDHA-SDHB subcomplex formation occurs in the mitochondrial matrix. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9855252 | ACCEPT | Summary: TAS from Reactome for matrix localization, associated with SDHA:SDHB binding to SDHC:SDHD. The final assembly step of Complex II. 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. |
| GO:0008177 succinate dehydrogenase (quinone) activity | IMP PMID:26925370 Mitochondrial leukoencephalopathy and complex II deficiency ... | MODIFY | 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. Reason: Valid IMP evidence. The homozygous SDHB D48V mutation causes decreased succinate dehydrogenase (ubiquinone) activity, demonstrating SDHB's contribution to the overall complex activity. Relation-only correction (go-annotation#6414): GO:0008177 is the whole-complex succinate:quinone reaction, which no single subunit carries out, so the GOA 'enables' relation should become 'contributes_to'. The term is kept; the intended contributes_to assertion is recorded as the paired NEW row below, pending the upstream GOA change. Proposed replacements: succinate dehydrogenase (quinone) activity Supporting Evidence: PMID:26925370 Reduction of cII (succinate-ubiquinone reductase) and SDH activities were documented both on muscle tissue and skin fibroblasts PMID:26925370 immunoblot analysis on proband's fibroblasts showed strongly decreased levels of SDHB, suggesting a deleterious effect of the identified SDHB variant on protein stability |
| GO:0008177 succinate dehydrogenase (quinone) activity | IMP PMID:27604842 Leukoencephalopathy due to Complex II Deficiency and Bi-Alle... | MODIFY | 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. Reason: Valid IMP evidence. Bi-allelic SDHB mutations cause complex II deficiency, confirming SDHB's contribution to SDH quinone activity. Relation-only correction (go-annotation#6414): GO:0008177 is the whole-complex succinate:quinone reaction, which no single subunit carries out, so the GOA 'enables' relation should become 'contributes_to'. The term is kept; the intended contributes_to assertion is recorded as the paired NEW row below, pending the upstream GOA change. Proposed replacements: succinate dehydrogenase (quinone) activity Supporting Evidence: PMID:27604842 two additional patients with respiratory chain deficiency due to bi-allelic SDHB mutations |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-70994 | ACCEPT | 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. Reason: Correct. SDHB is part of Complex II which resides in the inner mitochondrial membrane. |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-9855252 | ACCEPT | 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. Reason: Correct. The SDHA:SDHB subcomplex assembles with SDHC:SDHD at the inner membrane. |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for inner membrane localization by transfer from bovine ortholog (UniProtKB:Q007T0). Consistent with other annotations and cryo-EM evidence. Reason: Correct. Transfer from well-characterized bovine SDH complex. Confirmed by cryo-EM (PMID:37098072). |
| GO:0048039 ubiquinone binding | ISS GO_REF:0000024 | ACCEPT | 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. Reason: Correct. SDHB directly participates in ubiquinone binding, confirmed by the cryo-EM structure showing specific SDHB residues (Pro197, Trp201, Ile246) contacting ubiquinone. Supporting Evidence: PMID:37098072 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 |
| GO:0051537 2 iron, 2 sulfur cluster binding | ISS GO_REF:0000024 | ACCEPT | 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. 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. Supporting Evidence: PMID:37098072 SDHB contains two domains: the N-terminal domain (residues A35 to A142) and the C-terminal domain (residues A143 to A273) |
| GO:0051538 3 iron, 4 sulfur cluster binding | ISS GO_REF:0000024 | ACCEPT | 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. Reason: Correct. The [3Fe-4S] cluster is bound in the C-terminal domain of SDHB. |
| GO:0051539 4 iron, 4 sulfur cluster binding | ISS GO_REF:0000024 | ACCEPT | 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. Reason: Correct. The [4Fe-4S] cluster is bound in the C-terminal domain of SDHB. |
| GO:0005515 protein binding | IPI PMID:15961414 Frataxin interacts functionally with mitochondrial electron ... | KEEP AS NON CORE | 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. 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. Supporting Evidence: PMID:15961414 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 |
| GO:0005739 mitochondrion | TAS PMID:2302193 Human complex II (succinate-ubiquinone oxidoreductase): cDNA... | ACCEPT | 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. Reason: Correct. The original study isolated the SDHB cDNA from liver mitochondria, establishing mitochondrial localization. Supporting Evidence: PMID:2302193 the amino acid sequence of iron sulfur-subunit in human liver mitochondria was deduced from cDNA |
| GO:0006099 tricarboxylic acid cycle | TAS PMID:2302193 Human complex II (succinate-ubiquinone oxidoreductase): cDNA... | ACCEPT | 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. Reason: Correct. Complex II is a canonical TCA cycle enzyme. Supporting Evidence: PMID:2302193 Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme complex of both the tricarboxylic acid cycle and of the aerobic respiratory chains |
| GO:0009060 aerobic respiration | TAS PMID:2302193 Human complex II (succinate-ubiquinone oxidoreductase): cDNA... | ACCEPT | Summary: TAS annotation for aerobic respiration from Kita et al. (1990). The study describes Complex II as part of the aerobic respiratory chains. Reason: Correct. Consistent with IBA annotation for the same term. Supporting Evidence: PMID:2302193 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 |
| GO:0008177 succinate dehydrogenase (quinone) activity | IDA PMID:37098072 Structure of the human respiratory complex II. | NEW | Summary: Intended replacement for the three GOA 'enables' GO:0008177 rows (IEA GO_REF:0000120; IMP PMID:26925370; IMP PMID:27604842), recording the go-annotation#6414 decision that each Complex II subunit contributes_to the whole-complex succinate:quinone oxidoreductase activity. Purified human Complex II containing all four subunits, including SDHB, was assayed directly for succinate-coupled ubiquinone reduction (PMID:37098072). Reason: SDHB supplies the Fe-S electron relay between the SDHA flavin and the quinone site and contacts ubiquinone, so it does part of the work of the reaction but cannot catalyse it alone; contributes_to is the correct relation. Recorded here pending the upstream GOA qualifier change. Supporting Evidence: PMID:37098072 The succinate-quinone oxidoreductase enzymatic activity of human CII was determined by performing a succinate-2,6-dichlorophenolindophenol (DCIP, Sigma) assay in the presence of ubiquinone-1 (UQ1, Sigma) PMID:37098072 Human CII coupled succinate oxidation to ubiquinone reduction gave a catalytic constant (kcat) 0.67 |
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