SDHAF2 (also known as SDH5, PGL2, C11orf79) is a soluble mitochondrial-matrix assembly factor for succinate dehydrogenase (SDH), the respiratory chain Complex II that links the tricarboxylic acid cycle and the electron transport chain. SDHAF2 is not a subunit of the mature enzyme and has no succinate dehydrogenase catalytic activity of its own. Its defining role is to bind the flavoprotein subunit SDHA and, acting as a chaperone/assembly factor together with a dicarboxylate cofactor, to remodel and orient the flavin and capping domains of SDHA so that covalent attachment of the FAD cofactor (flavinylation) can occur. This covalent flavinylation is required for SDH assembly and activity. Germline loss-of-function mutations in SDHAF2 cause hereditary pheochromocytoma/paraganglioma (PPGL2); the G78R variant abolishes both SDHA binding and SDHA flavinylation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred mitochondrial localization. Consistent with the experimentally established mitochondrial-matrix localization of SDHAF2; a more specific matrix term is available and captured by other annotations, but this general term is correct. Supporting Evidence: file:human/SDHAF2/SDHAF2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0006121 mitochondrial electron transport, succinate to ubiquinone | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: This term describes the catalytic electron-transport activity of the mature Complex II, not the function of the assembly factor. SDHAF2 is required for SDH assembly/activity but does not itself carry out succinate-to-ubiquinone electron transport. Over-annotation propagated by IBA from the catalytic SDH subunits in the shared PANTHER family; the honest role is captured by the Complex II assembly and protein-FAD linkage terms. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION Supporting Evidence: file:human/SDHAF2/SDHAF2-uniprot.txt Plays an essential role in the assembly of succinate |
| GO:0034553 mitochondrial respiratory chain complex II assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Correct and core. SDHAF2 is a dedicated assembly factor for respiratory Complex II (SDH). Phylogenetic inference here agrees with direct experimental evidence (PMID:32887801, PMID:19628817). Supporting Evidence: file:human/SDHAF2/SDHAF2-uniprot.txt Plays an essential role in the assembly of succinate |
| GO:0006099 tricarboxylic acid cycle | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: SDH (Complex II) is a TCA-cycle enzyme, but SDHAF2 is an assembly factor and does not itself carry out TCA-cycle chemistry. This is an over-annotation transferred by IBA from the catalytic subunits; SDHAF2 acts upstream by enabling SDHA maturation rather than participating in the cycle. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION Supporting Evidence: file:human/SDHAF2/SDHAF2-uniprot.txt Required for flavinylation (covalent |
| GO:0005739 mitochondrion | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic annotation of mitochondrial localization. Correct and supported by experimental data; general term subsumed by the more specific mitochondrial matrix annotation. Supporting Evidence: file:human/SDHAF2/SDHAF2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (UniRule/SubCell) annotation of mitochondrial-matrix localization. This is the correct, specific subcellular location, corroborated experimentally (PMID:19628817, EXP). Supporting Evidence: file:human/SDHAF2/SDHAF2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0006121 mitochondrial electron transport, succinate to ubiquinone | IEA GO_REF:0000104 | MARK AS OVER ANNOTATED | Summary: Electronic UniRule annotation of the mature-enzyme catalytic process. As with the IBA version, this is an over-annotation for an assembly factor that does not itself perform electron transport. Marked as over-annotated rather than removed since SDHAF2 is genuinely required for this activity to occur. Supporting Evidence: file:human/SDHAF2/SDHAF2-uniprot.txt Plays an essential role in the assembly of succinate |
| GO:0010719 negative regulation of epithelial to mesenchymal transition | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning electronic annotation echoing the cancer-context moonlighting role reported for SDH5 (PMID:23983127). This is a disease/cancer-associated regulatory phenotype, indirect and cell-type dependent, not the core mitochondrial assembly function. Kept as non-core; the underlying experimental MGI annotation is retained separately. Supporting Evidence: PMID:23983127 loss of succinate dehydrogenase 5 (SDH5) expression initiates epithelial-mesenchymal transition (EMT) |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation reflecting the SDH5βGSK-3Ξ²βΞ²-catenin (Wnt) axis reported in lung cancer (PMID:23983127). A moonlighting/regulatory role, indirect and context dependent, not part of the core assembly-factor function. Kept as non-core. Supporting Evidence: PMID:23983127 SDH5 functions as a negative regulator of Wnt-Ξ²-catenin signaling |
| GO:0005515 protein binding | IPI PMID:19628817 SDH5, a gene required for flavination of succinate dehydroge... | MARK AS OVER ANNOTATED | Summary: Experimental IPI documenting the physical interaction between SDHAF2 (SDH5) and the SDH catalytic subunit SDHA (P31040) β the biologically central interaction of this protein. Retained, but "protein binding" (GO:0005515) is uninformative as a molecular function; the informative activity is captured in core_functions as protein-folding chaperone activity toward SDHA. Marked as over-annotated per policy (experimental IPI is not removed). Supporting Evidence: PMID:19628817 Both yeast and human Sdh5 interact with the catalytic subunit of the succinate dehydrogenase (SDH) complex |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MARK AS OVER ANNOTATED | Summary: High-throughput quantitative-interactome IPI (with SDHA, P31040). Corroborates the SDHAF2βSDHA interaction but "protein binding" is an uninformative MF. Over-annotated per policy. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome (BioPlex) IPI, WITH/FROM SDHA (P31040). Consistent with the known SDHAF2βSDHA interaction; "protein binding" is uninformative as an MF. Over-annotated per policy. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Binary (Y2H) high-throughput interactome IPI, WITH/FROM CYP4F2 (P78329) and SEC22A (Q96IW7). These are isolated high-throughput pairs with no biological follow-up and are not part of the known SDHAF2 biology; "protein binding" is uninformative as an MF. Over-annotated per policy. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome (BioPlex 3.0) IPI, WITH/FROM SDHA (P31040). Corroborates the SDHAF2βSDHA interaction; "protein binding" is uninformative as an MF. Over-annotated per policy. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based (HPA) IDA localizing SDHAF2 to the mitochondrion. Correct; subsumed by the more specific mitochondrial-matrix location. Supporting Evidence: file:human/SDHAF2/SDHAF2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial-proteome study placing SDHAF2 in the mitochondrion. Consistent with all other localization evidence. Supporting Evidence: file:human/SDHAF2/SDHAF2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | EXP PMID:19628817 SDH5, a gene required for flavination of succinate dehydroge... | ACCEPT | Summary: Experimental (EXP) evidence for mitochondrial-matrix localization from the founding SDH5 study. This is the correct, specific subcellular location and is a core location. Supporting Evidence: file:human/SDHAF2/SDHAF2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0034553 mitochondrial respiratory chain complex II assembly | IDA PMID:32887801 The roles of SDHAF2 and dicarboxylate in covalent flavinylat... | ACCEPT | Summary: Direct experimental evidence (X-ray structure of the human SDHAβSDHAF2 complex, PDB 6VAX) for SDHAF2's role in Complex II assembly, showing it works with a dicarboxylate to orient the SDHA flavin and capping domains to support covalent FAD attachment. This is a core function. Supporting Evidence: PMID:32887801 works in synergy with SDHAF2 to properly orient the flavin and capping domains of SDHA |
| GO:0006470 protein dephosphorylation | IGI PMID:23983127 Succinate dehydrogenase 5 (SDH5) regulates glycogen synthase... | KEEP AS NON CORE | Summary: MGI IGI (acts_upstream_of_or_within) based on the report that SDH5 interaction with GSK-3Ξ² facilitates its activation through Ser-9 dephosphorylation. SDHAF2 is not itself a phosphatase; the dephosphorylation is a downstream consequence of the SDH5βGSK-3Ξ² interaction in a cancer context. Retained but non-core (moonlighting/regulatory role, not the mitochondrial assembly function). Supporting Evidence: PMID:23983127 The physical interaction between SDH5 and GSK-3Ξ² facilitates GSK-3Ξ² activation through Ser-9 dephosphorylation |
| GO:0010719 negative regulation of epithelial to mesenchymal transition | IMP PMID:23983127 Succinate dehydrogenase 5 (SDH5) regulates glycogen synthase... | KEEP AS NON CORE | Summary: Experimental MGI IMP: loss of SDH5 initiates EMT in lung-cancer models. A genuine cancer-context regulatory phenotype, but indirect and cell-type dependent, and distinct from the core mitochondrial assembly-factor function. Kept as non-core. Supporting Evidence: PMID:23983127 loss of succinate dehydrogenase 5 (SDH5) expression initiates epithelial-mesenchymal transition (EMT) |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IGI PMID:23983127 Succinate dehydrogenase 5 (SDH5) regulates glycogen synthase... | KEEP AS NON CORE | Summary: MGI IGI (with Ξ²-catenin, P35222) for SDH5 acting as a negative regulator of Wnt/Ξ²-catenin signaling via GSK-3Ξ². A moonlighting/regulatory role in a cancer context, indirect and not the core function. Kept as non-core. Supporting Evidence: PMID:23983127 SDH5 functions as a negative regulator of Wnt-Ξ²-catenin signaling |
| GO:0005739 mitochondrion | IDA PMID:19628817 SDH5, a gene required for flavination of succinate dehydroge... | ACCEPT | Summary: IDA mitochondrial localization from the founding SDH5 study. Correct; subsumed by the more specific mitochondrial-matrix location also annotated from this paper. Supporting Evidence: file:human/SDHAF2/SDHAF2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0018293 protein-FAD linkage | IMP PMID:19628817 SDH5, a gene required for flavination of succinate dehydroge... | ACCEPT | Summary: Core function. Experimental IMP: SDH5 is required for the flavination (covalent incorporation of FAD) of the SDH flavoprotein subunit. GO:0018293 "protein-FAD linkage" (a child of GO:0017013 protein flavinylation) is the precise term for the covalent FAD-attachment step that SDHAF2 promotes/enables. Supporting Evidence: PMID:19628817 Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin adenine dinucleotide cofactor) |
| GO:0044183 protein folding chaperone | IDA PMID:32887801 The roles of SDHAF2 and dicarboxylate in covalent flavinylat... | NEW | Summary: Proposed molecular function (NEW). SDHAF2 has no catalytic activity of its own and does not bind FAD directly; it is a dedicated chaperone/assembly factor (UniProt keyword "Chaperone") that binds SDHA and, with a dicarboxylate cofactor, remodels/orients its flavin and capping domains to license covalent flavinylation. GO:0044183 "protein folding chaperone" (MF) captures this activity far more informatively than the existing "protein binding" IPIs. Supported by the SDHAβSDHAF2 structure (PMID:32887801) and the requirement of SDHAF2 for SDHA flavinylation (PMID:19628817). Supporting Evidence: PMID:32887801 works in synergy with SDHAF2 to properly orient the flavin and capping domains of SDHA |
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