SDHAF1 (succinate dehydrogenase assembly factor 1) is a small (115 aa) LYR-motif protein of the mitochondrial matrix that acts as an assembly factor for succinate dehydrogenase (SDH, respiratory Complex II), the enzyme that couples oxidation of succinate to fumarate with reduction of ubiquinone and links the TCA cycle to the electron transport chain. SDHAF1 is not a structural subunit of the mature complex and is not itself catalytic. It promotes maturation of the iron-sulfur (Fe-S) subunit SDHB: through an N-terminal LYR motif it binds the DnaJ/Hsp40-type co-chaperone HSC20 (HSCB), recruiting the HSC20-HSPA9 chaperone system and the ISCU scaffold, while an arginine-rich C-terminal region binds SDHB, thereby positioning the Fe-S transfer machinery to insert iron-sulfur clusters into SDHB and protecting SDHB from oxidative damage. It is a member of the complex I LYR family, SDHAF1 subfamily. Biallelic loss-of-function variants cause an autosomal-recessive, riboflavin-responsive mitochondrial complex II deficiency presenting as infantile leukoencephalopathy with succinate accumulation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) localization of SDHAF1 to mitochondrion. Correct but non-specific; the protein is more precisely in the mitochondrial matrix. Kept as non-core because the specific matrix localization and the assembly BP better capture the biology. Reason: UniProt states subcellular location is mitochondrion matrix, consistent with this broader mitochondrion term. Retained but subsumed by the more specific matrix term. Supporting Evidence: file:human/SDHAF1/SDHAF1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0034553 mitochondrial respiratory chain complex II assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of the core biological process. This is exactly the process SDHAF1 performs and is consistent with the experimental IMP annotation and with UniProt. Accepted as a core function. Reason: SDHAF1 is a bona fide SDH (Complex II) assembly factor; the IBA agrees with the experimental IMP annotation (PMID:19465911) and UniProt. Supporting Evidence: PMID:19465911 SDHAF1 is the first bona fide SDH assembly factor reported in any organism. |
| GO:0005739 mitochondrion | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO (IEA) mitochondrial localization. Correct but non-specific relative to the matrix localization. Kept as non-core. Reason: Consistent with the curated mitochondrion/matrix localization; less specific than the matrix term. Supporting Evidence: file:human/SDHAF1/SDHAF1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping (IEA) to mitochondrial matrix. This is the correct, specific compartment for SDHAF1 and is supported by the curated UniProt location. Accepted. Reason: Matches the experimentally supported UniProt subcellular location (matrix). Supporting Evidence: file:human/SDHAF1/SDHAF1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0034553 mitochondrial respiratory chain complex II assembly | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO (IEA) assignment of the core biological process from the SDHAF1-specific InterPro signature. Correct and consistent with the experimental and phylogenetic annotations. Accepted. Reason: The InterPro family (IPR045295, Complex1_LYR_SDHAF1_LYRM8) is SDHAF1-specific and the inferred assembly process matches the experimental IMP annotation. Supporting Evidence: PMID:19465911 SDHAF1 is the first bona fide SDH assembly factor reported in any organism. |
| GO:0005515 protein binding | IPI PMID:24606901 Cochaperone binding to LYR motifs confers specificity of iro... | KEEP AS NON CORE | Summary: IPI "protein binding" from IntAct curation of the HSC20/LYR-motif study; the recorded partners are SDHB (P21912, substrate) and HSCB/HSC20 (Q8IWL3, co-chaperone). These are the functionally central interactions, but the bare "protein binding" term is uninformative. Kept as non-core; the specific molecular function is captured by protein-folding chaperone binding (GO:0051087) in core_functions. Reason: Real, physiologically meaningful interactions (co-chaperone HSC20 and substrate SDHB), but GO:0005515 is too general; superseded in core_functions by the chaperone-binding MF. Supporting Evidence: PMID:24606901 members of the LYR motif family which assist assembly of complexes II or III, SDHAF1 and LYRM7, respectively, are HSC20 binding partners. |
| GO:0005515 protein binding | IPI PMID:26749241 Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clu... | KEEP AS NON CORE | Summary: IPI "protein binding" from IntAct curation of the disease-mechanism paper; partners are SDHB (P21912) and HSCB/HSC20 (Q8IWL3). Functionally meaningful but uninformative as a bare term. Kept as non-core; specific MF captured as protein-folding chaperone binding. Reason: Meaningful SDHB and HSC20 interactions underpinning Fe-S transfer, but GO:0005515 is too general; superseded by GO:0051087 in core_functions. Supporting Evidence: PMID:26749241 SDHAF1 transiently binds to aromatic peptides of SDHB through an arginine-rich region in its C terminus and specifically engages a Fe-S donor complex, consisting of the scaffold, holo-ISCU, and the co-chaperone-chaperone pair, HSC20-HSPA9, through an LYR motif near its N-terminal domain. |
| GO:0005515 protein binding | IPI PMID:28380382 A Single Adaptable Cochaperone-Scaffold Complex Delivers Nas... | KEEP AS NON CORE | Summary: IPI "protein binding" from IntAct curation; recorded partner is HSCB/HSC20 (Q8IWL3). This HSC20-centered study places SDHAF1 in the LYR-family Fe-S delivery network. Meaningful interaction but uninformative as a bare term; kept as non-core. Reason: Genuine co-chaperone (HSC20) interaction, but GO:0005515 is too general; superseded by GO:0051087 protein-folding chaperone binding in core_functions. Supporting Evidence: PMID:28380382 Binding of HSC20 to the LYR motif of LYRM7 in a pre-assembled UQCRFS1-LYRM7 intermediate in the mitochondrial matrix facilitates Fe-S cluster transfer to UQCRFS1. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI "protein binding" from the HuRI large-scale binary (Y2H) interactome; recorded partners are KRT27 (Q7Z3Y8, a keratin) and CIDEB (Q9UHD4). Neither is a plausible physiological partner for a mitochondrial-matrix assembly factor; these are likely high-throughput screen artifacts. Marked as over-annotated: the bare "protein binding" term adds no functional information and the partners are not biologically relevant. Reason: Large-scale Y2H hits (keratin KRT27, CIDEB) are non-physiological for a matrix protein; GO:0005515 is uninformative and not supported by any functional role. Supporting Evidence: PMID:32296183 With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: IPI "protein binding" from the BioPlex 3.0 AP-MS interactome; recorded partner is SDHB (P21912), the physiological substrate of SDHAF1. Consistent with the curated SDHAF1-SDHB interaction. Kept as non-core because GO:0005515 is uninformative; the specific activity is captured elsewhere. Reason: Real SDHB interaction (consistent with UniProt SUBUNIT), but GO:0005515 is too general. Supporting Evidence: file:human/SDHAF1/SDHAF1-uniprot.txt Interacts with SDHB within an SDHA-SDHB subcomplex |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Direct (IDA) immunofluorescence localization to mitochondrion (Human Protein Atlas). Correct but non-specific; the protein resides in the matrix. Kept as non-core. Reason: Consistent with the curated matrix localization; less specific than the matrix term. Supporting Evidence: file:human/SDHAF1/SDHAF1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput (HTP) detection of SDHAF1 in the high-confidence human mitochondrial proteome, confirming mitochondrial localization. Correct but non-specific relative to the matrix. Kept as non-core. Reason: Supports mitochondrial residence via a quantitative mito-proteome dataset; subsumed by the more specific matrix term. Supporting Evidence: file:human/SDHAF1/SDHAF1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9854984 | ACCEPT | Summary: Reactome (TAS) matrix localization within the SDH assembly pathway (Transfer of Fe-S clusters to SDHB). Matches the curated UniProt matrix location. Accepted. Reason: Correct, specific compartment consistent with UniProt and with SDHAF1's role in the matrix-localized Fe-S transfer step. Supporting Evidence: file:human/SDHAF1/SDHAF1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9855212 | ACCEPT | Summary: Reactome (TAS) matrix localization (SDHA binds to SDHB reaction). Correct, specific compartment consistent with UniProt. Accepted. Reason: Matches the curated matrix localization. Supporting Evidence: file:human/SDHAF1/SDHAF1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9855252 | ACCEPT | Summary: Reactome (TAS) matrix localization (SDHA:SDHB binds to SDHC:SDHD reaction). Correct, specific compartment consistent with UniProt. Accepted. Reason: Matches the curated matrix localization. Supporting Evidence: file:human/SDHAF1/SDHAF1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005739 mitochondrion | IDA PMID:19465911 SDHAF1, encoding a LYR complex-II specific assembly factor, ... | KEEP AS NON CORE | Summary: Direct (IDA) localization of SDHAF1 to mitochondrion in the founding paper. Correct but non-specific; the curated location is the matrix. Kept as non-core. Reason: Experimental mitochondrial localization; subsumed by the more specific matrix term. Supporting Evidence: file:human/SDHAF1/SDHAF1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0034553 mitochondrial respiratory chain complex II assembly | IMP PMID:19465911 SDHAF1, encoding a LYR complex-II specific assembly factor, ... | ACCEPT | Summary: Experimental (IMP) assignment of the core biological process from the founding SDHAF1 paper: SDHAF1 mutations cause SDH (Complex II) deficiency, and SDH activity/amount are restored proportionally with re-expression of the wild-type gene. This is the defining function of SDHAF1. Accepted as the primary core annotation. Reason: Directly supported experimental annotation establishing SDHAF1 as a Complex II assembly factor; consistent with UniProt FUNCTION. Supporting Evidence: PMID:19465911 SDH activity and amount were restored in mutant fibroblasts proportionally with re-expression of the wild-type gene. |
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