UniProt: A6NFY7 (SDHF1_HUMAN). Gene: SDHAF1 (HGNC:33867); synonym LYRM8. Human, 115 aa.
SDHAF1 is a small (115 aa) mitochondrial-matrix assembly factor for succinate
dehydrogenase (SDH, respiratory Complex II). It is a LYR-motif protein (complex I LYR
family, SDHAF1 subfamily) and is NOT a structural subunit of the mature Complex II and is
not itself succinate-dehydrogenase catalytic. Its documented job is to promote maturation
of the iron-sulfur (Fe-S) subunit SDHB: it binds SDHB and recruits the Fe-S transfer
machinery (HSC20/HSCB co-chaperone + HSPA9 chaperone + ISCU scaffold) via direct binding
to the co-chaperone HSC20, thereby helping insert Fe-S clusters into SDHB.
There is no catalytic MF here. The honest, specific, experimentally supported MF is
protein-folding chaperone binding (GO:0051087): SDHAF1 binds the DnaJ/Hsp40-type
co-chaperone HSC20 (HSCB) directly through its N-terminal LYR motif. HSC20 is "the sole
human DnaJ type III cochaperone dedicated to Fe-S cluster biogenesis" and works with its
cognate HSP70 chaperone HSPA9 [PMID:24606901 full text]. SDHAF1 also acts as a
substrate-recruiting adaptor for SDHB, but "protein binding" (GO:0005515) is uninformative;
the chaperone-binding term captures the specific, defining molecular activity.
Supporting text:
- "members of the LYR motif family which assist assembly of complexes II or III, SDHAF1 and
LYRM7, respectively, are HSC20 binding partners" [PMID:24606901,
publications/PMID_24606901.md, full text].
- "SDHAF1 (LYRM8), which is involved in SDH assembly" PMID:24606901.
- "SDHAF1 associates with SDHB through a non-LYR binding site, and utilizes its own LYR
motif to position an ISCU-HSC20-HSPA9 complex" PMID:24606901.
- "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" [PMID:26749241 abstract, publications/PMID_26749241.md].
Core BP = mitochondrial respiratory chain complex II assembly (GO:0034553). This is the
exact term used in both GOA (IMP PMID:19465911; IBA; IEA) and in the UniProt DR GO line
(GO:0034553 IMP:UniProtKB). Verified current/non-obsolete via OLS. The founding paper showed
loss-of-function causes SDH deficiency, rescued by wild-type re-expression:
- "SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective
infantile leukoencephalopathy ... SDHAF1 is the first bona fide SDH assembly factor
reported in any organism" [PMID:19465911 abstract].
- "SDH activity and amount were restored in mutant fibroblasts proportionally with
re-expression of the wild-type gene" PMID:19465911.
Mitochondrial matrix (SL-0170 -> GO:0005759) and mitochondrion (GO:0005739). UniProt DR GO
gives GO:0005739 IDA:UniProtKB and GO:0005759 TAS:Reactome. GOA also has HPA IDA
(GO_REF:0000052), FlyBase HTP (PMID:34800366 mito proteome), and IDA PMID:19465911 to
mitochondrion. All consistent; matrix is the more specific/accurate compartment.
- "SUBCELLULAR LOCATION: Mitochondrion matrix" [file:human/SDHAF1/SDHAF1-uniprot.txt].
GOA carries several bare GO:0005515 "protein binding" IPI annotations from IntAct-curated
interaction datasets:
- PMID:24606901 with SDHB (P21912) and HSCB/HSC20 (Q8IWL3) — the functionally meaningful
interactions (substrate + co-chaperone).
- PMID:26749241 with SDHB (P21912) and HSCB (Q8IWL3) — disease-mechanism paper.
- PMID:28380382 with HSCB (Q8IWL3) — HSC20-centered Fe-S delivery paper.
- PMID:32296183 (HuRI binary interactome) with KRT27 (Q7Z3Y8) and CIDEB (Q9UHD4) —
large-scale Y2H; keratin/CIDEB are not biologically meaningful partners for a matrix
assembly factor (likely screen artifacts / non-physiological).
- PMID:33961781 (BioPlex) with SDHB (P21912).
Per policy, IPI "protein binding" annotations are not removed; the meaningful ones
(SDHB, HSCB) are kept as non-core (they underpin, but are less informative than, the
GO:0051087 chaperone-binding MF), and the large-scale screen hits (KRT27, CIDEB) are
marked as over-annotated because "protein binding" is uninformative and the partners are
not physiologically relevant to SDHAF1's matrix assembly-factor role.
Biallelic SDHAF1 variants cause mitochondrial complex II deficiency, nuclear type 2
(MC2DN2; MIM 619166) = infantile leukoencephalopathy with succinate accumulation; riboflavin
responsive [file:human/SDHAF1/SDHAF1-uniprot.txt; PMID:26749241 abstract].