AIM6 (YDL237W) — curation notes

Journal of research for the AI GO-annotation review of Saccharomyces cerevisiae AIM6.

Identity (verified from UniProt record)

• UniProt: Q07716 (AIM6_YEAST), reviewed, 390 aa, PE=1 (evidence at protein level).
• SGD systematic name: YDL237W; standard name AIM6; SGD:S000002396.
• Name: "Altered inheritance of mitochondria protein 6" (UniProt) / "Altered Inheritance rate of Mitochondria" (SGD). The AIM series was named in the mitochondrial-biogenesis screen of PMID:19300474.
• Flags: Precursor; predicted N-terminal signal peptide 1–17 (ECO:0000255), mature chain 18–390 (PRO_0000242484). Keyword: Signal.
• Family: "Belongs to the AIM6 family" (a UniProt family essentially defined by this protein and close fungal orthologs, not a characterized enzyme family).

Domain / fold reasoning (done inline from UniProt DR lines + InterPro API)

InterPro domain matches for Q07716 (from InterPro REST API):
- IPR017946 homologous_superfamily — "PLC-like phosphodiesterase, TIM beta/alpha-barrel domain superfamily", residues 117–385.
- IPR039559 domain — "Altered inheritance of mitochondria protein 6, PI-PLC-like catalytic domain", residues 115–382.
- IPR051236 family — "Histone acetyltransferase RTT109-like", residues 80–387.
- CDD: cd08577 = "PI-PLCc_GDPD_SF_unchar3" ("Uncharacterized hypothetical proteins similar to the catalytic domains of Phosphoinositide-specific phospholipase and Glycerophosphodiester phosphodiesterases").
- SUPFAM: SSF51695 (PLC-like phosphodiesterases). PANTHER: PTHR31571 "ALTERED INHERITANCE OF MITOCHONDRIA PROTEIN 6".

Interpretation:
- The mature protein is essentially one domain adopting the PLC-like phosphodiesterase TIM (β/α)8-barrel fold — the fold shared by phosphoinositide-specific phospholipase C (PI-PLC) and glycerophosphodiester phosphodiesterases (GDPD). This is the structural basis for the IEA MF annotation GO:0008081 "phosphoric diester hydrolase activity".
- InterPro itself states "The function of Aim6 is not clear", and the CDD source group is explicitly labelled "uncharacterized". So the phosphodiesterase activity is a fold-level homology prediction only, from a divergent, uncharacterized subgroup — not an experimentally established activity, and the substrate/specificity is unknown.
- The IPR051236 "Histone acetyltransferase RTT109-like" family match is a noisy/over-broad PANTHER grouping; it does NOT imply AIM6 is a histone acetyltransferase (RTT109 is nuclear; AIM6 carries a secretory signal peptide, incompatible with a nucleosomal HAT). Do not annotate to acetyltransferase on this basis.

Inline check of catalytic residues (script over the sequence): the catalytic-domain region carries conserved His/Asp residues consistent with the fold, notably an "HSHND" motif at H118-S119-H120-N121-D122 (GDPD/PLC-superfamily catalytic-type residues sit at the N-terminal end of the barrel), plus H156 (GHNEAY), H313/H318 (HCGSDHWK), H343 (GAHAL). So catalytic machinery is at least partially retained at the fold level — enough that the phosphodiesterase prediction cannot be confidently refuted as a dead pseudoenzyme, but there is no positive evidence for any catalytic activity, substrate, or the "lipid metabolic process" leap.

What is KNOWN (experimental)

• Disruption phenotype: impairs respiratory growth (UniProt CC, ECO:0000269|PubMed:19300474). AIM6/YDL237W was one of the previously uncharacterized ORFs whose deletion gave a mitochondrial-biogenesis/petite phenotype in the Hess et al. quantitative screen. Note: the per-gene datum sits in that paper's Table S2 (not in the cached full text); the cached full text establishes the screen and its phenotype interpretations but does not name YDL237W/AIM6 in the running text.
• PMID:19300474
• The screen explicitly cautions the phenotype does not prove a direct mitochondrial molecular role: PMID:19300474 and PMID:19300474.
• SGD locus summary (web, 2026): "Protein whose biological role and cellular location are unknown." Verified ORF, non-essential. Additional deletion phenotypes catalogued at SGD (from various high-throughput datasets): inability to grow on glycerol, increased competitive fitness on fermentable medium, altered heat-stress survival, decreased H2S production with excess cysteine — all HTP, none establishing a molecular function.
• Protein-level evidence (PE=1): detected by mass spectrometry (PMID:29897761, proteogenomics of S. cerevisiae) and present in abundance datasets (~6,000 molecules/cell per SGD). Confirms the protein exists and is expressed; says nothing about function.

What is NOT known

• Molecular function: unknown. Only a fold-based PI-PLC/GDPD-like phosphodiesterase prediction (IEA). No demonstrated catalytic activity, no substrate, no assay. The specific claim "phosphoric diester hydrolase" and the "lipid metabolic process" inference (borrowing PI-PLC's lipid substrate) are unsupported over-reaches from the divergent fold.
• Cellular localization: unknown/unresolved. UniProt gives no subcellular-location CC. There is a predicted N-terminal signal peptide (suggesting entry into the secretory pathway / a non-cytosolic destination), which is hard to reconcile with a direct intramitochondrial role — so the mitochondrial phenotype is plausibly indirect. SGD: "cellular location ... unknown."
• Biological role / mechanism behind the AIM screen phenotype: unknown. The petite/respiratory phenotype places AIM6 loss upstream of normal respiratory competence, but whether this is a direct role in mitochondrial biogenesis or an indirect/pleiotropic effect (e.g. via a secretory-pathway or lipid-related activity) is undetermined.

Annotation plan

GOA has 5 annotations:
1. GO:0006629 lipid metabolic process — IEA (InterPro, IPR017946). MARK_AS_OVER_ANNOTATED: extrapolates PI-PLC's lipid role to a divergent uncharacterized domain; no evidence AIM6 acts on lipids.
2. GO:0008081 phosphoric diester hydrolase activity — IEA (InterPro, IPR017946). UNDECIDED/MARK_AS_OVER_ANNOTATED: fold-level prediction from an "uncharacterized" CDD group; retain awareness but not as a confident core function.
3. GO:0003674 molecular_function — ND (SGD). ACCEPT (root/ND placeholder; correctly signals unknown MF).
4. GO:0005575 cellular_component — ND (SGD). ACCEPT (root/ND placeholder).
5. GO:0008150 biological_process — ND (SGD). ACCEPT (root/ND placeholder).

core_functions: minimal/none with confidence (dark gene). knowledge_gaps is the primary deliverable.

Deep research provenance

Falcon deep research was attempted twice (just deep-research-falcon yeast AIM6) and both attempts
failed: first attempt timed out after 600s (Edison/falcon endpoint) and the perplexity-lite fallback
returned HTTP 401 (quota exceeded); retry disconnected (RemoteProtocolError, exit 143). No
AIM6-deep-research-*.md file was produced, and per project policy I did NOT fabricate one. This
review is therefore grounded in: the UniProt record (Q07716), the GOA TSV, the cached full text of
PMID:19300474 (verbatim-quoted), and manually verified public resources (SGD locus page, InterPro
IPR039559 / IPR017946 REST API, CDD cd08577, PANTHER PTHR31571). All non-PMID assertions are recorded
here with their source.