OCA6 (YDR067C) — S. cerevisiae — curation notes

Reviewer journal. Provenance recorded inline as [PMID:xxxx "verbatim supporting text"] or [source URL].
This is a DARK / understudied gene: the primary deliverable is an honest knowledge_gaps section
plus carefully-reasoned description/core_functions grounded in domain, orthology, and literature.
OCA6-specific evidence is carefully separated from evidence about other OCA-family members.

Identity

• UniProt: Q12454 (OCA6_YEAST), 224 aa, MW ~26 kDa.
• Systematic name: YDR067C; SGD: S000002474; standard name OCA6 = "Oxidant-induced Cell-cycle Arrest protein 6".
• UniProt RecName: "Putative tyrosine-protein phosphatase OCA6"; EC=3.1.3.48 (marked Putative).
• PANTHER family PTHR31126 (TYROSINE-PROTEIN PHOSPHATASE); subfamily PTHR31126:SF14 (TYROSINE-PROTEIN PHOSPHATASE OCA6-RELATED).
• CDD: cd17663 = PFA-DSP_Oca6 (Plant-and-Fungi Atypical Dual-Specificity Phosphatase, Oca6 clade).
• Pfam: PF03162 (Y_phosphatase2 / Siw14-like); InterPro IPR004861 (Siw14-like), IPR029021 (PTP-like fold),
  IPR020422 (TYR_PHOSPHATASE_DUAL). Gene3D 3.90.190.10 (PTP superfamily fold). SUPFAM SSF52799.

Domain / catalytic-motif analysis (done INLINE from OCA6-uniprot.txt sequence)

Full sequence (224 aa):

MTLVTPLQFS TVQPNLYRGS YPREINLPFL RTLRLKYILS LTPEPLSTDP   (1-50)
LMVKFCEENN IKTIHIKCQS ERKADKTKPK IKRKKKTVPI EYDVVVRCVK   (51-100)
FLIDKGHYPC YMHCTNGELI ISLVVACMRK FSYWSTVSIL NEFLVYNSSI   (101-150)
NIHERNFIEN FNSEIEVDDL DIKDKVPWIT VRYIARTATE SKDELRVDDA   (151-200)
NASEKVARVS SVSNSLPKLK FHSM                               (201-224)

• UniProt annotates a single PTP DOMAIN (residues 8–170) and ACT_SITE at Cys114 ("Phosphocysteine intermediate",
  ECO:0000255 PROSITE-ProRule PRU00160 — i.e. a rule/profile prediction, NOT experimental).
• The catalytic P-loop of PTP/DSP enzymes (and of the PFA-DSP family specifically) is the CX5R signature:
  the nucleophilic Cys, then five residues, then an invariant Arg that binds the substrate phosphate.
  [CDD PFA-DSP family: "C x x x x x R" active site, 7 residue positions — https://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=350351]
• Inline finding: OCA6 has NO intact CX5R motif. Region around the predicted catalytic Cys is
  ...HYP C(110) YMH C(114) TNGELI I(120) I(121) S.... Taking Cys114 as the nucleophile, positions 115–120 are
  T-N-G-E-L-I; the P-loop +6 position (where the invariant catalytic Arg must sit) is Ile120, not Arg.
  A regex scan of the whole protein for C.{5}R (CX5R) and HC.{5}R returns zero matches anywhere.
  All Cys are at 56,68,98,110,114,127; all Arg at 18,23,31,34,72,83,97,129,155,182,186,196,208 — none form a CX5R.

• Interpretation: the invariant P-loop arginine of the CX5R catalytic loop appears absent/substituted in OCA6.
  This is the classic signature of a pseudophosphatase (fold retained, catalytic machinery degenerate).
  This is my own sequence-level analysis; it should be treated as strong but not laboratory-confirmed.

• Independent literature corroboration of a degenerate motif in OCA6:
  the 2026 fungal pseudophosphatome analysis reports that the Oca family is a CC1/DUSP-type
  fungal pseudophosphatase group, and specifically that Oca1, Oca2 and Oca6 have substitutions
  in the core catalytic motif.
  PMID:42222812

• CAVEAT: active-site substitutions do not prove inactivity in every PFA-DSP-family enzyme.
  PMID:42222812 notes that fungal pseudophosphatase active-site mutations can produce
  "loss of activity, retained activity, or lineage-specific functional divergence". The
  Oca-family evidence nevertheless weighs against a positive phosphatase annotation for
  OCA6: Oca1, from the same Oca1/Oca2/Oca6 substitution group, was experimentally inactive
  in PMID:21409566; PMID:42222812 and the newer PP-InsP review PMID:42347707 both classify
  Oca proteins with active-site substitutions as predicted pseudophosphatases; and no paper
  in the cache directly measures OCA6 catalytic activity.
• MOD_RES: Thr2 phosphorylated (large-scale phosphoproteomics) PMID:18407956. Peripheral to function.

What is KNOWN about OCA6 specifically (with attribution)

1. Subcellular location = cytoplasm. Genome-wide GFP-fusion localization.
   [PMID:14562095 — "Global analysis of protein localization in budding yeast"; abstract-only cache].
   GOA carries this as HDA (cytoplasm) plus a UniProt IEA (SubCell) duplicate.
2. Deletion reduces Brome mosaic virus (BMV) RNA replication in yeast. OCA6 is one of ~100 host genes from a
   genome-wide single-gene-deletion screen whose loss altered BMV replication.
   [PMID:14671320 — "Systematic, genome-wide identification of host genes affecting replication of a
   positive-strand RNA virus"; abstract-only]. This is a low-specificity, high-throughput hit; the abstract does
   NOT describe an OCA6-specific mechanism ("nearly 100 genes whose absence inhibited or stimulated BMV RNA
   replication"). UniProt promotes this to -!- FUNCTION: Required for replication of Brome mosaic virus (BMV)
   with ECO:0000269, but it is a screen-level phenotype, not a demonstrated biochemical role.
3. OCA6 is a member of the fungal OCA family of PFA-DSP-related atypical DSPs.
   [PMID:21409566 — "novel PFA-DSP-related proteins in fungi (Oca1, Oca2, Oca4 and Oca6 in Saccharomyces
   cerevisiae)"; "The closest yeast homolog for these proteins was the PFA-DSP from S. cerevisiae
   ScPFA-DSP1/Siw14/Oca3."].
4. OCA6 participates in caffeine/rapamycin stress responses, genetically linked to the OCA family.
   [PMID:21409566 — "Oca1, Oca2, Siw14/Oca3, Oca4, and Oca6 were involved in the yeast response to caffeine and
   rapamycin stresses"; "overexpression of Siw14/Oca3 suppressed the caffeine sensitivity of oca1, oca2, oca4,
   and oca6 deleted strains, indicating a genetic linkage and suggesting a functional relationship for these
   proteins."]. So OCA6-null caffeine sensitivity is rescued by the active paralog Siw14 — consistent with OCA6
   working in a shared pathway rather than providing unique catalysis.
5. SGD phenotype survey (large-scale): oca6Δ shows decreased oxidative-stress resistance, decreased chemical
   resistance, abnormal chemical-compound accumulation, decreased competitive fitness, vacuolar morphology
   abnormalities. [SGD locus S000002474, https://www.yeastgenome.org/locus/S000002474 — SGD summarizes
   "biological role is unknown"; molecular function ND].
6. OCA "complex". Transcriptional profiles of oca1/oca2/oca3(SIW14)/oca5/oca6 deletion strains are highly
   similar and there is evidence for physical interactions among OCA proteins — hence the "OCA complex" framing.
   [web summary of high-throughput yeast complex/chemical-stress mapping; PMID:22282571 (Hillenmeyer et al. /
   related large-scale complex mapping) — NOT directly quoted from cache; treat as supporting, not primary].

What is NOT known about OCA6 (knowledge gaps)

• Is OCA6 catalytically active? No direct assay of OCA6 phosphatase activity exists in the cache. The 2011
  paper measured Siw14 (active) and Oca1 (inactive), NOT OCA6. Sequence analysis (no CX5R Arg) and the
  pseudophosphatase-scanner classification both point to likely catalytically dead / pseudophosphatase, but this
  is inferred, not measured.
• What is its physiological substrate? The active family prototype Siw14/Oca3 is a 5-InsP7 inositol
  pyrophosphate phosphatase (not a protein-tyrosine phosphatase). Whether OCA6 has any residual activity on
  inositol pyrophosphates, on a phosphoprotein, or acts purely as a non-catalytic scaffold/regulator within the
  OCA complex is unknown.
• Its specific role in the OCA complex / oxidative-stress response. The "OCA" (oxidant-induced cell-cycle
  arrest) name derives from OCA1/YNL099C [PMID:11408586, Alic et al. 2001: YNL099C required for G1 arrest on
  linoleic-acid-hydroperoxide]. OCA6 was named by family membership; there is no direct demonstration that OCA6
  itself mediates oxidant-induced cell-cycle arrest. Whether OCA6 is a catalytic subunit, a regulatory subunit,
  or functionally redundant within the complex is unresolved.
• Mechanism of the BMV-replication phenotype. Whether OCA6 acts directly on viral replication or indirectly
  (via stress signaling / membrane lipid / inositol-pyrophosphate homeostasis) is unknown.

Attribution discipline: OCA6 vs other OCA members

• Siw14/Oca3: the biochemically characterized active PFA-DSP (5-InsP7 phosphatase). Do NOT transfer its
  measured catalytic activity to OCA6.
• Oca1/YNL099C: founding OCA gene (oxidant-induced G1 arrest); shown catalytically inactive in vitro.
• Oca2, Oca4, Oca5: other family members; Oca4 has lost its catalytic motif; Oca5 reported as an inositol
  pyrophosphatase in another study. None of their specific data should be attributed to OCA6.
• OCA6-specific direct evidence is limited to: cytoplasmic localization (HTP), BMV-screen phenotype,
  caffeine-sensitivity/genetic-linkage as an oca6Δ member of the family, SGD phenotype survey, and the Thr2
  phosphosite. Everything else is family-level or orthology-based inference.

Annotation review plan (6 GOA annotations)

1. GO:0016791 phosphatase activity (IBA, GO_REF:0000033) — family/fold supports a phosphatase-like domain; but
   catalytic Arg is degenerate. Keep as a cautious non-core general MF (KEEP_AS_NON_CORE) — IBA reflects the fold,
   and "phosphatase activity" is general enough to be defensible for the family; flag catalytic uncertainty in
   reason. (Do not promote to a specific PTP activity.)
2. GO:0004725 protein tyrosine phosphatase activity (IEA, GO_REF:0000120 = UniProtKB-EC from the Putative EC
   3.1.3.48) — this is the over-annotation. It asserts a specific protein-tyrosine-phosphatase catalysis that
   (a) is contradicted by the degenerate CX5R motif, and (b) is biochemically wrong even for the active family
   member (Siw14 is an inositol-pyrophosphate phosphatase, not a PTP). MARK_AS_OVER_ANNOTATED (specific PTP
   activity not supported; likely pseudophosphatase).
3. GO:0005737 cytoplasm (IEA, GO_REF:0000044 SubCell) — ACCEPT (or non-core); supported.
4. GO:0005737 cytoplasm (HDA, PMID:14562095) — ACCEPT; direct HTP localization evidence, this is the core CC.
5. GO:0003674 molecular_function (ND, GO_REF:0000015) — ACCEPT as ND placeholder (SGD's honest "unknown").
6. GO:0008150 biological_process (ND, GO_REF:0000015) — ACCEPT as ND placeholder.

Core function: uncertain molecular function within a PTP-superfamily / PFA-DSP fold, acting in the cytoplasm as
a member of the OCA family implicated in caffeine/rapamycin and oxidative-stress responses; likely a
pseudophosphatase (degenerate CX5R). Location cytoplasm is the one high-confidence attribute.

Deep research (infra failure — documented, not fabricated)

Automated deep research could not be produced for OCA6:
- just deep-research-falcon yeast OCA6 --fallback perplexity-lite was run TWICE (initial + one retry per policy).
Both runs HUNG with no output and were killed (~20 min then an 8-min bounded retry; SIGTERM exit 143).
- The perplexity-lite fallback returned HTTP 401 insufficient_quota (Perplexity API out of quota).

Per repository policy I did NOT fabricate a -deep-research-{provider}.md file. All findings in this review are
grounded directly in: the cached UniProt record (Q12454), the GOA TSV, cached PMIDs
(14562095, 14671320, 21409566, 42222812, 18407956, 11408586), SGD (S000002474), CDD (cd17663 / PFA-DSP family),
PANTHER (PTHR31126 / SF14), and the reviewer's own inline CX5R catalytic-motif analysis of the UniProt sequence.
The review therefore does not depend on an automated deep-research file.

2026-09-28 IBA/new-literature re-review

• OCA6 has one current IBA: broad GO:0016791 phosphatase activity transferred from
  PANTHER:PTN001258896.
• The current PTHR31126 PAINT cache shows that PTN001258896 is the IBD node for the broad
  phosphatase activity assertion across bacterial, plant, protozoan, and fungal family members.
• New 2026 paper PMID:42222812 is now cached with PMC full text. It independently supports the
  pseudophosphatase interpretation by placing Oca1/Oca2/Oca6 in the CC1-Oca pseudophosphatase
  group with core catalytic-motif substitutions.
• The September 2026 FEBS Letters review PMID:42347707 is also cached with PMC full text.
  It independently frames the S. cerevisiae OCA clade as PFA-DSP-related predicted
  pseudophosphatases, including Oca6, due to active-site substitutions.
• The IBA should therefore be treated as a pseudoenzyme propagation failure for OCA6, not as a
  weak-source or short-donor-list problem.

ND literature-search citations (2026-11-06)

• existing_annotations[5], GO:0008150 biological_process (ND, GO_REF:0000015), ACCEPT: the ND may be stale. These notes cite PMID:21409566, a study of the yeast OCA family that reports oca6 deletion strains are caffeine-sensitive and that Oca6 is "involved in the yeast response to caffeine and rapamycin stresses", and PMID:14671320, a genome-wide deletion screen in which loss of OCA6 changes Brome mosaic virus RNA replication. Both are phenotypes for this gene product in S. cerevisiae tied to a process, so a curator should decide whether either supports a BP annotation (for example a caffeine-response term from PMID:21409566). The review action was left unchanged.