MOH1 (YBL049W, P38191) — research notes

Research journal for the AI GO-annotation review. MOH1 is a genuinely
understudied ("dark") S. cerevisiae gene. This file separates what is KNOWN
from what is NOT known, with inline provenance.

Identity / basic facts (KNOWN)

• UniProt P38191, gene MOH1, systematic name YBL049W (chromosome II,
  left arm). 138 aa, 16 kDa. SGD S000000145. Verified ORF, protein of
  unknown function (SGD).
• Member of the Yippee family (UniProt SIMILARITY: "Belongs to the yippee
  family"). InterPro: IPR034751 (Yippee), IPR004910 (Yippee/Mis18/Cereblon),
  IPR039058 (Yippee_fam); Pfam PF03226 (Yippee-Mis18); PROSITE PS51792 (YIPPEE);
  PANTHER PTHR13848.
• Single yeast ortholog of the human YPEL1–YPEL5 family. The human paralogs
  arose by gene duplication; yeast has one member.

Domain / molecular architecture (KNOWN, independently verified)

• UniProt annotates a Yippee domain (residues 41–138) with a structural
  Zn(2+) site coordinated by Cys45, Cys48, Cys101, Cys104 (ProRule
  PRU01128).
• My own bioinformatics analysis (MOH1-bioinformatics/) independently
  confirms the Yippee zinc signature: two CxxC pairs C45-x2-C48 … C101-x2-C104
  separated by a 52-residue spacer — the canonical Yippee motif
  (Cys-X₂-Cys-X₅₂-Cys-X₂-Cys). See file:yeast/MOH1/MOH1-bioinformatics/RESULTS.md.
• Conservation vs human YPEL1–5: ~37–45% identity; all four Zn-cysteines are
  perfectly conserved in every human ortholog, supporting a retained structural
  zinc site. (Bioinformatics RESULTS.md.)
• The Yippee/Mis18/CULT fold is a zinc-stabilized β-fold with a cradle-shaped
  pocket implicated in protein/nucleic-acid binding — a binding/scaffold module,
  not a recognized catalytic fold. No EC number; no catalytic motif detected.
  PMID:11240639

What the primary literature actually establishes

Ashrafi, Farazi & Gordon 1998 (JBC) — the founding paper (KNOWN, but indirect)

• MOH1/YBL049W was identified as a putative N-myristoylprotein whose deletion
  (in NMT1 cells) mimics the starvation-sensitive phenotype of an nmt1 mutant.
  PMID:9748261
• The paper's parenthetical "(homology to Snf7p)" is an early, superseded
  homology guess; the protein was later recognized as a Yippee-family member.
• This links MOH1 (phenotypically) to maintenance of proliferative potential /
  survival during stationary phase, not to a molecular activity.
  [PMID:9748261 "specific N-myristoylproteins contribute to stationary-phase
  survival" — paraphrase; verbatim: "These proteins provide opportunities to
  further define the molecular mechanisms that regulate survival during stationary
  phase"]
• NOTE: whether Moh1 is genuinely N-myristoylated in vivo was inferred from a
  genome-wide sequence search for Nmt substrates plus deletion phenotype, not
  demonstrated biochemically here. Treat "N-myristoylprotein" as predicted.

Lee et al. 2017 (J Microbiol Biotechnol) — the "pro-apoptotic" paper (KNOWN, moderate quality)

• Basis for UniProt's "Pro-Apoptotic protein MOH1" RecName and the Apoptosis
  keyword. moh1Δ shows enhanced viability under apoptogenic stress (UV, MMS,
  camptothecin, 50°C heat shock, 1.2 M KCl), and Moh1 protein is up-regulated
  under stress. PMID:28173693
• Human YPEL5 (and other YPELs) partially complement moh1Δ; YPEL5 conferred
  UV sensitivity similar to WT-MOH1. PMID:28173693
• Authors frame this as "mitochondria-dependent apoptosis induced by DNA damage."
  PMID:28173693
• CAVEAT (my judgment): "yeast apoptosis" / metacaspase-dependent regulated cell
  death is a contested framework; the assay is a heterologous-complementation
  viability study, abstract-only in our cache. The robust, model-independent
  observation is that moh1Δ increases stress resistance and Moh1 is
  stress-induced — i.e. Moh1 sensitizes cells to lethal stress. The molecular
  mechanism is not established. This is a "pro-death phenotype," not a demonstrated
  molecular activity, and does not by itself justify a GO apoptosis annotation for
  a yeast gene.

Roxström-Lindquist & Faye 2001 (Insect Mol Biol) — family founding paper (KNOWN, context)

• Defines the Yippee family; Drosophila Yippee found as interactor of Hemolin;
  "putative zinc-finger-like metal binding domain"; family conserved slime-mould
  → human. Human clone 76% identical to Drosophila Yippee.
  PMID:11240639
• Even the founding family paper leaves molecular function open:
  PMID:11240639.

Wang et al. 2018 (Metallomics) — the RCA zinc annotation source (KNOWN, computational)

• GO:0008270 (zinc ion binding, RCA, PMID:30358795) derives from a proteome-wide
  bioinformatic + MS survey of the yeast zinc proteome; MOH1 is included among 582
  known/potential zinc-binding proteins by domain/motif prediction, not by direct
  metal-binding assay of Moh1. PMID:30358795

Olgun et al. 2025 (bioRxiv preprint 10.1101/2025.10.30.685511) — most recent (KNOWN, NOT peer-reviewed)

• Title: "Yippee-like protein Moh1 links gene expression to metabolism and
  selective stress resistance in Saccharomyces cerevisiae." Preprint, no PMID.
• Reports: moh1Δ increases sensitivity to sodium azide and sulfuric acid but
  increases resistance to H2O2 and acetic acid; H2O2 resistance attributed to
  decreased cellular uptake from altered membrane permeability, not lowered
  mitochondrial ROS; transcriptional reprogramming + metabolic remodeling (lipids,
  proteins, cell-wall polysaccharides).
• This reinforces a role in stress resistance / membrane and metabolic
  remodeling but still does not assign a molecular activity. Because it is a
  non-peer-reviewed preprint with no PMID, it is used here for context/knowledge-gap
  framing only (status CLOSING/NARROWING for some gaps), NOT as the basis of a
  positive GO core function. Verbatim quoting deferred (no cached full text; the
  reference validator only checks PMID/file: quotes).

SGD-curated phenotypes (KNOWN, from SGD locus S000000145)

• Null mutant: increased innate thermotolerance, increased chemical resistance,
  increased UV resistance, decreased stationary-phase survival, decreased
  chronological lifespan, increased competitive fitness; haploinsufficient;
  abnormal vacuolar morphology; decreased vegetative growth (large-scale).
• Interactions: ~49 total (11 affinity-capture-MS, 26 negative genetic, 8 positive
  genetic, etc.) — no single strong, function-defining partner has emerged.
• "Essential for stationary-phase survival; not required for growth on
  nonfermentable carbon sources; possibly linked with vacuolar transport" (SGD).

Synthesis of KNOWN

MOH1 is a small, low-abundance, cytoplasmic (inferred) Yippee-family zinc-binding
protein — the single yeast representative of the metazoan YPEL family. Its
structural Zn(2+) site is intact and deeply conserved. Loss of MOH1 makes cells
more resistant to multiple lethal stresses (UV, MMS, CPT, heat, hyperosmotic,
H2O2, acetic acid) while impairing long-term stationary-phase/chronological
survival; Moh1 is stress-induced. It is functionally interchangeable enough with
human YPEL5 for partial cross-complementation.

What is NOT known (the deliverable)

1. Molecular activity. No biochemical activity is demonstrated. Zinc binding
   (GO:0008270) is predicted from the domain, and the fold is a putative
   binding/scaffold module, but what Moh1 does biochemically (binds what? acts
   on what?) is unknown. No catalytic activity is supported.
2. Direct physical partners / substrates. Despite ~49 recorded interactions,
   no functionally validated, direct partner or cargo is established. The
   Drosophila Yippee–Hemolin interaction has no yeast counterpart.
3. Mechanism linking Moh1 to stress resistance and stationary-phase survival.
   Why does deletion increase acute stress resistance yet decrease long-term
   survival? The 2025 preprint proposes altered membrane permeability/metabolic
   remodeling, but the causal molecular step (and whether Moh1 acts directly on
   membranes, transcription, or metabolism) is undetermined.
4. Whether the "pro-apoptotic"/regulated-cell-death framing is the correct
   biological process. The apoptosis label rests on one heterologous
   complementation study in a contested yeast-apoptosis paradigm.
5. Subcellular localization. No reliable curated localization; UniProt/GOA
   record cellular_component unknown (ND). "Possibly linked with vacuolar
   transport" (SGD) is a hypothesis.
6. Whether Moh1 is actually N-myristoylated in vivo (predicted in 1998; not
   biochemically confirmed).

Annotation-review plan

• GO:0000151 ubiquitin ligase complex (IBA, GO_REF:0000033, from PANTHER node
  PTN002302768 seeded by human YPEL5 P62699): scrutinize. No yeast evidence
  places Moh1 in a ubiquitin-ligase complex; the IBA is a family-level
  propagation from the Mis18/cereblon(CULT) neighborhood. The Yippee fold is
  related to cereblon's thalidomide-binding CULT domain (which is a substrate
  receptor of a CRL4 E3), but Moh1/YPEL proteins are not established E3 components.
  Lean MARK_AS_OVER_ANNOTATED (family over-propagation; not core), unless deep
  research surfaces yeast evidence.
• GO:0008270 zinc ion binding (RCA, PMID:30358795): KEEP — corroborated by
  UniProt features and my bioinformatics; the only defensible molecular function.
  Structural zinc, so KEEP_AS_NON_CORE / ACCEPT (it is the core molecular feature
  even if biochemical output is unknown).
• GO:0005575 cellular_component (ND) and GO:0008150 biological_process (ND):
  root/placeholder ND annotations — ACCEPT as-is (standard ND practice; they
  correctly record "unknown").

Martinez et al. 2004 (Mol Biol Cell) — dedicated stationary-phase genetics (KNOWN)

• Surfaced by the falcon deep-research report and added as PMID:15456898. Genome-wide
  stationary-phase study that identified 32 genes essential for survival in stationary
  phase at 37C; MOH1 is among the stationary-phase-essential set and is NOT required
  for growth on nonfermentable carbon sources — i.e. a specific quiescence-survival
  role, not a generic respiratory defect. PMID:15456898. (MOH1-specific numbers are in the full text; the
  cached record is abstract-only.) The paper also (per full text, via falcon) still
  described Moh1p using the superseded "related to Snf7p" homology and as a
  "myristolated protein of unknown function."

Deep research outcome (falcon)

The falcon deep-research job completed successfully (~1553 s, Edison Scientific
model, 26 citations) → MOH1-deep-research-falcon.md. It is on the correct gene
and organism and independently corroborates every substantive conclusion here: the
Yippee/Mis18/Cereblon β-tent fold with a Zn-coordinating CXXC pair and a
cradle-shaped binding pocket; MOH1 as the single yeast member of the human YPEL1–5
family; stationary-phase-survival requirement (Martinez 2004); and the explicit
conclusion that "MOH1 is not an enzyme, transporter, or structural protein in the
classical sense" but a "small regulatory or adaptor protein" whose "precise
biochemical activity in budding yeast remains unresolved." It adds context sources
(Mis18 centromere biology, cereblon/CULT, FAM72, C. glabrata MOH1 Y5H variant that
did NOT confer echinocandin resistance) but no new yeast molecular function.

Provenance discipline note

Cached publications are abstract-only (full_text_available: false for
PMID:9748261, 28173693, 30358795, 11240639, 15456898). All PMID supporting_text
quotes are verbatim substrings of the cached abstracts (grep-verified). The 2025
bioRxiv preprint has no PMID and no cached full text; it is cited as context only in
prose, with no fabricated quotes. file: quotes (bioinformatics RESULTS.md, falcon
report) were grep-verified as verbatim substrings before use.