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• The paper's parenthetical "(homology to Snf7p)" is an early, superseded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. 2026 (Microbial Cell, PMID:42404825) — most recent (KNOWN, peer-reviewed)

• Title: "Yippee-like protein Moh1 links gene expression to metabolism and
  selective stress resistance in Saccharomyces cerevisiae."
• 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).
• The Discussion summarizes prior AP-MS evidence that Moh1p associates with
  CCT2/CCT3 and multiple core GID subunits; GID is the yeast multisubunit
  E3 ubiquitin ligase, so this changes the GO:0000151 call from family
  over-propagation to a plausible but accessory/conditional complex association.
• This reinforces a role in stress resistance / membrane and metabolic
  remodeling but still does not assign a molecular activity. The peer-reviewed
  paper was published after the initial MOH1 review and is now cached as full text.

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. CCT2/CCT3
   and core GID subunits are now the leading co-purification candidates. 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 2026 Microbial Cell paper shows altered membrane
   permeability/metabolic remodeling, but the causal molecular step (and whether
   Moh1 acts directly through GID, CCT, 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): KEEP_AS_NON_CORE. QuickGO
  confirms that the PAINT node also gives YPEL5 this term, UniProt places YPEL5 in
  the human CTLH E3 ligase complex with an ancillary role, and the 2026 MOH1 paper
  summarizes prior AP-MS association with multiple core yeast GID subunits. Moh1 is
  not in the structurally defined yeast GID core, so the IBA should be kept as a
  non-core contextual complex association.
• 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.

2026-10-01 - current GOA and IBA refresh

• Forced a current just fetch-gene yeast MOH1 --force refresh. Live GOA still
  has four MOH1 rows: GO:0000151 ubiquitin ligase complex by IBA,
  GO:0008270 zinc ion binding by RCA, and the standard SGD GO:0005575 and
  GO:0008150 ND placeholders. No newly seeded PENDING rows or stale retired
  rows were introduced.
• Rechecked the single IBA. GO:0000151 still comes from PANTHER:PTN002302768
  in the PTHR13848 Yippee family with human YPEL5 (UniProtKB:P62699) as the
  extant donor. The existing KEEP_AS_NON_CORE action remains appropriate:
  current evidence supports a plausible accessory/conditional Moh1 association
  with the yeast GID ubiquitin ligase complex, not a structurally defined core
  GID subunit role. Lampert et al. 2018 (PMID:29911972) directly support both
  sides of that boundary: YPEL5 clusters as a human GID subunit, whereas yeast
  Moh1 is dispensable for Fbp1 turnover in the canonical GID-substrate assay.
• The IBA propagation_review already traced the transfer to the PAINT ancestral
  node rather than treating YPEL5 as a source node. The forced fetch only
  backfilled supporting_entities so the live GOA PTN and donor accession are
  preserved explicitly.
• Refreshed UniProt to entry version 149. The live UniProt record no longer
  carries the older keyword-derived IEA GO cross-references to generic metal ion
  binding or apoptotic process; current GOA likewise has no live apoptotic-process
  assertion for MOH1.
• Re-read the cached 2026 Olgun et al. full text (PMID:42404825) and searched
  for newer direct MOH1/Moh1/YBL049W papers. No paper newer than Olgun et al. was
  found that changes the current curation boundary: Moh1 has strong stress and
  cell-envelope phenotypes but still lacks a direct ligand, biochemical output,
  and reliable subcellular localization.

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

• existing_annotations[3] GO:0008150 biological_process (ND) may be stale. Martinez et al. 2004 PMID:15456898 identify MOH1 as one of the genes essential for stationary-phase survival (moh1 deletion loses viability in stationary phase but grows on nonfermentable carbon), and Ashrafi et al. 1998 PMID:9748261 link its deletion to stationary-phase survival; this is a specific mutant phenotype in this species tied to a process (stationary-phase survival / cellular quiescence). A curator should decide whether this supports a process annotation; the row action is unchanged.