MOH1 (YBL049W) is a small (138 aa), low-abundance protein of the Yippee family, the single Saccharomyces cerevisiae representative of the family that expanded to the five YPEL paralogs (YPEL1-YPEL5) in humans. It comprises a Yippee/Mis18/Cereblon (CULT) fold — a zinc-stabilized double beta-meander that coordinates one structural Zn(2+) ion through four conserved cysteines (Cys45, Cys48, Cys101, Cys104) and presents a cradle-shaped pocket implicated in protein or nucleic-acid binding. The fold is a binding/scaffold module rather than a catalytic one, and no enzymatic activity has been demonstrated. Functionally, MOH1 is understudied: it is stress-inducible, and its deletion increases acute resistance to several lethal stresses (UV, methyl methanesulfonate, camptothecin, heat, hyperosmotic shock, hydrogen peroxide and acetic acid), increases sensitivity to sodium azide and sulfuric acid, remodels the cell envelope in a way that appears to reduce hydrogen-peroxide uptake, and impairs long-term stationary-phase and chronological survival. Human YPEL genes can partially substitute for MOH1, indicating conservation of function across the family. The direct molecular activity, subcellular site of action, and the mechanism linking MOH1 to stress tolerance and quiescence remain undetermined. Moh1 co-purifies with CCT/TRiC and GID-complex subunits, but its direct binding partner and its function in those complexes remain to be established.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000151 ubiquitin ligase complex | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Family-level phylogenetic propagation (IBA) from PANTHER PTN002302768, seeded by human YPEL5 (UniProtKB:P62699). YPEL5 is curated as an ancillary component of the human CTLH E3 ubiquitin ligase, and the single yeast ortholog Moh1 has reported AP-MS association with multiple core GID E3-ligase subunits. The transfer is therefore biologically plausible, but this is kept as non-core because Moh1 is not among the structurally defined core yeast GID components and has not yet been functionally validated as a GID subunit or regulator. Reason: The PAINT node links the YPEL5/Moh1 clade to the CTLH/GID E3-ligase complex rather than to a remote Mis18/cereblon structural neighborhood, and 2026 literature connects Moh1 to yeast GID co-purifications. Retain the component annotation as contextual, while not elevating an unvalidated accessory or conditional association to a core cellular component. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002302768 · Yippee-like ancestral node (PTHR13848) SUPPORTS TRANSFER Node seeded by human YPEL5 (UniProtKB:P62699), an ancillary CTLH E3-ligase-complex component. The single yeast ortholog Moh1 co-purifies with GID-complex subunits, supporting transfer as a non-core complex association. Supporting Evidence: PMID:42404825 Moh1p was reported to interact with the multiple core GID subunits by immuno-affinity purification coupled with mass spectrometry PMID:29911972 Moh1-deficient cells degrade TAP-tagged Fbp1 with wild-type kinetics |
| GO:0008270 zinc ion binding | RCA PMID:30358795 The cellular economy of the Saccharomyces cerevisiae zinc pr... | ACCEPT | Summary: Zinc ion binding is the single well-supported molecular feature of Moh1. It is predicted by proteome-wide domain/motif analysis (RCA, PMID:30358795), corroborated by the UniProt Zn(2+)-binding features (Cys45, Cys48, Cys101, Cys104) and independently by in-repo bioinformatics, which recovers the canonical Yippee two-CxxC zinc signature and shows perfect conservation of all four cysteines across human YPEL1-5. The bound zinc is structural (folds the Yippee domain); it is not evidence of a catalytic activity. Accepted as the core molecular feature, though the downstream biochemical output remains unknown. Supporting Evidence: PMID:30358795 582 known or potential zinc-binding proteins was identified using a bioinformatics analysis that combined global domain searches with local motif searches file:yeast/MOH1/MOH1-bioinformatics/RESULTS.md MOH1 contains exactly the two CxxC motifs that define the Yippee zinc site |
| GO:0005575 cellular_component | ND GO_REF:0000015 | ACCEPT | Summary: Root cellular_component annotation with the ND (no data) code, the standard placeholder recording that no experimental localization is available for Moh1. This correctly reflects the state of knowledge; high-throughput localization for this low-abundance protein is not curated. |
| GO:0008150 biological_process | ND GO_REF:0000015 | ACCEPT | Summary: Root biological_process annotation with the ND (no data) code. Although phenotypes are recorded (stress resistance, stationary-phase survival), no specific molecular biological process has been assigned to Moh1, so the ND placeholder is appropriate. Reason: Possibly stale: the 2026-11-06 ND citation pass found literature on this gene in this species that may identify a biological process; see MOH1-notes.md, section "ND literature-search citations (2026-11-06)". A curator should check it before this ACCEPT stands. |
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Download this section (compressed HTML)Q: What does the Yippee-domain pocket of Moh1 bind (protein, nucleic acid, small molecule), and does the bound zinc have any role beyond folding the domain?
Q: By what molecular mechanism does moh1 deletion simultaneously increase acute stress resistance and decrease long-term stationary-phase survival?
Q: Is the human YPEL family's proliferation/senescence role mechanistically the same as the yeast Moh1 stress/quiescence role, given cross-species complementation?
Experiment: Affinity-purify endogenously tagged Moh1 under basal and stress conditions and identify co-purifying proteins/nucleic acids by mass spectrometry and RNA sequencing; validate top candidates by reciprocal pulldown and epistasis with moh1delta stress phenotypes.
Hypothesis: Moh1 acts as a zinc-dependent binding module for a specific partner that mediates its stress-sensitizing function.
Type: interaction proteomics
Experiment: Construct Cys-to-Ala/Ser substitutions at Cys45/48/101/104, test protein stability and rescue of moh1delta stress phenotypes, to determine whether the zinc site is required for function in vivo.
Hypothesis: The four conserved cysteines are required for Moh1 function via structural zinc coordination.
Type: structure-function mutagenesis
Experiment: Measure intracellular ROS, H2O2 uptake kinetics, and membrane lipid/permeability in wild-type vs moh1delta cells, and combine those assays with structure-function MOH1 alleles to test the 2026 Olgun et al. cell-envelope model.
Hypothesis: moh1delta hydrogen-peroxide resistance stems from decreased uptake due to altered membrane permeability rather than altered ROS metabolism.
Type: cell physiology / permeability assay
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The molecular activity of Moh1 is undetermined. Beyond structural zinc binding by the Yippee domain, it is not known what Moh1 binds (protein? nucleic acid?) or what biochemical output, if any, the cradle-shaped Yippee pocket produces. No catalytic activity is supported.
OPEN BIOLOGY MF_DARK
What is known: The Yippee/Mis18/CULT fold and its structural Zn(2+) site (Cys45/48/101/104) are firmly established by UniProt features, PROSITE/Pfam/InterPro domain calls and independent in-repo bioinformatics; the fold is a zinc-stabilized binding scaffold, not a known catalytic fold.
Significance: Moh1 is the single yeast ortholog of the human YPEL family, which is implicated in proliferation, senescence and stress adaptation; defining the yeast protein's biochemistry would anchor mechanism for the whole conserved family.
What would resolve it: Biochemical identification of Moh1 ligands/substrates (e.g. interaction proteomics of tagged Moh1, in vitro binding assays with the purified Yippee domain, structural studies of the pocket) and tests for any enzymatic activity.
Provenance (the field's own admissions):
Gap: No functionally validated direct physical partner or substrate of Moh1 is known. CCT2/CCT3 and multiple core GID-complex subunits are now the strongest co-purification candidates, but the Drosophila Yippee-Hemolin interaction has no established yeast counterpart and Moh1's function in the CCT/GID network remains untested.
OPEN BIOLOGY MF_DARK
What is known: Large-scale interaction datasets (affinity-capture-MS, genetic interactions) exist for Moh1, Olgun et al. highlight prior AP-MS associations with CCT2/CCT3 and core GID E3-ligase subunits, and human YPEL proteins partially complement moh1delta, indicating a conserved but unspecified activity.
Significance: Identifying a direct partner would convert the family from "putative binding module" to a defined pathway component.
What would resolve it: Targeted co-purification/crosslinking-MS with tagged Moh1, and validation of candidate partners by reciprocal pulldown and phenotype epistasis.
Provenance (the field's own admissions):
Gap: The mechanism by which Moh1 shapes stress tolerance and quiescence is unknown. It is unexplained why loss of Moh1 increases acute resistance to several lethal stresses yet decreases long-term stationary-phase/chronological survival, and whether Moh1 acts directly on membranes, metabolism, transcription, or cell death machinery.
NARROWING BIOLOGY BP_DARK
What is known: The phenotypes are reproducible: moh1delta increases viability under UV, MMS, camptothecin, heat and hyperosmotic shock and is stress-induced (PMID:28173693); MOH1 is one of the stationary-phase-essential genes required for long-term survival in quiescence (PMID:15456898, PMID:9748261). Newer primary work shows that moh1delta cells have stress-specific permeability and cell-envelope phenotypes, including decreased intracellular hydrogen-peroxide accumulation through decreased uptake (PMID:42404825).
Significance: Resolving the mechanism would explain a conserved stress/aging factor and clarify whether the human YPEL "senescence/stress" phenotypes share this mechanism.
What would resolve it: Epistasis of moh1delta with defined stress-response and membrane/metabolic pathways, and Moh1 localization/partner studies that test whether the observed cell-envelope remodeling is a direct or downstream consequence of Moh1 loss.
Provenance (the field's own admissions):
Gap: Whether "apoptotic process"/regulated cell death is the correct biological-process framing for Moh1 is unresolved. The label derives from a single heterologous complementation study interpreted within the contested yeast programmed-cell-death paradigm.
OPEN BIOLOGY BP_DARK
What is known: It is established that Moh1 sensitizes cells to lethal stress (deletion is protective) and that human YPEL5 restores this sensitization; the interpretation as caspase/mitochondria-dependent apoptosis is the uncertain part.
Significance: Determines whether GO apoptosis/regulated-cell-death terms are appropriate for this gene and its orthologs.
What would resolve it: Independent replication with genetic dissection of the metacaspase (YCA1) and mitochondrial pathways, distinguishing bona fide regulated cell death from passive stress-induced death.
Provenance (the field's own admissions):
Gap: The subcellular site of Moh1 action is unknown; no reliable localization is curated, and the GOA cellular_component annotation is ND.
OPEN BIOLOGY CC_DARK
What is known: Moh1 is a low-abundance soluble protein; SGD notes a possible link to vacuolar transport and an abnormal-vacuolar-morphology deletion phenotype, but these are hypotheses, not localization data.
Significance: Localization would constrain candidate functions (e.g. membrane vs nuclear vs cytosolic activity).
What would resolve it: Endogenous fluorescent tagging and fractionation of Moh1 under normal and stress conditions.
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Download this section (compressed HTML)Protein of unknown function, essential for stationary phase survival; influences metabolic and physiological processes important for selective stress adaptation and survival; possibly linked with vacuolar transport; Yippee-like (YPEL) family member, predicted to form a zinc-finger like metal binding pocket; human ortholog YPEL2 complements stress phenotypes associated with the null mutant
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