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 β 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) while impairing 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, physical partners, subcellular site of action, and the mechanism linking MOH1 to stress tolerance and quiescence remain undetermined.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000151 ubiquitin ligase complex | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Family-level phylogenetic propagation (IBA) from PANTHER PTHR13848, seeded by human YPEL5 (UniProtKB:P62699). There is no yeast experimental evidence that Moh1 is a component of a ubiquitin ligase complex. Although the Yippee fold is structurally related to the CULT domain of cereblon (a substrate receptor of a CRL4 E3 ligase), Yippee/YPEL proteins are not themselves established ubiquitin ligase complex subunits, and no such complex has been demonstrated for Moh1. This is an over-propagation from a distant structural relative. Reason: IBA propagated from a structurally related but functionally distinct neighborhood (Mis18/cereblon-CULT); no experimental or orthology evidence places Moh1 in a ubiquitin ligase complex in yeast. Not a core function. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN002302768 Β· Yippee-like ancestral node (PTHR13848) SUPPORTS SOURCE BUT NOT TARGET Node seeded by human YPEL5 (UniProtKB:P62699); the ubiquitin-ligase-complex role does not transfer to the Yippee/YPEL subfamily, which shares only the zinc-binding beta-fold with the Mis18/cereblon(CULT) neighborhood. Supporting Evidence: file:yeast/MOH1/MOH1-bioinformatics/RESULTS.md The Yippee fold (two four-stranded Ξ²-meanders coordinating one ZnΒ²βΊ at the apex, forming a cradle-shaped pocket) is a **structural/binding scaffold, not a recognized catalytic fold**. file:yeast/MOH1/MOH1-deep-research-falcon.md MOH1 is not an enzyme, transporter, or structural protein in the classical sense |
| 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. |
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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, following up the 2025 preprint under peer-reviewed conditions.
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 β 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. Despite ~49 recorded high-throughput interactions, none has been shown to be a direct, function-defining partner, and the Drosophila Yippee-Hemolin interaction has no established yeast counterpart.
OPEN BIOLOGY MF_DARK
What is known: Large-scale interaction datasets (affinity-capture-MS, genetic interactions) exist for Moh1, 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). A 2025 preprint additionally reports altered membrane permeability and metabolic remodeling in moh1delta.
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; peer-reviewed follow-up of the 2025 preprint's permeability and transcriptome findings.
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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