YET2 (Yet2p, systematic name YMR040W) is a small (160 aa, ~19 kDa) polytopic integral membrane protein of the endoplasmic reticulum in Saccharomyces cerevisiae. It is one of three budding-yeast members of the BCAP29/BCAP31 (BAP29/BAP31) family — Yet1p, Yet2p and Yet3p — that are homologs of the mammalian B-cell receptor- associated proteins BAP29 and BAP31, ER membrane proteins implicated in ER quality control, ER export of secretory cargo, and apoptosis. Yet2p has the canonical BAP31-type architecture: three transmembrane helices with a lumenal N-terminus, a large lumenal loop, and a charged, leucine-rich cytoplasmic C-terminal tail ending in a di-lysine (KKxx-type) ER-retrieval motif that supports its steady-state ER membrane residence. The gene is non-essential; Yet2p is the lowest-abundance member of the family and, unlike its paralogs, is not constitutively expressed, implying conditional regulation whose triggers are not established. Unlike its paralogs Yet1p and Yet3p, which form a stable Yet1p-Yet3p complex associated with the Sec translocation apparatus and are required for inositol prototrophy, Yet2p is not a stable member of that complex and has no demonstrated molecular activity or defined physiological cargo; its specific molecular function remains uncharacterized.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that Yet2p is active in the ER membrane, propagated from the mammalian BAP29/BAP31 ortholog (UniProtKB:P51572, PANTHER PTN000294723). This localization is independently supported: Yet2p belongs to the BCAP29/BCAP31 family, is predicted to be a triple-pass membrane protein, and carries a C-terminal di-lysine ER-retrieval motif; it is directly observed in the ER by high-throughput localization (PMID:26928762). Reason: Well-supported core localization for an ER polytopic membrane protein of the BAP31 family. The ER membrane is where Yet2p resides and where any function it has would be exerted. Supporting Evidence: file:yeast/YET2/YET2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane file:yeast/YET2/YET2-uniprot.txt The di-lysine motif confers endoplasmic reticulum localization |
| GO:0030970 retrograde protein transport, ER to cytosol | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) inference of a role in ERAD-associated dislocation of unfolded/misfolded proteins from the ER lumen to the cytosol through the translocon, propagated from the mammalian BAP31 ortholog. Mammalian BAP31 is implicated in ER-associated degradation, and the related Yet1p-Yet3p complex associates with the Sec translocation apparatus (PMID:20378542), which is consistent with a translocon-proximal locale. However, there is no direct evidence that Yet2p itself participates in retrograde/ERAD transport, and Yet2p is not a stable member of the characterized Yet1p-Yet3p complex. Reason: Biologically plausible family-level inference but not demonstrated for Yet2p. Retained as a non-core, phylogenetically inferred process rather than removed, since the family and translocon association make it credible; it does not represent a validated core YET2 function. Supporting Evidence: PMID:20378542 a fraction of the Yet complex was detected in association with the ER translocation apparatus (Sec complex) |
| GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) inference of a positive-regulatory role in ubiquitin- dependent (ERAD-type) protein catabolism, propagated from the mammalian BAP31 ortholog, which has documented roles in ER quality control and degradation of client proteins. No YET2-specific experimental evidence supports this; it is a family-level inference. Reason: Plausible for the BAP31 family but unproven for Yet2p, and the specific molecular role of Yet2p in any degradation pathway is unknown. Kept as a non-core inferred process rather than removed. Supporting Evidence: file:yeast/YET2/YET2-uniprot.txt Belongs to the BCAP29/BCAP31 family |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic (InterPro2GO) annotation to the endoplasmic reticulum based on BAP29/BAP31 family membership (IPR008417). Correct compartment but less specific than the ER membrane annotation. Reason: Correct localization; consistent with direct localization data. The more specific GO:0005789 (ER membrane) better captures the protein's polytopic membrane residence. Supporting Evidence: PMID:26928762 SWAp-Tag |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation to ER membrane from the UniProtKB Subcellular Location mapping (SL-0097). Consistent with the domain architecture (three TM helices) and the IBA/HDA evidence for ER-membrane residence. Reason: Correct and redundant with the IBA ER-membrane annotation; supported by the UniProt subcellular location and topology. Supporting Evidence: file:yeast/YET2/YET2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane |
| GO:0006886 intracellular protein transport | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Electronic (InterPro2GO) annotation to intracellular protein transport from BAP29/BAP31 family membership. This is a generic process term consistent with the family's association with ER protein transport/export and with the (hedged) UniProt FUNCTION statement, but there is no direct YET2 evidence for a specific transport step. Reason: Generic, family-inferred process. Consistent with the ER protein-transport theme of the family but not a demonstrated YET2 core function; retained as non-core. Supporting Evidence: file:yeast/YET2/YET2-uniprot.txt May play a role in anterograde transport of membrane proteins |
| GO:0016020 membrane | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Electronic annotation to the generic parent term "membrane" from family membership. True but uninformative given the more specific ER membrane annotations. Reason: Correct but overly general; the ER membrane annotation (GO:0005789) supersedes it. Retained as non-core. Supporting Evidence: file:yeast/YET2/YET2-uniprot.txt Multi-pass membrane protein |
| GO:0005783 endoplasmic reticulum | HDA PMID:26928762 One library to make them all: Streamlining the creation of y... | ACCEPT | Summary: High-throughput direct assay (HDA) localization from the SWAp-Tag yeast library (Yofe et al. 2016) placing Yet2p in the endoplasmic reticulum. This is the strongest experimental localization evidence for Yet2p and corroborates the family/topology-based ER-membrane assignment. Reason: Direct experimental localization to the ER, consistent with all other evidence. Core localization (the ER membrane sub-term is the more precise form). Supporting Evidence: PMID:26928762 SWAp-Tag |
| GO:0003674 molecular_function | ND GO_REF:0000015 | ACCEPT | Summary: Root molecular_function annotated with ND (No biological Data available) by SGD. This is the honest, correct record that no specific molecular function of Yet2p has been experimentally determined — the central knowledge gap for this gene. Yet2p has no catalytic domain; the BAP31-family scaffold/adapter mode of action is inferred but not demonstrated for Yet2p. Reason: The ND root MF correctly represents the current state of knowledge: the specific molecular activity of Yet2p is unknown. Retained as an accurate statement of ignorance; see knowledge_gaps. Recent work reinforces this: Yet2p is the lowest-abundance, non-constitutively-expressed family member and is argued to be functionally distinct from (not simply redundant with) Yet1p/Yet3p, so its activity cannot be assumed identical to the characterized paralogs. Supporting Evidence: file:yeast/YET2/YET2-uniprot.txt Belongs to the BCAP29/BCAP31 family file:yeast/YET2/YET2-deep-research-falcon.md Yet2 does not express constitutively |
| GO:0008150 biological_process | ND GO_REF:0000015 | ACCEPT | Summary: Root biological_process annotated with ND by SGD (dated 2013), recording that no specific biological process has been experimentally established for Yet2p. Note that GOA also now carries newer IBA/IEA BP annotations (retrograde transport, ubiquitin-dependent catabolism, intracellular protein transport; dated 2026), so this 2013 ND row is technically stale/inconsistent with the co-existing substantive BP terms and would normally be superseded. It is retained here as a correct statement about the primary-data gap because those newer BP terms are phylogenetic/electronic family (BAP31) inferences rather than direct YET2 experimental evidence — i.e. no experimentally established biological process exists for Yet2p itself. Reason: Correctly records that the biological role of Yet2p is not experimentally defined (the co-existing IBA/IEA BP terms are family inferences, not YET2 data). Retained; see knowledge_gaps. Supporting Evidence: file:yeast/YET2/YET2-uniprot.txt May play a role in anterograde transport of membrane proteins |
Loading supporting content…
Download this section (compressed HTML)Q: Does Yet2p have a distinct molecular activity or client set from the Yet1p-Yet3p complex, and under what conditions is its (non-constitutive) expression induced — does its regulation point to a specialized role in the unfolded protein response or ERAD?
Q: What accounts for the yet2 yet3 double-deletion growth phenotype if yet2 single deletion is phenotypically silent — is Yet2p a conditional backup for Yet3p?
Experiment: Affinity-purification mass spectrometry of chromosomally tagged Yet2p under basal and ER-stress (e.g. DTT/tunicamycin) conditions to identify stress-dependent interactors and candidate cargo, compared side-by-side with tagged Yet1p/Yet3p.
Hypothesis: Yet2p acts as a stress-induced ER membrane scaffold/adapter with a client set distinct from the constitutive Yet1p-Yet3p complex.
Type: affinity purification-mass spectrometry
Experiment: Combinatorial deletion analysis (yet1, yet2, yet3 single/double/triple mutants) with quantitative growth, secretion (e.g. invertase/CPY), and UPR-reporter readouts under ER-stress and high-secretory-load conditions to isolate a Yet2p-specific contribution.
Hypothesis: Yet2p contributes conditionally to a process shared with YET3, explaining the yet2 yet3 genetic interaction.
Type: genetic interaction / phenotypic profiling
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The specific molecular function (molecular activity) of Yet2p is undetermined. Yet2p has no catalytic domain and SGD annotates its molecular_function as ND. Whether it acts as a cargo receptor, a scaffold/adapter for ER membrane-protein biogenesis, or in some other capacity — as inferred from the BAP31 family — has never been demonstrated for Yet2p itself.
OPEN BIOLOGY MF_DARK
What is known: Established: Yet2p is an ER polytopic membrane protein of the BCAP29/BCAP31 family with three TM helices and a C-terminal di-lysine ER-retrieval motif; it is non-essential and, unlike its paralogs, non-constitutively expressed at low abundance (Zung 2024). Its localization and family membership are firm; its molecular activity is not.
Significance: Yet2p is a conserved-family ER membrane protein whose activity is unknown despite a well-defined localization — a classic "MF-dark" case where rich family/CC context makes the protein look understood while the mechanism is a hole. Resolving it would clarify the division of labor within the yeast BAP31 family.
What would resolve it: Biochemical identification of Yet2p interactors/clients (e.g. affinity-purification mass spectrometry, ideally across conditions that induce Yet2p expression) and reconstitution or genetic assays testing a specific activity (cargo binding, chaperone/adapter function). A GO molecular_function term beyond the ND root should follow such data.
Provenance (the field's own admissions):
Gap: The physiological cargo and interaction partners of Yet2p are unidentified. Unlike its paralogs Yet1p and Yet3p, which form a stable Yet1p-Yet3p complex that associates with the Sec translocation apparatus, Yet2p is not a stable member of that complex and its own binding partners are unknown.
OPEN BIOLOGY MF_DARK
What is known: Established (from Wilson & Barlowe 2010, full text): Yet2p associates only minimally with the Yet1p-Yet3p complex and the translocation machinery, and yet2 deletion does not cause the inositol-prototrophy defect of yet1/yet3 deletion. Yet2p is therefore functionally distinct from the characterized Yet complex, but what it does associate with is not known.
Significance: Identifying Yet2p partners/cargo is the most direct route to its function and would reveal whether the three yeast BAP31 paralogs handle distinct client sets.
What would resolve it: Co-immunoprecipitation / crosslinking-MS of tagged Yet2p (including under ER stress), and genetic-interaction profiling to place Yet2p in a pathway.
Provenance (the field's own admissions):
Gap: The biological role of Yet2p and its degree of functional redundancy with YET1 and YET3 are unknown. SGD annotates its biological_process as ND. Single yet2 deletion has no strong reported phenotype; the only phenotypic signal is a genetic interaction with YET3 (a yet2 yet3 double-deletion growth phenotype reported by Toikkanen et al. 2006).
OPEN BIOLOGY BP_DARK
What is known: Established: the YET genes are non-essential with partially overlapping functions, and a yet2 yet3 double disruptant shows a growth phenotype. Recent work (Zung et al. 2024) finds Yet2p is the lowest-abundance paralog and, unlike Yet1p/Yet3p, is not constitutively expressed — arguing against simple redundancy. What conditions induce Yet2p, what process it serves, and whether it backs up YET1/YET3, are all undetermined.
Significance: A low-abundance, non-constitutively-expressed paralog whose role only surfaces in combination is a candidate for conditional/specialized function rather than plain redundancy; defining it would complete the functional map of the yeast BAP31 family.
What would resolve it: Phenotypic profiling of yet2 single and yet1/yet2/yet3 combinatorial mutants under ER stress and secretory-load conditions; conditional-expression and cargo-flux assays to detect a Yet2p-specific contribution.
Provenance (the field's own admissions):
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)