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 a low-abundance member of the family relative to Yet3p and, unlike Yet1p and Yet3p, is not constitutively expressed; Wilson and Barlowe detected Yet2p-MYC after DTT-induced ER stress but not without DTT. Unlike 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, placed by PAINT at the PANTHER:PTN000294723 BAP29/BAP31-family ancestral node. 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. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000294723 · BCAP29/BCAP31 family ancestral node (PTHR12701) SUPPORTS TRANSFER The IBD places ER membrane residence at the broad eukaryotic BAP29/BAP31-family ancestor. This transfer is appropriate for Yet2p because its core family architecture is an ER polytopic membrane protein with a C-terminal retrieval motif. RGD:1302944 · rat Bcap31 SUPPORTS TRANSFER Rat Bcap31 is one of the two curated extant seeds for this ER-membrane IBD and supports placing membrane residence at the eukaryotic BAP29/BAP31 ancestor. UniProtKB:P51572 · human BCAP31 SUPPORTS TRANSFER Human BCAP31 is the second extant seed for the ER-membrane IBD and supports inheritance of this localization by BAP29/BAP31-family descendants, including Yet2p. 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, placed at the PANTHER:PTN000294723 BAP29/BAP31-family ancestral node from human BCAP31 descendant evidence. 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. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000294723 · BCAP29/BCAP31 family ancestral node (PTHR12701) SUPPORTS TRANSFER The IBD places the BCAP31 ERAD-associated retrotranslocation process at the broad BAP29/BAP31-family node. The Yet1p-Yet3p complex associates with the Sec translocon, but Wilson & Barlowe found no general CPY/alpha-factor translocation defect in the yet1/yet2/yet3 triple mutant and no obvious CPY*/ Ste6* turnover defect. Those negative, data-not-shown assays argue against a core YET2 ERAD role without excluding an untested client-specific one. UniProtKB:P51572 · human BCAP31 SUPPORTS TRANSFER Human BCAP31 seeds the ERAD retrotranslocation IBD and supports the source-side process placement, while the lack of direct Yet2p ERAD assays keeps the transferred annotation non-core. Supporting Evidence: PMID:18555783 promotes its retrotranslocation from the ER and degradation by the cytoplasmic 26S proteasome system 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, placed at the PANTHER:PTN000294723 BAP29/BAP31-family ancestral node from human BCAP31 descendant evidence. Human BCAP31 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: Human BCAP31 supports the source-side PAINT placement of this ERAD-related regulatory process at the BAP29/BAP31 node. The inherited term is plausible for BAP31-family Yet2p but unproven in yeast, and the specific molecular role of Yet2p in any degradation pathway is unknown. Kept as a non-core inferred process rather than removed. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000294723 · BCAP29/BCAP31 family ancestral node (PTHR12701) SUPPORTS TRANSFER The IBD traces the proteasomal-degradation regulatory term to the same broad BCAP29/BCAP31-family node. The human BCAP31 source supports the source-side ERAD biology, but yeast CPY* and Ste6* turnover assays in the yet1/yet2/yet3 triple mutant were reported as wild type, so the YET2 annotation remains no more than a non-core family hypothesis. UniProtKB:P51572 · human BCAP31 SUPPORTS TRANSFER Human BCAP31 is the extant seed for the proteasomal-degradation regulatory IBD; its Sec61/Derlin-1 work supports the source-side family inference but is not direct evidence for Yet2p. Supporting Evidence: PMID:18555783 promotes its retrotranslocation from the ER and degradation by the cytoplasmic 26S proteasome system |
| 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 we constructed and investigated a library of ∼1,800 strains carrying SWAT-GFP modules at the amino termini of endomembrane proteins |
| 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 we constructed and investigated a library of ∼1,800 strains carrying SWAT-GFP modules at the amino termini of endomembrane proteins |
| 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 low-abundance, non-constitutively expressed relative to Yet1p/Yet3p and is argued to be functionally distinct rather than simply redundant, 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 PMID:38766039 Yet2 does not express constitutively |
| GO:0008150 biological_process | ND GO_REF:0000015 | ACCEPT | Summary: Root biological process ND annotation: when it was made, no biological process had been curated for this gene product from literature. Reason: ACCEPT under the ND acceptance rule (projects/NO_DATA.md). The evidence this review cites for the biological process is inferred (from orthologs, family membership or sequence features) or comes from other species; none of it is literature on this gene product in this species. This was judged from the review's own content during the NO_DATA re-action pass, not from a new literature search. Earlier action: REMOVE. The gene's falcon literature search finds no study directly assigning Yet2 to a biological process. Supporting Evidence: file:yeast/YET2/YET2-deep-research-falcon.md Yet2 has not been directly assigned to specific biochemical pathways |
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Download this section (compressed HTML)Q: Does Yet2p itself have the translocon-associated protein translocation chaperone activity that PAINT now places at the BAP29/BAP31 ancestral node, and which yeast Sec61/ERAD clients would depend on that activity?
Q: Does Yet2p have a distinct molecular activity or client set from the Yet1p-Yet3p complex, and do ER stresses beyond DTT or specific client loads induce its expression — 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. PAINT now places protein translocation chaperone activity at the BAP29/BAP31 ancestral node from human BCAP31, but that family-level activity has not 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. The current PAINT cache asserts GO:0140388 at PANTHER:PTN000294723, so translocon-associated chaperone activity is the explicit family-level hypothesis. The yet1/yet2/yet3 triple mutant was nevertheless fully competent for CPY/alpha-factor translocation; the yeast-specific activity, clients, and pathway context are not established.
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 whether Yet2p has protein translocation chaperone activity. A direct yeast GO molecular_function annotation 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 low-abundance relative to Yet3p and, unlike Yet1p/Yet3p, is not constitutively expressed — arguing against simple redundancy. Wilson & Barlowe showed DTT induces Yet2p-MYC, but what physiological role that induced pool serves and whether it backs up YET1/YET3 are 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):
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Download this section (compressed HTML)Protein of unknown function that may interact with ribosomes; based on co-purification experiments; homolog of human BAP31 protein; YET2 has a paralog, YET1, that arose from the whole genome duplication
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