HAP4 (Heme activator protein 4) is the transcriptional activation subunit of the CCAAT-binding factor (CBF/HAP complex), a heterotetrameric transcription factor (Hap2/3/4/5). HAP4 does not bind DNA directly but associates with the DNA-binding Hap2/3/5 heterotrimer and provides the primary transcriptional activation domains necessary for stimulating gene expression. The HAP complex regulates the diauxic shift from fermentation to respiration by activating transcription of genes encoding mitochondrial proteins and electron transport chain components in response to nutrient depletion (low glucose). HAP4 expression is induced by SNF1/AMPK signaling under low glucose conditions and is glucose-repressible. Core functions include transcriptional activation of respiratory metabolism genes and metabolic adaptation to nutrient availability.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003677 DNA binding | IEA GO_REF:0000043 | REMOVE | Summary: HAP4 is annotated with generic DNA binding activity. However, the literature shows HAP4 does not directly bind DNA. The abstract of PMID:2676721 states that in hap4 mutants, "the binding of HAP2 and HAP3 (HAP2/3) is not observed in vitro," and that HAP4 "encodes a regulatory subunit of the bound complex" - not the DNA-binding subunit. PMID:16278450 confirms that "the Hap2p/Hap3p/Hap5p heterotrimer is the DNA-binding component" while "the Hap4p subunit contains the transcriptional activation domain." The IEA annotation appears to be incorrectly transferred from keyword-based mapping. Reason: This annotation is mechanistically incorrect. HAP4 does not directly bind DNA - it provides transcriptional activation domains to the DNA-bound Hap2/3/5 complex. The annotation misrepresents HAP4's function by conflating complex membership with direct DNA binding capability. Supporting Evidence: PMID:2676721 In the hap4 mutant, the binding of HAP2 and HAP3 (HAP2/3) is not observed in vitro. PMID:2676721 The HAP4 gene is regulated transcriptionally by a carbon source, suggesting that it encodes a regulatory subunit of the bound complex. PMID:16278450 The Hap2p/Hap3p/Hap5p heterotrimer is the DNA-binding component of the complex that binds to the consensus 5'-CCAAT-3' sequence in the promoter of target genes. file:yeast/HAP4/HAP4-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear localization is appropriate for HAP4, which functions as a transcriptional activator in the nucleus as part of the CCAAT-binding complex at target promoters. Reason: Nuclear localization is correct and consistent with HAP4's role as a transcriptional regulator. This is a core cellular localization feature. |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | MODIFY | Summary: HAP4 is annotated with DNA-templated transcription, which describes the process of RNA synthesis itself. This is overly generic for a transcriptional regulator. HAP4's specific role is not in performing transcription but in regulating it. Reason: This term describes the core enzymatic process (RNA polymerase activity), not HAP4's function. HAP4 regulates transcription through activation domains, not by performing the transcription reaction. More specific regulatory terms better represent its function. Proposed replacements: positive regulation of transcription by RNA polymerase II Supporting Evidence: PMID:2676721 The sequence of HAP4 shows a highly acidic region, which innactivated the protein when deleted. Replacement of this region with the activation domain of GAL4 restored activity, suggesting that it provides the principal activation domain to the bound HAP2/3/4 complex. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: This annotation appropriately captures HAP4's function as a transcriptional regulator through its interaction with the DNA-binding CCAAT-binding factor complex. Reason: This is a mechanistically accurate annotation for a transcriptional regulator/activator. The IEA evidence based on InterPro domain mapping is reasonable for transcription factor domains. Supporting Evidence: PMID:2676721 it provides the principal activation domain to the bound HAP2/3/4 complex |
| GO:0006109 regulation of carbohydrate metabolic process | NAS PMID:16278450 Assembly of the Hap2p/Hap3p/Hap4p/Hap5p-DNA complex in Sacch... | MARK AS OVER ANNOTATED | Summary: HAP4 is annotated with regulation of carbohydrate metabolism. While HAP4 responds to glucose/carbohydrate availability through glucose-repressible expression, it does not directly regulate carbohydrate metabolic enzymes. Instead, it activates respiratory/mitochondrial genes that oxidize carbohydrates. The annotation conflates metabolic context with direct molecular targets. Reason: HAP4 regulates genes encoding respiratory proteins, not carbohydrate metabolism enzymes. The annotation overstates the scope of HAP4's direct function. GO:0043457 (regulation of cellular respiration) is more accurate. Supporting Evidence: PMID:2676721 The CYC1 gene of Saccharomyces cerevisiae is positively regulated by the HAP2 and HAP3 proteins...and which activate transcription in a nonfermentable carbon source. |
| GO:0006355 regulation of DNA-templated transcription | NAS PMID:16278450 Assembly of the Hap2p/Hap3p/Hap4p/Hap5p-DNA complex in Sacch... | ACCEPT | Summary: This is a duplicate annotation with different evidence source (NAS vs IEA). Both document HAP4's function as a transcriptional regulator, which strengthens confidence in this core annotation. Reason: Legitimate duplicate with different evidence code. Multiple independent evidence types support this core function annotation. Supporting Evidence: PMID:16278450 The Hap4p subunit contains the transcriptional activation domain necessary for stimulating transcription after interacting with Hap2p/Hap3p/Hap5p. |
| GO:0043457 regulation of cellular respiration | IMP PMID:2676721 Identification and characterization of HAP4: a third compone... | ACCEPT | Summary: This annotation accurately reflects HAP4's core function identified through the landmark genetic analysis of CYC1, a respiratory gene encoding cytochrome c. HAP4 is shown to be essential for activating respiratory genes in response to nonfermentable carbon sources. Reason: This is mechanistically accurate and represents a core function. The IMP evidence directly supports HAP4's role as a transcriptional activator of respiratory genes. This is among the most informative annotations for HAP4. Supporting Evidence: PMID:2676721 The CYC1 gene of Saccharomyces cerevisiae is positively regulated by the HAP2 and HAP3 proteins, which form a heteromeric complex that binds to a CCAAT box in the upstream activation site, UAS2, and which activate transcription in a nonfermentable carbon source. |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IDA PMID:11423663 Recruitment of HAT complexes by direct activator interaction... | ACCEPT | Summary: This annotation documents HAP4's protein-protein interactions with coactivator complexes (HAT complexes SAGA and NuA4) through Tra1p binding, which is a key mechanism for its transcriptional activation function. Reason: The IDA evidence correctly documents HAP4's interactions with transcription factor/coactivator complexes. This represents an important molecular mechanism of transcriptional activation. Supporting Evidence: PMID:11423663 acidic activators directly interact with Tra1p, a shared subunit of SAGA and NuA4 |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:11423663 Recruitment of HAT complexes by direct activator interaction... | ACCEPT | Summary: Duplicate annotation with IPI evidence code documenting the same protein interaction. Both IDA and IPI evidence strengthen confidence in HAP4's interaction with transcriptional machinery. Reason: Legitimate duplicate with complementary evidence code. Multiple independent evidence types document this important molecular mechanism. Supporting Evidence: PMID:11423663 acidic activators directly interact with Tra1p, a shared subunit of SAGA and NuA4 |
| GO:0003713 transcription coactivator activity | IMP PMID:2123465 The HAP2 subunit of yeast CCAAT transcriptional activator co... | ACCEPT | Summary: This annotation directly captures HAP4's fundamental function. The source demonstrates through functional analysis that HAP4 provides the primary transcriptional activation domain, and that deletion of the acidic activation region inactivates the protein, while replacement with GAL4 activation domain restores activity. Reason: The IMP evidence directly demonstrates HAP4's coactivator function. This is one of HAP4's most fundamental and well-characterized functions, accurately representing its role as the activating subunit. Supporting Evidence: PMID:2123465 the HAP4 subunit provides the primary transcriptional activation domain |
| GO:0016602 CCAAT-binding factor complex | IDA PMID:2676721 Identification and characterization of HAP4: a third compone... | ACCEPT | Summary: HAP4 is a bona fide subunit of the CCAAT-binding factor (CBF/HAP) complex, which consists of Hap2, Hap3, Hap4, and Hap5. This annotation correctly reflects complex membership. Reason: This is accurate and represents a fundamental structural feature of HAP4. Complex membership is core information about HAP4's molecular organization. Supporting Evidence: PMID:2676721 a new locus, HAP4, which is shown to encode a subunit of the DNA-binding complex at UAS2 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:2676721 Identification and characterization of HAP4: a third compone... | ACCEPT | Summary: This annotation captures HAP4's core function as a transcriptional activator. The source demonstrates that HAP4 provides the principal activation domain of the CCAAT-binding complex that activates respiratory genes. Reason: This is a core function annotation with appropriate experimental evidence. HAP4 is a bona fide transcriptional activator of RNA Pol II-transcribed respiratory genes. This represents one of HAP4's most important functions. Supporting Evidence: PMID:2676721 The sequence of HAP4 shows a highly acidic region, which innactivated the protein when deleted. Replacement of this region with the activation domain of GAL4 restored activity, suggesting that it provides the principal activation domain to the bound HAP2/3/4 complex. |
| GO:0098803 respiratory chain complex | IMP PMID:21108829 cAMP/PKA signaling balances respiratory activity with mitoch... | REMOVE | Summary: HAP4 is annotated as a component of respiratory chain complex. However, HAP4 is a transcription factor that regulates genes encoding respiratory chain components, not a structural component of the respiratory chain itself. The source (PMID:21108829) describes HAP4 as a "transcriptional regulator" involved in "mitochondrial biogenesis," not as a complex component. Reason: This annotation is mechanistically incorrect. HAP4 is a transcription factor that activates genes encoding respiratory chain proteins, not a structural component of respiratory chain complexes (Complexes I-IV in the inner mitochondrial membrane). The annotation conflates transcriptional regulation of respiratory genes with structural participation in respiratory complexes. GO:0043457 (regulation of cellular respiration) is the appropriate annotation. Supporting Evidence: PMID:21108829 the loss of mitochondrial function and production of ROS requires the activity of the transcriptional regulators HAP4, SOK2 and SKO1 |
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