Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005783 endoplasmic reticulum	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for ER localization. IRE1 is a well-established ER-resident transmembrane protein (PMID:8358794). Supported by IDA and HDA evidence. Reason: ER localization is fundamental to IRE1 function as the ER stress sensor. Confirmed by IDA (PMID:8358794) and HDA (PMID:26928762).
GO:0036498 IRE1-mediated unfolded protein response	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for the IRE1-mediated UPR. IRE1 is the defining component of this pathway in yeast, sensing unfolded proteins and activating HAC1 mRNA splicing (PMID:8358794, PMID:9323131). Reason: This is the core biological process of IRE1. The gene is named after this pathway. Confirmed by IDA (PMID:19079236) and IMP (PMID:8358794, PMID:8513503).
GO:0004521 RNA endonuclease activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for RNA endonuclease activity. IRE1 is a site-specific endonuclease that cleaves HAC1 pre-mRNA at two specific sites to initiate unconventional mRNA splicing (PMID:9323131, PMID:18191223). Reason: RNA endonuclease activity is a core molecular function of IRE1. Confirmed by IDA (PMID:9323131). The KEN domain (residues 983-1115) is the catalytic domain for this activity.
GO:0004674 protein serine/threonine kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for protein Ser/Thr kinase activity. IRE1 undergoes trans-autophosphorylation on Ser-840, Ser-841, and Thr-844, which is required for activation of the endoribonuclease domain (PMID:8663458, PMID:18191223). Reason: Kinase activity is a core molecular function of IRE1. Confirmed by IDA (PMID:8663458) and crystal structure (PMID:18191223). Kinase activation is required for RNase activation.
GO:0051082 unfolded protein binding	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: GO:0051082 is proposed for obsoletion. IRE1 does directly bind unfolded proteins via its lumenal domain (PMID:17923530), but it functions as a sensor/signaling molecule, not a chaperone. The binding triggers oligomerization and UPR activation, not protein folding. Reason: GO:0051082 "unfolded protein binding" is proposed for obsoletion. While IRE1 does bind unfolded proteins via its lumenal domain (PMID:17923530), this binding serves a signaling function (sensor), not a chaperone function. IRE1 does not assist protein folding. The unfolded protein binding by IRE1 is mechanistically part of its sensor function in the UPR, which is already captured by GO:0036498. There is currently no appropriate GO MF term for "unfolded protein sensor activity" to use as a replacement.
GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: IBA annotation for apoptotic signaling in response to ER stress. This is primarily a metazoan function (IRE1alpha/beta in mammals). Yeast does not have classical apoptosis, although programmed cell death mechanisms exist. The IBA inference from mammalian orthologs may not be fully appropriate for yeast. Reason: This annotation appears to be inferred from mammalian IRE1 orthologs where IRE1 contributes to apoptotic signaling under prolonged ER stress. S. cerevisiae does not have classical apoptosis. While yeast has programmed cell death pathways, this specific term is too metazoan-centric for yeast IRE1.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for nucleotide binding from UniProt keyword. IRE1 binds ATP/ADP in its kinase domain (PMID:18191223, crystal structure with ADP). Reason: Correct but very broad. IRE1 binds ATP for its kinase activity. Acceptable as an IEA.
GO:0003824 catalytic activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for catalytic activity from UniProt keyword. IRE1 has both kinase and endoribonuclease catalytic activities. Reason: Correct but extremely broad. Both kinase and RNase activities are catalytic. Acceptable as a broad IEA.
GO:0004521 RNA endonuclease activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for RNA endonuclease activity from combined automated methods. Consistent with IBA and IDA evidence. Reason: Correct. Consistent with experimental evidence (PMID:9323131, PMID:18191223).
GO:0004540 RNA nuclease activity	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for RNA nuclease activity from InterPro. Broader parent of RNA endonuclease activity. Reason: Correct but less specific than GO:0004521. Acceptable as a broad IEA.
GO:0004672 protein kinase activity	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for protein kinase activity from InterPro. Broader parent of protein serine/threonine kinase activity. Reason: Correct but less specific than GO:0004674. Acceptable as an IEA.
GO:0004674 protein serine/threonine kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for protein Ser/Thr kinase from combined automated methods. Consistent with IBA and IDA evidence. Reason: Correct. Consistent with experimental evidence (PMID:8663458, PMID:18191223).
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for ATP binding. IRE1 binds ATP in its kinase domain. Crystal structure shows ADP bound in the active site (PMID:18191223). Reason: Correct. ATP binding is essential for kinase activity and confirmed by crystal structure.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation for ER membrane from UniProt subcellular location. IRE1 is a type I transmembrane protein spanning the ER membrane. Reason: Correct. Confirmed by IDA (PMID:8358794) and topology studies.
GO:0006397 mRNA processing	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for mRNA processing from InterPro. IRE1 processes HAC1 mRNA through unconventional splicing. Reason: Correct. IRE1 endoribonuclease activity directly processes HAC1 pre-mRNA (PMID:9323131).
GO:0006986 response to unfolded protein	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for response to unfolded protein from UniProt keyword. IRE1 is the primary sensor and effector of the unfolded protein response in yeast. Reason: Correct. This is the core biological process of IRE1.
GO:0016301 kinase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for kinase activity from UniProt keyword. Broader parent of protein kinase activity. Reason: Correct but very broad. Acceptable as an IEA.
GO:0016740 transferase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for transferase activity from UniProt keyword. Very broad parent of kinase activity. Reason: Correct but extremely broad. Acceptable as an IEA.
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for hydrolase activity from UniProt keyword. Broad parent of RNA nuclease activity. Reason: Correct but extremely broad. Acceptable as an IEA.
GO:0030968 endoplasmic reticulum unfolded protein response	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for ER UPR from combined automated methods. Consistent with IMP evidence. Reason: Correct. IRE1 is the master regulator of the ER UPR in yeast.
GO:0031505 fungal-type cell wall organization	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: IEA annotation for fungal-type cell wall organization from ARBA. This is consistent with IMP and IGI evidence (PMID:18971375, PMID:8898193) showing IRE1 is required for cell wall integrity. Reason: Cell wall organization is a downstream consequence of IRE1's UPR signaling function. The UPR regulates expression of cell wall biosynthesis genes. Not a core function of IRE1 itself.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for metal ion binding from UniProt keyword. IRE1 kinase domain binds Mg2+ as a cofactor (PMID:18191223). Reason: Correct. Mg2+ is required as a cofactor for kinase activity. Confirmed by crystal structure (PMID:18191223).
GO:0106310 protein serine kinase activity	IEA GO_REF:0000116	ACCEPT	Summary: IEA annotation for protein serine kinase activity from Rhea mapping. IRE1 autophosphorylates on serine residues (Ser-840, Ser-841). Reason: Correct. Serine autophosphorylation is confirmed (PMID:18191223, PMID:8670804).
GO:0005515 protein binding	IPI PMID:16990850 Dcr2 targets Ire1 and downregulates the unfolded protein res...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding showing interaction with DCR2 (Q05924). Reason: Protein binding is uninformative. The specific interaction with DCR2 may be relevant to IRE1 regulation but is not captured by the generic term.
GO:0042802 identical protein binding	IPI PMID:18191223 Structure of the dual enzyme Ire1 reveals the basis for cata...	ACCEPT	Summary: IPI annotation for identical protein binding (homodimerization). IRE1 homodimerizes upon ER stress, and dimerization is essential for both kinase trans-autophosphorylation and RNase activation (PMID:18191223, PMID:8663458). Reason: Homodimerization is functionally critical for IRE1 activation. Crystal structures confirm the dimer interface (PMID:18191223, PMID:16365312).
GO:0042802 identical protein binding	IPI PMID:19079236 The unfolded protein response signals through high-order ass...	ACCEPT	Summary: IPI annotation for identical protein binding. Additional evidence for IRE1 homodimerization. Reason: Consistent with other evidence for functionally important homodimerization.
GO:0042802 identical protein binding	IPI PMID:20625545 BiP binding to the ER-stress sensor Ire1 tunes the homeostat...	ACCEPT	Summary: IPI annotation for identical protein binding from study of BiP binding to IRE1 and its regulation of UPR homeostasis. Reason: Additional evidence for IRE1 homodimerization, studied in the context of BiP regulation.
GO:0005789 endoplasmic reticulum membrane	NAS PMID:17923530 Two regulatory steps of ER-stress sensor Ire1 involving its ...	ACCEPT	Summary: NAS annotation for ER membrane from ComplexPortal. Consistent with IDA evidence. Reason: Correct. Consistent with IDA (PMID:8358794) and topology studies.
GO:0036498 IRE1-mediated unfolded protein response	IDA PMID:19079236 The unfolded protein response signals through high-order ass...	ACCEPT	Summary: IDA annotation for IRE1-mediated UPR from ComplexPortal. Reason: Core biological process of IRE1. Experimentally demonstrated.
GO:0005789 endoplasmic reticulum membrane	IDA PMID:8358794 A transmembrane protein with a cdc2+/CDC28-related kinase ac...	ACCEPT	Summary: IDA annotation for ER membrane localization from the founding paper on IRE1 (PMID:8358794). IRE1 is a transmembrane protein with lumenal and cytoplasmic domains. Reason: Primary experimental evidence for ER membrane localization from the original characterization.
GO:0004521 RNA endonuclease activity	IDA PMID:9323131 The transmembrane kinase Ire1p is a site-specific endonuclea...	ACCEPT	Summary: IDA annotation for RNA endonuclease activity. IRE1 is a site-specific endonuclease that cleaves HAC1 pre-mRNA at two specific positions (PMID:9323131). Reason: Core molecular function demonstrated by direct assay. This is the key enzymatic activity that mediates UPR signaling.
GO:0005783 endoplasmic reticulum	HDA PMID:26928762 One library to make them all - streamlining the creation of ...	ACCEPT	Summary: HDA annotation for ER localization from large-scale yeast library analysis. Reason: Consistent with IDA and IBA evidence for ER localization.
GO:0004672 protein kinase activity	HDA PMID:16319894 Global analysis of protein phosphorylation in yeast.	ACCEPT	Summary: HDA annotation for protein kinase activity from global phosphorylation analysis in yeast. Reason: Consistent with IDA evidence for kinase activity (PMID:8663458).
GO:0034067 protein localization to Golgi apparatus	IMP PMID:26966233 Unfolded protein response regulates yeast small GTPase Arl1p...	KEEP AS NON CORE	Summary: IMP annotation for protein localization to Golgi apparatus. IRE1 influences protein sorting and Golgi function through UPR target gene regulation. Reason: Protein localization to Golgi is a downstream effect of IRE1's UPR signaling function, not a direct function of IRE1.
GO:0034976 response to endoplasmic reticulum stress	IMP PMID:26966233 Unfolded protein response regulates yeast small GTPase Arl1p...	ACCEPT	Summary: IMP annotation for response to ER stress. IRE1 is the primary ER stress sensor and signaling molecule in yeast. Reason: Core biological process. IRE1 is the defining component of the ER stress response in yeast.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-SCE-535524	ACCEPT	Summary: TAS annotation for ER membrane from Reactome pathway. Reason: Correct. Consistent with IDA evidence.
GO:0004674 protein serine/threonine kinase activity	IDA PMID:8663458 The unfolded protein response pathway in Saccharomyces cerev...	ACCEPT	Summary: IDA annotation for protein Ser/Thr kinase activity. IRE1 undergoes trans-autophosphorylation requiring oligomerization (PMID:8663458). K702A mutation abolishes autophosphorylation. Reason: Core molecular function demonstrated by direct assay. Trans-autophosphorylation is essential for activating the endoribonuclease domain.
GO:0005634 nucleus	IDA PMID:17035634 The unfolded protein response transducer Ire1p contains a nu...	UNDECIDED	Summary: IDA annotation for nuclear localization. This may reflect a minor population of IRE1 or a specific experimental condition. Reason: Unable to access PMID:17035634 to verify the nuclear localization claim. IRE1 is primarily an ER membrane protein, so nuclear localization would be unusual and requires verification.
GO:0006020 inositol metabolic process	IMP PMID:1625574 IRE1 encodes a putative protein kinase containing a membrane...	KEEP AS NON CORE	Summary: IMP annotation for inositol metabolic process. IRE1 was originally identified as required for inositol prototrophy (PMID:1625574). The UPR regulates inositol biosynthesis genes. Reason: Inositol metabolism is regulated by the UPR pathway. IRE1 influences inositol levels through transcriptional regulation of biosynthetic genes, but this is a downstream consequence of UPR signaling.
GO:0030968 endoplasmic reticulum unfolded protein response	IMP PMID:8358794 A transmembrane protein with a cdc2+/CDC28-related kinase ac...	ACCEPT	Summary: IMP annotation for ER UPR from the founding paper on IRE1 signaling (PMID:8358794). IRE1 is required for signaling from the ER to the nucleus. Reason: Core biological process. This is the defining function of IRE1.
GO:0030968 endoplasmic reticulum unfolded protein response	IMP PMID:8513503 Transcriptional induction of genes encoding endoplasmic reti...	ACCEPT	Summary: IMP annotation for ER UPR from additional evidence. Reason: Additional experimental evidence for the core biological process.
GO:0031505 fungal-type cell wall organization	IMP PMID:18971375 The unfolded protein response is induced by the cell wall in...	KEEP AS NON CORE	Summary: IMP annotation for fungal-type cell wall organization. IRE1 mutants have cell wall defects. Reason: Cell wall organization is a downstream consequence of UPR signaling. The UPR regulates genes involved in cell wall biosynthesis.
GO:0031505 fungal-type cell wall organization	IGI PMID:18971375 The unfolded protein response is induced by the cell wall in...	KEEP AS NON CORE	Summary: IGI annotation for fungal-type cell wall organization based on genetic interaction data. Reason: Same as above - downstream consequence of UPR signaling.
GO:0031505 fungal-type cell wall organization	IMP PMID:8898193 A novel mechanism for regulating activity of a transcription...	KEEP AS NON CORE	Summary: IMP annotation for fungal-type cell wall organization from earlier study. Reason: Downstream consequence of UPR signaling. Not a core function of IRE1.
GO:0051082 unfolded protein binding	IDA PMID:17923530 Two regulatory steps of ER-stress sensor Ire1 involving its ...	MARK AS OVER ANNOTATED	Summary: IDA annotation for unfolded protein binding based on direct demonstration that IRE1 lumenal domain directly interacts with unfolded proteins (PMID:17923530). This paper showed two regulatory steps: cluster formation and direct interaction with unfolded proteins. Reason: GO:0051082 is proposed for obsoletion. While the experimental evidence is solid that IRE1 binds unfolded proteins (PMID:17923530), the function of this binding is as a sensor/signal transducer, not as a chaperone. IRE1 does not assist protein folding. The binding triggers oligomerization and UPR activation. There is currently no appropriate GO MF term for "unfolded protein sensor activity." The sensing function is best captured at the BP level by GO:0030968 and GO:0036498.
GO:0051082 unfolded protein binding	IMP PMID:17923530 Two regulatory steps of ER-stress sensor Ire1 involving its ...	MARK AS OVER ANNOTATED	Summary: IMP annotation for unfolded protein binding. Same study as the IDA annotation above (PMID:17923530). Reason: Same reasoning as the IDA annotation. GO:0051082 is proposed for obsoletion. IRE1 binds unfolded proteins as a sensor, not a chaperone. The term does not accurately describe the functional role of this binding.

Core Functions

Protein serine/threonine kinase that undergoes trans-autophosphorylation upon ER stress-induced oligomerization, activating the endoribonuclease domain to splice HAC1 mRNA and trigger the unfolded protein response.

Molecular Function:

protein serine/threonine kinase activity

Directly Involved In:

IRE1-mediated unfolded protein response endoplasmic reticulum unfolded protein response response to endoplasmic reticulum stress

Cellular Locations:

endoplasmic reticulum membrane

RNA endonuclease that cleaves HAC1 pre-mRNA at two specific sites to initiate unconventional mRNA splicing, producing mature HAC1 mRNA encoding the UPR transcription factor.

Molecular Function:

RNA endonuclease activity

Directly Involved In:

mRNA processing IRE1-mediated unfolded protein response

Cellular Locations:

endoplasmic reticulum membrane

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:1625574

IRE1 encodes a putative protein kinase containing a membrane-spanning domain and is required for inositol phototrophy in Saccharomyces cerevisiae.

PMID:16319894

Global analysis of protein phosphorylation in yeast.

PMID:16365312

On the mechanism of sensing unfolded protein in the endoplasmic reticulum.

PMID:16990850

Dcr2 targets Ire1 and downregulates the unfolded protein response in Saccharomyces cerevisiae.

PMID:17035634

The unfolded protein response transducer Ire1p contains a nuclear localization sequence recognized by multiple beta importins.

PMID:17923530

Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins.

PMID:18191223

Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing.

PMID:18971375

The unfolded protein response is induced by the cell wall integrity mitogen-activated protein kinase signaling cascade and is required for cell wall integrity in Saccharomyces cerevisiae.

PMID:19079236

The unfolded protein response signals through high-order assembly of Ire1.

PMID:20625545

BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.

PMID:26928762

One library to make them all - streamlining the creation of yeast libraries via a SWAp-Tag strategy.

PMID:26966233

Unfolded protein response regulates yeast small GTPase Arl1p activation at late Golgi via phosphorylation of Arf GEF Syt1p.

PMID:8358794

A transmembrane protein with a cdc2+/CDC28-related kinase activity is required for signaling from the ER to the nucleus.

PMID:8513503

Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase.

PMID:8663458

The unfolded protein response pathway in Saccharomyces cerevisiae. Oligomerization and trans-phosphorylation of Ire1p (Ern1p) are required for kinase activation.

PMID:8670804

Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.

PMID:8898193

A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response.

PMID:9323131

The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response.

PMID:9528768

Protein serine/threonine phosphatase Ptc2p negatively regulates the unfolded-protein response by dephosphorylating Ire1p kinase.

Reactome:R-SCE-535524

Phosphorylated Ire1 Dimer Binds ADP

📚 Additional Documentation

Deep Research Bioreason

(IRE1-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 02:03 AM

Organism: Saccharomyces cerevisiae

Sequence:

MRLLRRNMLVLTLLVCVFSSIISCSIPLSSRTSRRQIVEDEVASTKKLNFNYGVDKNINSPIPAPRTTEGLPNMKLSSYPTPNLLNTADNRRANKKGRRAANSISVPYLENRSLNELSLSDILIAADVEGGLHAVDRRNGHIIWSIEPENFQPLIEIQEPSRLETYETLIIEPFGDGNIYYFNAHQGLQKLPLSIRQLVSTSPLHLKTNIVVNDSGKIVEDEKVYTGSMRTIMYTINMLNGEIISAFGPGSKNGYFGSQSVDCSPEEKIKLQECENMIVIGKTIFELGIHSYDGASYNVTYSTWQQNVLDVPLALQNTFSKDGMCIAPFRDKSLLASDLDFRIARWVSPTFPGIIVGLFDVFNDLRTNENILVPHPFNPGDHESISSNKVYLDQTSNLSWFALSSQNFPSLVESAPISRYASSDRWRVSSIFEDETLFKNAIMGVHQIYNNEYDHLYENYEKTNSLDTTHKYPPLMIDSSVDTTDLHQNNEMNSLKEYMSPEDLEAYRKKIHEQISRELDEKNQNSLLLKFGSLVYRIIETGVFLLLFLIFCAILQRFKILPPLYVLLSKIGFMPEKEIPIVESKSLNCPSSSENVTKPFDMKSGKQVVFEGAVNDGSLKSEKDNDDADEDDEKSLDLTTEKKKRKRGSRGGKKGRKSRIANIPNFEQSLKNLVVSEKILGYGSSGTVVFQGSFQGRPVAVKRMLIDFCDIALMEIKLLTESDDHPNVIRYYCSETTDRFLYIALELCNLNLQDLVESKNVSDENLKLQKEYNPISLLRQIASGVAHLHSLKIIHRDLKPQNILVSTSSRFTADQQTGAENLRILISDFGLCKKLDSGQSSFRTNLNNPSGTSGWRAPELLEESNNLQCQVETEHSSSRHTVVSSDSFYDPFTKRRLTRSIDIFSMGCVFYYILSKGKHPFGDKYSRESNIIRGIFSLDEMKCLHDRSLIAEATDLISQMIDHDPLKRPTAMKVLRHPLFWPKSKKLEFLLKVSDRLEIENRDPPSALLMKFDAGSDFVIPSGDWTVKFDKTFMDNLERYRKYHSSKLMDLLRALRNKYHHFMDLPEDIAELMGPVPDGFYDYFTKRFPNLLIGVYMIVKENLSDDQILREFLYS

Thinking Trace

I begin by dissecting the InterPro architecture and its order along the sequence. The N-terminal half is dominated by beta-propeller-like modules: IPR015943 (WD40/YVTN repeat-like-containing domain superfamily, residues 105–283), IPR018391 (Pyrrolo-quinoline quinone beta-propeller repeat, residues 116–349), and IPR011047 (Quinoprotein alcohol dehydrogenase-like superfamily, residues 121–337). These overlapping signatures collectively define a multi-bladed beta-propeller scaffold that forms a rigid interaction platform. In soluble quinoprotein dehydrogenases this fold binds cofactors, but here—especially in conjunction with the absence of catalytic motifs and the presence of downstream signaling domains—this propeller functions primarily as an assembly and sensing module rather than an enzyme active site. Immediately downstream, the architecture transitions into the hallmark IRE1/2-like sensor-effector core: IPR045133 (Serine/threonine-protein kinase/endoribonuclease IRE1/2-like family, residues 295–1112), which encodes a bifunctional signaling machine that couples RNA-responsive sensing to phosphorylation and endoribonuclease activities.

The central catalytic module is IPR000719 (Protein kinase domain, residues 674–980), reinforced by IPR011009 (Protein kinase-like domain superfamily, residues 677–992) and an embedded catalytic signature IPR008271 (Serine/threonine-protein kinase, active site, residues 793–805). This arrangement establishes a bona fide serine/threonine kinase core capable of autophosphorylation and substrate phosphorylation. C-terminal to the kinase, IPR010513 (KEN domain, residues 983–1115) and its superfamily IPR038357 (KEN domain superfamily, residues 983–1115) specify an RNA endonuclease module. The juxtaposition of the kinase and KEN domains is diagnostic of the IRE1/2 lineage: kinase-driven conformational switching exposes and activates the KEN RNase. Together, the N-terminal beta-propeller scaffold, the IRE1/2-like signaling core, and the C-terminal KEN RNase causally define a bifunctional signaling enzyme that senses signals via oligomerization, phosphorylates itself and targets, and cleaves RNA.

From this architecture, the molecular function resolves into two coupled chemistries. The protein kinase domain with its active-site motif (IPR000719; IPR008271; IPR011009) imposes ATP-dependent serine/threonine phosphorylation. The KEN domain imposes endoribonuclease activity toward RNA substrates. Thus, the most parsimonious functional set includes ATP binding and protein serine/threonine kinase activity, alongside endoribonuclease activity that is conditional and signal-gated.

These activities position the protein squarely in stress-adaptive pathways. The IRE1/2-like family (IPR045133) is specialized for integrating environmental and translational cues; the beta-propeller platform and KEN RNase support regulated RNA processing, while the kinase core propagates phosphorylation cascades. In yeast, such bifunctional signaling enzymes orchestrate responses to heat, nutrient limitation, and oxidative stress by coordinating mRNA cleavage and translational control. Consequently, the biological process is best captured by stress-adaptive signaling culminating in RNA processing and translational reprogramming.

Cellular location follows from the soluble beta-propeller and cytosolic kinase/RNase composition, together with the absence of transmembrane segments. The soluble nature and assembly-prone N-terminal propeller argue for a cytoplasmic residency, consistent with a role in RNA handling and phosphorylation within cytoplasmic ribonucleoprotein hubs.

Mechanistically, I hypothesize that the N-terminal beta-propeller nucleates higher-order assemblies that sense cytoplasmic stress and drive oligomerization. Oligomerization allosterically activates the internal serine/threonine kinase (IPR000719), which then autophosphorylates to stabilize an active conformation that exposes the KEN RNase (IPR010513). The RNase cleaves target RNA(s), tuning mRNA pools and enabling broader stress-adaptive programs. Likely interaction partners include cytoplasmic RNA-binding factors and ribosome-associated assemblies that deliver substrates and scaffold the signaling complex.

Functional Summary

A cytoplasmic bifunctional signaling enzyme that assembles via an N-terminal beta‑propeller scaffold, activates an internal serine/threonine kinase core, and couples this switching mechanism to a C‑terminal endoribonuclease. By integrating phosphorylation with regulated RNA cleavage, it coordinates stress-adaptive signaling and translational reprogramming in the cytoplasm, likely responding to environmental cues by oligomerizing, autophosphorylating, and cleaving RNA to remodel mRNA pools.

UniProt Summary

Probable serine/threonine-protein kinase.

InterPro Domains

WD40/YVTN repeat-like-containing domain superfamily (IPR015943, homologous_superfamily) — residues 105-283
Pyrrolo-quinoline quinone beta-propeller repeat (IPR018391, repeat) — residues 116-349
Quinoprotein alcohol dehydrogenase-like superfamily (IPR011047, homologous_superfamily) — residues 121-337
Serine/threonine-protein kinase/endoribonuclease IRE1/2-like (IPR045133, family) — residues 295-1112
Protein kinase domain (IPR000719, domain) — residues 674-980
Protein kinase-like domain superfamily (IPR011009, homologous_superfamily) — residues 677-992
Serine/threonine-protein kinase, active site (IPR008271, active_site) — residues 793-805
KEN domain (IPR010513, domain) — residues 983-1115
KEN domain superfamily (IPR038357, homologous_superfamily) — residues 983-1115

GO Terms

Molecular Function: molecular_function (GO:0003674), binding (GO:0005488), catalytic activity (GO:0003824), transferase activity (GO:0016740), hydrolase activity (GO:0016787), catalytic activity, acting on a nucleic acid (GO:0140640), catalytic activity, acting on a protein (GO:0140096), protein binding (GO:0005515), catalytic activity, acting on RNA (GO:0140098), hydrolase activity, acting on ester bonds (GO:0016788), unfolded protein binding (GO:0051082), transferase activity, transferring phosphorus-containing groups (GO:0016772), protein kinase activity (GO:0004672), identical protein binding (GO:0042802), protein serine/threonine kinase activity (GO:0004674), kinase activity (GO:0016301), nuclease activity (GO:0004518), phosphotransferase activity, alcohol group as acceptor (GO:0016773), ribonuclease activity (GO:0004540), RNA endonuclease activity (GO:0004521), endoribonuclease activity (GO:0004519)

Biological Process: biological_process (GO:0008150), metabolic process (GO:0008152), localization (GO:0051179), regulation of biological process (GO:0050789), signaling (GO:0023052), biological regulation (GO:0065007), response to stimulus (GO:0050896), cellular process (GO:0009987), cellular localization (GO:0051641), response to chemical (GO:0042221), regulation of metabolic process (GO:0019222), nitrogen compound metabolic process (GO:0006807), cellular component organization or biogenesis (GO:0071840), organic substance metabolic process (GO:0071704), macromolecule localization (GO:0033036), cellular metabolic process (GO:0044237), small molecule metabolic process (GO:0044281), cell wall organization or biogenesis (GO:0071554), regulation of cellular process (GO:0050794), cellular response to stimulus (GO:0051716), response to stress (GO:0006950), cell communication (GO:0007154), signal transduction (GO:0007165), primary metabolic process (GO:0044238), organic hydroxy compound metabolic process (GO:1901615), organonitrogen compound metabolic process (GO:1901564), heterocycle metabolic process (GO:0046483), protein metabolic process (GO:0019538), regulation of macromolecule metabolic process (GO:0060255), alcohol metabolic process (GO:0006066), cellular aromatic compound metabolic process (GO:0006725), carbohydrate metabolic process (GO:0005975), cellular nitrogen compound metabolic process (GO:0034641), macromolecule metabolic process (GO:0043170), response to organic substance (GO:0010033), phosphorus metabolic process (GO:0006793), fungal-type cell wall organization or biogenesis (GO:0071852), organic cyclic compound metabolic process (GO:1901360), endoplasmic reticulum unfolded protein response (GO:0030968), nucleobase-containing compound metabolic process (GO:0006139), cellular response to chemical stimulus (GO:0070887), cellular response to stress (GO:0033554), regulation of biosynthetic process (GO:0009889), response to topologically incorrect protein (GO:0035966), regulation of nitrogen compound metabolic process (GO:0051171), cellular macromolecule localization (GO:0070727), cellular component organization (GO:0016043), regulation of cellular metabolic process (GO:0031323), regulation of primary metabolic process (GO:0080090), cell wall organization (GO:0071555), cellular carbohydrate metabolic process (GO:0044262), fungal-type cell wall organization (GO:0031505), inositol metabolic process (GO:0006020), regulation of macromolecule biosynthetic process (GO:0010556), cellular response to organic substance (GO:0071310), phosphate-containing compound metabolic process (GO:0006796), external encapsulating structure organization (GO:0045229), regulation of gene expression (GO:0010468), protein modification process (GO:0036211), response to endoplasmic reticulum stress (GO:0034976), cellular response to topologically incorrect protein (GO:0035967), macromolecule modification (GO:0043412), nucleic acid metabolic process (GO:0090304), polyol metabolic process (GO:0019751), regulation of DNA-templated transcription in response to stress (GO:0043620), regulation of cellular biosynthetic process (GO:0031326), regulation of nucleobase-containing compound metabolic process (GO:0019219), response to unfolded protein (GO:0006986), protein localization (GO:0008104), regulation of RNA metabolic process (GO:0051252), gene expression (GO:0010467), protein localization to organelle (GO:0033365), RNA metabolic process (GO:0016070), nucleic acid phosphodiester bond hydrolysis (GO:0090305), regulation of RNA biosynthetic process (GO:2001141), protein phosphorylation (GO:0006468), cellular response to unfolded protein (GO:0034620), regulation of DNA-templated transcription (GO:0006355), RNA processing (GO:0006396), phosphorylation (GO:0016310), RNA phosphodiester bond hydrolysis (GO:0090501), mRNA processing (GO:0006397), mRNA metabolic process (GO:0016071), protein localization to Golgi apparatus (GO:0034067), regulation of nucleic acid-templated transcription (GO:1903506), protein autophosphorylation (GO:0046777), mRNA cleavage (GO:0006379), mRNA cleavage involved in mRNA processing (GO:0098787)

Cellular Component: cellular_component (GO:0005575), protein-containing complex (GO:0032991), cellular anatomical entity (GO:0110165), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), endoplasmic reticulum protein-containing complex (GO:0140534), membrane (GO:0016020), membrane protein complex (GO:0098796), organelle subcompartment (GO:0031984), intracellular protein-containing complex (GO:0140535), catalytic complex (GO:1902494), cytoplasm (GO:0005737), endomembrane system (GO:0012505), organelle membrane (GO:0031090), transferase complex (GO:1990234), intracellular organelle (GO:0043229), endonuclease complex (GO:1905348), endoplasmic reticulum subcompartment (GO:0098827), nuclear outer membrane-endoplasmic reticulum membrane network (GO:0042175), endoplasmic reticulum (GO:0005783), membrane-bounded organelle (GO:0043227), intracellular membrane-bounded organelle (GO:0043231), transferase complex, transferring phosphorus-containing groups (GO:0061695), endoplasmic reticulum membrane (GO:0005789), endoribonuclease complex (GO:1902555), nucleus (GO:0005634), protein kinase complex (GO:1902911), serine/threonine protein kinase complex (GO:1902554)

Generated by BioReason

Deep Research Bioreason Rl

(IRE1-deep-research-bioreason-rl.md)

BioReason Chat Export

Exported on March 22, 2026 at 02:03 AM

Organism: Saccharomyces cerevisiae

Sequence:

MRLLRRNMLVLTLLVCVFSSIISCSIPLSSRTSRRQIVEDEVASTKKLNFNYGVDKNINSPIPAPRTTEGLPNMKLSSYPTPNLLNTADNRRANKKGRRAANSISVPYLENRSLNELSLSDILIAADVEGGLHAVDRRNGHIIWSIEPENFQPLIEIQEPSRLETYETLIIEPFGDGNIYYFNAHQGLQKLPLSIRQLVSTSPLHLKTNIVVNDSGKIVEDEKVYTGSMRTIMYTINMLNGEIISAFGPGSKNGYFGSQSVDCSPEEKIKLQECENMIVIGKTIFELGIHSYDGASYNVTYSTWQQNVLDVPLALQNTFSKDGMCIAPFRDKSLLASDLDFRIARWVSPTFPGIIVGLFDVFNDLRTNENILVPHPFNPGDHESISSNKVYLDQTSNLSWFALSSQNFPSLVESAPISRYASSDRWRVSSIFEDETLFKNAIMGVHQIYNNEYDHLYENYEKTNSLDTTHKYPPLMIDSSVDTTDLHQNNEMNSLKEYMSPEDLEAYRKKIHEQISRELDEKNQNSLLLKFGSLVYRIIETGVFLLLFLIFCAILQRFKILPPLYVLLSKIGFMPEKEIPIVESKSLNCPSSSENVTKPFDMKSGKQVVFEGAVNDGSLKSEKDNDDADEDDEKSLDLTTEKKKRKRGSRGGKKGRKSRIANIPNFEQSLKNLVVSEKILGYGSSGTVVFQGSFQGRPVAVKRMLIDFCDIALMEIKLLTESDDHPNVIRYYCSETTDRFLYIALELCNLNLQDLVESKNVSDENLKLQKEYNPISLLRQIASGVAHLHSLKIIHRDLKPQNILVSTSSRFTADQQTGAENLRILISDFGLCKKLDSGQSSFRTNLNNPSGTSGWRAPELLEESNNLQCQVETEHSSSRHTVVSSDSFYDPFTKRRLTRSIDIFSMGCVFYYILSKGKHPFGDKYSRESNIIRGIFSLDEMKCLHDRSLIAEATDLISQMIDHDPLKRPTAMKVLRHPLFWPKSKKLEFLLKVSDRLEIENRDPPSALLMKFDAGSDFVIPSGDWTVKFDKTFMDNLERYRKYHSSKLMDLLRALRNKYHHFMDLPEDIAELMGPVPDGFYDYFTKRFPNLLIGVYMIVKENLSDDQILREFLYS

Thinking Trace

Functional Summary

UniProt Summary

Probable serine/threonine-protein kinase.

InterPro Domains

WD40/YVTN repeat-like-containing domain superfamily (IPR015943, homologous_superfamily) — residues 105-283
Pyrrolo-quinoline quinone beta-propeller repeat (IPR018391, repeat) — residues 116-349
Quinoprotein alcohol dehydrogenase-like superfamily (IPR011047, homologous_superfamily) — residues 121-337
Serine/threonine-protein kinase/endoribonuclease IRE1/2-like (IPR045133, family) — residues 295-1112
Protein kinase domain (IPR000719, domain) — residues 674-980
Protein kinase-like domain superfamily (IPR011009, homologous_superfamily) — residues 677-992
Serine/threonine-protein kinase, active site (IPR008271, active_site) — residues 793-805
KEN domain (IPR010513, domain) — residues 983-1115
KEN domain superfamily (IPR038357, homologous_superfamily) — residues 983-1115

GO Terms

Generated by BioReason

Bioreason Rl Review

(IRE1-bioreason-rl-review.md)

BioReason-Pro RL Review: IRE1 (S. cerevisiae)

Source: IRE1-deep-research-bioreason-rl.md

Correctness: 3/5
Completeness: 3/5

Functional Summary Review

The BioReason summary states:

A cytoplasmic bifunctional signaling enzyme that assembles via an N-terminal beta-propeller scaffold, activates an internal serine/threonine kinase core, and couples this switching mechanism to a C-terminal endoribonuclease.

The identification of the bifunctional kinase/endoribonuclease is correct and well-supported. The curated review confirms both protein serine/threonine kinase activity (GO:0004674) and RNA endonuclease activity (GO:0004521) as core molecular functions. The coupling of kinase activation to RNase activation is also correctly described.

However, the localization as "cytoplasmic" is a significant error. IRE1 is a type I transmembrane protein of the ER membrane (GO:0005789). The curated review explicitly states: "IRE1 is a type I transmembrane serine/threonine-protein kinase and endoribonuclease... contains an N-terminal lumenal domain (residues 19-526) that senses unfolded proteins in the ER, a single transmembrane helix, and a cytoplasmic portion." Multiple IDA annotations confirm ER membrane localization (PMID:8358794).

The description of the N-terminal region as a "beta-propeller scaffold" is misleading. While InterPro matches beta-propeller superfamily signatures (IPR015943, IPR018391) for this region, the curated review identifies it as the ER lumenal sensor domain that binds unfolded proteins. BioReason interprets these domains as a generic "assembly and sensing module" but misses that this is the ER stress sensor.

By integrating phosphorylation with regulated RNA cleavage, it coordinates stress-adaptive signaling and translational reprogramming in the cytoplasm, likely responding to environmental cues by oligomerizing, autophosphorylating, and cleaving RNA to remodel mRNA pools.

The mechanistic description of oligomerization -> autophosphorylation -> RNase activation is correct in outline. But the summary completely misses the specific biological context: the unfolded protein response (UPR), HAC1 mRNA splicing, ER stress sensing, and the fact that IRE1 is the sole UPR sensor in yeast. The phrase "stress-adaptive signaling and translational reprogramming" is too vague to be useful when the specific pathway (GO:0036498 IRE1-mediated unfolded protein response; GO:0030968 ER UPR) is one of the best-characterized stress signaling pathways in yeast.

Comparison with interpro2go:

The interpro2go annotations (GO_REF:0000002) contribute RNA nuclease activity (GO:0004540), protein kinase activity (GO:0004672), mRNA processing (GO:0006397), and signal transduction (GO:0007165). BioReason's functional summary captures the kinase and RNase activities, which overlaps with interpro2go. Neither interpro2go nor BioReason reaches the specific UPR pathway terms -- those come from IBA and experimental evidence. BioReason does not meaningfully improve on interpro2go here; the ER membrane localization error is a regression from interpro2go's CC predictions, which include ER terms.

Notes on thinking trace

The trace misinterprets the N-terminal lumenal domain as a cytoplasmic beta-propeller. The reasoning states "the absence of transmembrane segments" -- but the protein has a transmembrane helix (residues ~527-549). The thinking trace appears to have missed the transmembrane segment or given it insufficient weight, leading to the cytoplasmic localization error. The model's strong prior for "soluble = cytosolic" overrides structural evidence for membrane anchoring.

📄 View Raw YAML

id: P32361
gene_symbol: IRE1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: >-
  IRE1 (also known as ERN1) is a type I transmembrane serine/threonine-protein kinase
  and endoribonuclease that serves as the primary ER stress sensor in S. cerevisiae.
  It contains an N-terminal lumenal domain (residues 19-526) that senses unfolded proteins
  in the ER, a single transmembrane helix, and a cytoplasmic portion with both kinase
  (residues 674-980) and KEN/endoribonuclease (residues 983-1115) domains. Upon ER stress,
  unfolded proteins bind the lumenal domain, triggering oligomerization and trans-
  autophosphorylation, which activates the endoribonuclease domain. The RNase domain
  then splices HAC1 precursor mRNA to produce mature HAC1 mRNA encoding a transcription
  factor that induces UPR target genes. IRE1 is the sole UPR sensor in yeast, unlike
  metazoans which have additional sensors (PERK, ATF6).
existing_annotations:
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for ER localization. IRE1 is a well-established ER-resident
      transmembrane protein (PMID:8358794). Supported by IDA and HDA evidence.
    action: ACCEPT
    reason: >-
      ER localization is fundamental to IRE1 function as the ER stress sensor.
      Confirmed by IDA (PMID:8358794) and HDA (PMID:26928762).
- term:
    id: GO:0036498
    label: IRE1-mediated unfolded protein response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for the IRE1-mediated UPR. IRE1 is the defining component
      of this pathway in yeast, sensing unfolded proteins and activating HAC1
      mRNA splicing (PMID:8358794, PMID:9323131).
    action: ACCEPT
    reason: >-
      This is the core biological process of IRE1. The gene is named after this
      pathway. Confirmed by IDA (PMID:19079236) and IMP (PMID:8358794, PMID:8513503).
- term:
    id: GO:0004521
    label: RNA endonuclease activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for RNA endonuclease activity. IRE1 is a site-specific
      endonuclease that cleaves HAC1 pre-mRNA at two specific sites to initiate
      unconventional mRNA splicing (PMID:9323131, PMID:18191223).
    action: ACCEPT
    reason: >-
      RNA endonuclease activity is a core molecular function of IRE1. Confirmed
      by IDA (PMID:9323131). The KEN domain (residues 983-1115) is the catalytic
      domain for this activity.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein Ser/Thr kinase activity. IRE1 undergoes
      trans-autophosphorylation on Ser-840, Ser-841, and Thr-844, which is
      required for activation of the endoribonuclease domain (PMID:8663458,
      PMID:18191223).
    action: ACCEPT
    reason: >-
      Kinase activity is a core molecular function of IRE1. Confirmed by IDA
      (PMID:8663458) and crystal structure (PMID:18191223). Kinase activation
      is required for RNase activation.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0051082 is proposed for obsoletion. IRE1 does directly bind unfolded
      proteins via its lumenal domain (PMID:17923530), but it functions as a
      sensor/signaling molecule, not a chaperone. The binding triggers
      oligomerization and UPR activation, not protein folding.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0051082 "unfolded protein binding" is proposed for obsoletion. While
      IRE1 does bind unfolded proteins via its lumenal domain (PMID:17923530),
      this binding serves a signaling function (sensor), not a chaperone function.
      IRE1 does not assist protein folding. The unfolded protein binding by IRE1
      is mechanistically part of its sensor function in the UPR, which is already
      captured by GO:0036498. There is currently no appropriate GO MF term for
      "unfolded protein sensor activity" to use as a replacement.
- term:
    id: GO:0070059
    label: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum
      stress
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for apoptotic signaling in response to ER stress.
      This is primarily a metazoan function (IRE1alpha/beta in mammals). Yeast
      does not have classical apoptosis, although programmed cell death mechanisms
      exist. The IBA inference from mammalian orthologs may not be fully appropriate
      for yeast.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This annotation appears to be inferred from mammalian IRE1 orthologs where
      IRE1 contributes to apoptotic signaling under prolonged ER stress. S. cerevisiae
      does not have classical apoptosis. While yeast has programmed cell death
      pathways, this specific term is too metazoan-centric for yeast IRE1.
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for nucleotide binding from UniProt keyword. IRE1 binds
      ATP/ADP in its kinase domain (PMID:18191223, crystal structure with ADP).
    action: ACCEPT
    reason: >-
      Correct but very broad. IRE1 binds ATP for its kinase activity. Acceptable
      as an IEA.
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for catalytic activity from UniProt keyword. IRE1 has both
      kinase and endoribonuclease catalytic activities.
    action: ACCEPT
    reason: >-
      Correct but extremely broad. Both kinase and RNase activities are catalytic.
      Acceptable as a broad IEA.
- term:
    id: GO:0004521
    label: RNA endonuclease activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for RNA endonuclease activity from combined automated methods.
      Consistent with IBA and IDA evidence.
    action: ACCEPT
    reason: >-
      Correct. Consistent with experimental evidence (PMID:9323131, PMID:18191223).
- term:
    id: GO:0004540
    label: RNA nuclease activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for RNA nuclease activity from InterPro. Broader parent of
      RNA endonuclease activity.
    action: ACCEPT
    reason: >-
      Correct but less specific than GO:0004521. Acceptable as a broad IEA.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for protein kinase activity from InterPro. Broader parent
      of protein serine/threonine kinase activity.
    action: ACCEPT
    reason: >-
      Correct but less specific than GO:0004674. Acceptable as an IEA.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for protein Ser/Thr kinase from combined automated methods.
      Consistent with IBA and IDA evidence.
    action: ACCEPT
    reason: >-
      Correct. Consistent with experimental evidence (PMID:8663458, PMID:18191223).
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for ATP binding. IRE1 binds ATP in its kinase domain. Crystal
      structure shows ADP bound in the active site (PMID:18191223).
    action: ACCEPT
    reason: >-
      Correct. ATP binding is essential for kinase activity and confirmed by
      crystal structure.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for ER membrane from UniProt subcellular location. IRE1 is
      a type I transmembrane protein spanning the ER membrane.
    action: ACCEPT
    reason: >-
      Correct. Confirmed by IDA (PMID:8358794) and topology studies.
- term:
    id: GO:0006397
    label: mRNA processing
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for mRNA processing from InterPro. IRE1 processes HAC1 mRNA
      through unconventional splicing.
    action: ACCEPT
    reason: >-
      Correct. IRE1 endoribonuclease activity directly processes HAC1 pre-mRNA
      (PMID:9323131).
- term:
    id: GO:0006986
    label: response to unfolded protein
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for response to unfolded protein from UniProt keyword. IRE1
      is the primary sensor and effector of the unfolded protein response in yeast.
    action: ACCEPT
    reason: >-
      Correct. This is the core biological process of IRE1.
- term:
    id: GO:0016301
    label: kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for kinase activity from UniProt keyword. Broader parent of
      protein kinase activity.
    action: ACCEPT
    reason: >-
      Correct but very broad. Acceptable as an IEA.
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for transferase activity from UniProt keyword. Very broad
      parent of kinase activity.
    action: ACCEPT
    reason: >-
      Correct but extremely broad. Acceptable as an IEA.
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for hydrolase activity from UniProt keyword. Broad parent
      of RNA nuclease activity.
    action: ACCEPT
    reason: >-
      Correct but extremely broad. Acceptable as an IEA.
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation for ER UPR from combined automated methods. Consistent with
      IMP evidence.
    action: ACCEPT
    reason: >-
      Correct. IRE1 is the master regulator of the ER UPR in yeast.
- term:
    id: GO:0031505
    label: fungal-type cell wall organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation for fungal-type cell wall organization from ARBA. This is
      consistent with IMP and IGI evidence (PMID:18971375, PMID:8898193) showing
      IRE1 is required for cell wall integrity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cell wall organization is a downstream consequence of IRE1's UPR signaling
      function. The UPR regulates expression of cell wall biosynthesis genes.
      Not a core function of IRE1 itself.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation for metal ion binding from UniProt keyword. IRE1 kinase
      domain binds Mg2+ as a cofactor (PMID:18191223).
    action: ACCEPT
    reason: >-
      Correct. Mg2+ is required as a cofactor for kinase activity. Confirmed by
      crystal structure (PMID:18191223).
- term:
    id: GO:0106310
    label: protein serine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  review:
    summary: >-
      IEA annotation for protein serine kinase activity from Rhea mapping. IRE1
      autophosphorylates on serine residues (Ser-840, Ser-841).
    action: ACCEPT
    reason: >-
      Correct. Serine autophosphorylation is confirmed (PMID:18191223, PMID:8670804).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16990850
  review:
    summary: >-
      IPI annotation for protein binding showing interaction with DCR2 (Q05924).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Protein binding is uninformative. The specific interaction with DCR2 may be
      relevant to IRE1 regulation but is not captured by the generic term.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18191223
  review:
    summary: >-
      IPI annotation for identical protein binding (homodimerization). IRE1
      homodimerizes upon ER stress, and dimerization is essential for both kinase
      trans-autophosphorylation and RNase activation (PMID:18191223, PMID:8663458).
    action: ACCEPT
    reason: >-
      Homodimerization is functionally critical for IRE1 activation. Crystal
      structures confirm the dimer interface (PMID:18191223, PMID:16365312).
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19079236
  review:
    summary: >-
      IPI annotation for identical protein binding. Additional evidence for
      IRE1 homodimerization.
    action: ACCEPT
    reason: >-
      Consistent with other evidence for functionally important homodimerization.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:20625545
  review:
    summary: >-
      IPI annotation for identical protein binding from study of BiP binding
      to IRE1 and its regulation of UPR homeostasis.
    action: ACCEPT
    reason: >-
      Additional evidence for IRE1 homodimerization, studied in the context of
      BiP regulation.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:17923530
  review:
    summary: >-
      NAS annotation for ER membrane from ComplexPortal. Consistent with IDA
      evidence.
    action: ACCEPT
    reason: >-
      Correct. Consistent with IDA (PMID:8358794) and topology studies.
- term:
    id: GO:0036498
    label: IRE1-mediated unfolded protein response
  evidence_type: IDA
  original_reference_id: PMID:19079236
  review:
    summary: >-
      IDA annotation for IRE1-mediated UPR from ComplexPortal.
    action: ACCEPT
    reason: >-
      Core biological process of IRE1. Experimentally demonstrated.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:8358794
  review:
    summary: >-
      IDA annotation for ER membrane localization from the founding paper on
      IRE1 (PMID:8358794). IRE1 is a transmembrane protein with lumenal and
      cytoplasmic domains.
    action: ACCEPT
    reason: >-
      Primary experimental evidence for ER membrane localization from the
      original characterization.
- term:
    id: GO:0004521
    label: RNA endonuclease activity
  evidence_type: IDA
  original_reference_id: PMID:9323131
  review:
    summary: >-
      IDA annotation for RNA endonuclease activity. IRE1 is a site-specific
      endonuclease that cleaves HAC1 pre-mRNA at two specific positions
      (PMID:9323131).
    action: ACCEPT
    reason: >-
      Core molecular function demonstrated by direct assay. This is the key
      enzymatic activity that mediates UPR signaling.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: HDA
  original_reference_id: PMID:26928762
  review:
    summary: >-
      HDA annotation for ER localization from large-scale yeast library analysis.
    action: ACCEPT
    reason: >-
      Consistent with IDA and IBA evidence for ER localization.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: HDA
  original_reference_id: PMID:16319894
  review:
    summary: >-
      HDA annotation for protein kinase activity from global phosphorylation
      analysis in yeast.
    action: ACCEPT
    reason: >-
      Consistent with IDA evidence for kinase activity (PMID:8663458).
- term:
    id: GO:0034067
    label: protein localization to Golgi apparatus
  evidence_type: IMP
  original_reference_id: PMID:26966233
  review:
    summary: >-
      IMP annotation for protein localization to Golgi apparatus. IRE1 influences
      protein sorting and Golgi function through UPR target gene regulation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Protein localization to Golgi is a downstream effect of IRE1's UPR
      signaling function, not a direct function of IRE1.
- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IMP
  original_reference_id: PMID:26966233
  review:
    summary: >-
      IMP annotation for response to ER stress. IRE1 is the primary ER stress
      sensor and signaling molecule in yeast.
    action: ACCEPT
    reason: >-
      Core biological process. IRE1 is the defining component of the ER stress
      response in yeast.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-SCE-535524
  review:
    summary: >-
      TAS annotation for ER membrane from Reactome pathway.
    action: ACCEPT
    reason: >-
      Correct. Consistent with IDA evidence.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:8663458
  review:
    summary: >-
      IDA annotation for protein Ser/Thr kinase activity. IRE1 undergoes
      trans-autophosphorylation requiring oligomerization (PMID:8663458).
      K702A mutation abolishes autophosphorylation.
    action: ACCEPT
    reason: >-
      Core molecular function demonstrated by direct assay. Trans-autophosphorylation
      is essential for activating the endoribonuclease domain.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:17035634
  review:
    summary: >-
      IDA annotation for nuclear localization. This may reflect a minor
      population of IRE1 or a specific experimental condition.
    action: UNDECIDED
    reason: >-
      Unable to access PMID:17035634 to verify the nuclear localization claim.
      IRE1 is primarily an ER membrane protein, so nuclear localization would
      be unusual and requires verification.
- term:
    id: GO:0006020
    label: inositol metabolic process
  evidence_type: IMP
  original_reference_id: PMID:1625574
  review:
    summary: >-
      IMP annotation for inositol metabolic process. IRE1 was originally
      identified as required for inositol prototrophy (PMID:1625574). The
      UPR regulates inositol biosynthesis genes.
    action: KEEP_AS_NON_CORE
    reason: >-
      Inositol metabolism is regulated by the UPR pathway. IRE1 influences
      inositol levels through transcriptional regulation of biosynthetic genes,
      but this is a downstream consequence of UPR signaling.
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:8358794
  review:
    summary: >-
      IMP annotation for ER UPR from the founding paper on IRE1 signaling
      (PMID:8358794). IRE1 is required for signaling from the ER to the
      nucleus.
    action: ACCEPT
    reason: >-
      Core biological process. This is the defining function of IRE1.
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: IMP
  original_reference_id: PMID:8513503
  review:
    summary: >-
      IMP annotation for ER UPR from additional evidence.
    action: ACCEPT
    reason: >-
      Additional experimental evidence for the core biological process.
- term:
    id: GO:0031505
    label: fungal-type cell wall organization
  evidence_type: IMP
  original_reference_id: PMID:18971375
  review:
    summary: >-
      IMP annotation for fungal-type cell wall organization. IRE1 mutants
      have cell wall defects.
    action: KEEP_AS_NON_CORE
    reason: >-
      Cell wall organization is a downstream consequence of UPR signaling.
      The UPR regulates genes involved in cell wall biosynthesis.
- term:
    id: GO:0031505
    label: fungal-type cell wall organization
  evidence_type: IGI
  original_reference_id: PMID:18971375
  review:
    summary: >-
      IGI annotation for fungal-type cell wall organization based on genetic
      interaction data.
    action: KEEP_AS_NON_CORE
    reason: >-
      Same as above - downstream consequence of UPR signaling.
- term:
    id: GO:0031505
    label: fungal-type cell wall organization
  evidence_type: IMP
  original_reference_id: PMID:8898193
  review:
    summary: >-
      IMP annotation for fungal-type cell wall organization from earlier study.
    action: KEEP_AS_NON_CORE
    reason: >-
      Downstream consequence of UPR signaling. Not a core function of IRE1.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:17923530
  review:
    summary: >-
      IDA annotation for unfolded protein binding based on direct demonstration
      that IRE1 lumenal domain directly interacts with unfolded proteins
      (PMID:17923530). This paper showed two regulatory steps: cluster formation
      and direct interaction with unfolded proteins.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      GO:0051082 is proposed for obsoletion. While the experimental evidence is
      solid that IRE1 binds unfolded proteins (PMID:17923530), the function of
      this binding is as a sensor/signal transducer, not as a chaperone. IRE1
      does not assist protein folding. The binding triggers oligomerization and
      UPR activation. There is currently no appropriate GO MF term for "unfolded
      protein sensor activity." The sensing function is best captured at the BP
      level by GO:0030968 and GO:0036498.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IMP
  original_reference_id: PMID:17923530
  review:
    summary: >-
      IMP annotation for unfolded protein binding. Same study as the IDA
      annotation above (PMID:17923530).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Same reasoning as the IDA annotation. GO:0051082 is proposed for obsoletion.
      IRE1 binds unfolded proteins as a sensor, not a chaperone. The term does not
      accurately describe the functional role of this binding.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:1625574
  title: IRE1 encodes a putative protein kinase containing a membrane-spanning domain and is required for inositol phototrophy in Saccharomyces cerevisiae.
  findings: []
- id: PMID:16319894
  title: Global analysis of protein phosphorylation in yeast.
  findings: []
- id: PMID:16365312
  title: On the mechanism of sensing unfolded protein in the endoplasmic reticulum.
  findings: []
- id: PMID:16990850
  title: Dcr2 targets Ire1 and downregulates the unfolded protein response in Saccharomyces cerevisiae.
  findings: []
- id: PMID:17035634
  title: The unfolded protein response transducer Ire1p contains a nuclear localization sequence recognized by multiple beta importins.
  findings: []
- id: PMID:17923530
  title: Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins.
  findings: []
- id: PMID:18191223
  title: Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing.
  findings: []
- id: PMID:18971375
  title: The unfolded protein response is induced by the cell wall integrity mitogen-activated protein kinase signaling cascade and is required for cell wall integrity in Saccharomyces cerevisiae.
  findings: []
- id: PMID:19079236
  title: The unfolded protein response signals through high-order assembly of Ire1.
  findings: []
- id: PMID:20625545
  title: BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response.
  findings: []
- id: PMID:26928762
  title: One library to make them all - streamlining the creation of yeast libraries via a SWAp-Tag strategy.
  findings: []
- id: PMID:26966233
  title: Unfolded protein response regulates yeast small GTPase Arl1p activation at late Golgi via phosphorylation of Arf GEF Syt1p.
  findings: []
- id: PMID:8358794
  title: A transmembrane protein with a cdc2+/CDC28-related kinase activity is required for signaling from the ER to the nucleus.
  findings: []
- id: PMID:8513503
  title: Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase.
  findings: []
- id: PMID:8663458
  title: The unfolded protein response pathway in Saccharomyces cerevisiae. Oligomerization and trans-phosphorylation of Ire1p (Ern1p) are required for kinase activation.
  findings: []
- id: PMID:8670804
  title: Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.
  findings: []
- id: PMID:8898193
  title: A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response.
  findings: []
- id: PMID:9323131
  title: The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response.
  findings: []
- id: PMID:9528768
  title: Protein serine/threonine phosphatase Ptc2p negatively regulates the unfolded-protein response by dephosphorylating Ire1p kinase.
  findings: []
- id: Reactome:R-SCE-535524
  title: Phosphorylated Ire1 Dimer Binds ADP
  findings: []
core_functions:
- description: >-
    Protein serine/threonine kinase that undergoes trans-autophosphorylation upon ER
    stress-induced oligomerization, activating the endoribonuclease domain to splice
    HAC1 mRNA and trigger the unfolded protein response.
  molecular_function:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  directly_involved_in:
  - id: GO:0036498
    label: IRE1-mediated unfolded protein response
  - id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  - id: GO:0034976
    label: response to endoplasmic reticulum stress
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
- description: >-
    RNA endonuclease that cleaves HAC1 pre-mRNA at two specific sites to initiate
    unconventional mRNA splicing, producing mature HAC1 mRNA encoding the UPR
    transcription factor.
  molecular_function:
    id: GO:0004521
    label: RNA endonuclease activity
  directly_involved_in:
  - id: GO:0006397
    label: mRNA processing
  - id: GO:0036498
    label: IRE1-mediated unfolded protein response
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane

IRE1

Gene Description

Existing Annotations Review

Core Functions

Protein serine/threonine kinase that undergoes trans-autophosphorylation upon ER stress-induced oligomerization, activating the endoribonuclease domain to splice HAC1 mRNA and trigger the unfolded protein response.

RNA endonuclease that cleaves HAC1 pre-mRNA at two specific sites to initiate unconventional mRNA splicing, producing mature HAC1 mRNA encoding the UPR transcription factor.

References

📚 Additional Documentation

Deep Research Bioreason

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Bioreason Rl

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Bioreason Rl Review

BioReason-Pro RL Review: IRE1 (S. cerevisiae)

Functional Summary Review

Notes on thinking trace

📄 View Raw YAML