Fbxo2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0036503 ERAD pathway	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for involvement in the ERAD pathway. This is a core function of Fbxo2, well-established by multiple experimental papers. Fbxo2 recognizes N-glycans on misfolded glycoproteins retrotranslocated from the ER and promotes their ubiquitination and proteasomal degradation (PMID:12140560, PMID:15723043). Reason: ERAD is the central biological pathway in which Fbxo2 operates. The IBA annotation is consistent with direct experimental evidence from PMID:12140560 and PMID:15723043. The phylogenetic inference is well-supported. Supporting Evidence: PMID:12140560 expression of the mutant Fbx2 Delta F, which lacks the F-box domain that is essential for forming the SCF complex, appreciably blocks degradation of typical substrates of the ER-associated degradation pathway PMID:15723043 the SCF(Fbs1,2) ubiquitin-ligase complexes that contribute to ubiquitination of glycoproteins are involved in the ER-associated degradation pathway file:mouse/Fbxo2/Fbxo2-deep-research-falcon.md Mouse Fbxo2 encodes a lectin-type F-box protein whose SBD specifically recognizes the inner core of N-linked glycans to target glycoproteins for SCF-mediated ubiquitination in ERAD.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for cytoplasm localization. Fbxo2 operates in the cytosol, where it recognizes retrotranslocated glycoproteins from the ER. More specifically it localizes to the cytosol and to microsome membrane peripheral cytoplasmic side (UniProt). Reason: Cytoplasm is a correct general localization. The IBA is consistent with IDA evidence for cytosol (PMID:12140560). The broader term cytoplasm is acceptable for an IBA. Supporting Evidence: PMID:12140560 Pre-integrin beta 1 is a target of Fbx2; these two proteins interact in the cytosol after inhibition of the proteasome
GO:0006516 glycoprotein catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for involvement in glycoprotein catabolic process. This is a core function. Fbxo2 promotes ubiquitination and subsequent proteasomal degradation of N-glycosylated proteins (PMID:12140560, PMID:15723043). Reason: Glycoprotein catabolism is the downstream consequence of Fbxo2-mediated substrate recognition and ubiquitination. Well-supported by direct experimental evidence. Supporting Evidence: PMID:12140560 SCF(Fbx2) ubiquitinates N-glycosylated proteins that are translocated from the ER to the cytosol by the quality control mechanism
GO:0019005 SCF ubiquitin ligase complex	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for membership in the SCF ubiquitin ligase complex. Fbxo2 is the F-box substrate recognition subunit of the SCF(Fbxo2) complex consisting of CUL1, RBX1, SKP1, and FBXO2 (PMID:12140560, PMID:17389369). Reason: SCF complex membership is a core structural aspect of Fbxo2 function, extensively validated by crystal structures (PMID:17389369) and biochemical data (PMID:12140560). Supporting Evidence: PMID:12140560 N-glycan serves as a signal for degradation by the Skp1-Cullin1-Fbx2-Roc1 (SCF(Fbx2)) ubiquitin ligase complex
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for involvement in SCF-dependent proteasomal ubiquitin-dependent protein catabolic process. This describes the pathway Fbxo2 participates in. Reason: This is the specific proteasomal degradation pathway that SCF(Fbxo2) mediates. Well-supported by PMID:12140560 demonstrating that SCF(Fbxo2) ubiquitinates glycoproteins for proteasomal degradation. Supporting Evidence: PMID:12140560 The F-box protein Fbx2 (ref. 4) binds specifically to proteins attached to N-linked high-mannose oligosaccharides and subsequently contributes to ubiquitination of N-glycosylated proteins
GO:0061630 ubiquitin protein ligase activity	IBA GO_REF:0000033	MODIFY	Summary: IBA annotation for ubiquitin protein ligase activity with qualifier "contributes_to". Fbxo2 is the substrate recognition component of the SCF(Fbxo2) E3 ligase complex; it does not itself possess catalytic E3 ligase activity but contributes to the complex's activity by conferring substrate specificity (PMID:12140560, PMID:17389369). Reason: While "contributes_to" ubiquitin protein ligase activity is technically defensible as Fbxo2 is a subunit of an active E3 ligase complex, the more precise molecular function of Fbxo2 is as a ubiquitin ligase substrate adaptor. GO:1990756 "ubiquitin-like ligase-substrate adaptor activity" better captures Fbxo2's actual role: bringing together the E3 ligase and its substrate through glycan recognition. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN000252369 SUPPORTS TRANSFER An F-box protein node; the family relationship to the target is not disputed. The objection is that a substrate-recognition F-box subunit carries the catalytic ligase activity of the SCF holo-complex it joins rather than its own adaptor role. MGI:MGI:1354743 · a mouse F-box family member; not mouse Fbxo2, whose own record is MGI:2446216 SUPPORTS SOURCE BUT NOT TARGET The seed is a different mouse gene from the target and its identity could not be resolved from the local caches, so it is named by identifier only. Whatever its identity, an F-box seed supports SCF participation rather than an intrinsic ligase activity residing in the F-box subunit. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:17389369 In SCF ubiquitin ligases, a diverse array of F-box proteins confers substrate specificity. Fbs1/Fbx2, a member of the F-box protein family, recognizes high-mannose oligosaccharides
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for cytoplasm localization. Redundant with IBA and IDA evidence for cytoplasm/cytosol localization. Reason: Correct and consistent with experimental evidence. IEA is broader than the IDA cytosol annotation but not incorrect.
GO:0006516 glycoprotein catabolic process	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for glycoprotein catabolic process, inferred by ARBA machine learning. Redundant with IBA and IDA evidence for the same term. Reason: Correct and consistent with experimental data from PMID:12140560 and PMID:15723043.
GO:0019005 SCF ubiquitin ligase complex	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for SCF ubiquitin ligase complex membership. Redundant with IBA and IDA evidence. Reason: Correct. Fbxo2 is a well-characterized component of the SCF(Fbxo2) complex.
GO:0030246 carbohydrate binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for carbohydrate binding, inferred from UniProt keyword "Lectin". Carbohydrate binding is a core molecular function of Fbxo2. The FBA (F-box associated) domain specifically binds high-mannose N-glycans (PMID:14990996, PMID:17389369). Reason: Correct and a core function. Carbohydrate binding is well-established experimentally. While a more specific term like oligosaccharide binding (GO:0070492) might be more precise, carbohydrate binding is not incorrect for an IEA annotation.
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for SCF-dependent proteasomal degradation. Redundant with IBA and IDA evidence for the same term. Reason: Correct and consistent with experimental evidence from PMID:12140560.
GO:0036503 ERAD pathway	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for ERAD pathway involvement. Redundant with IBA and IDA evidence. Reason: Correct. ERAD is the core biological pathway of Fbxo2 function.
GO:0005515 protein binding	IPI PMID:17389369 Structural basis for the selection of glycosylated substrate...	MODIFY	Summary: IPI annotation for protein binding based on crystal structure of SCF(Fbs1) with glycoprotein substrate RNase1 (PMID:17389369). The interaction partner is UniProtKB:P61823 (bovine RNase1). The crystal structure revealed the structural basis for how the sugar-binding domain selects glycosylated substrates. Reason: "Protein binding" is uninformative. The interaction demonstrated in PMID:17389369 is actually glycan-mediated binding of a glycoprotein substrate. The correct MF annotation is carbohydrate binding or more specifically oligosaccharide binding, or the substrate adaptor activity. Since these are already captured by other annotations, this particular "protein binding" annotation should be modified to the more informative substrate adaptor term. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:17389369 The structure of the SBD-glycoprotein complex indicates that the SBD primarily recognizes Man(3)GlcNAc(2), thereby explaining the broad activity of the enzyme against various glycoproteins
GO:0005515 protein binding	IPI PMID:17389369 Structural basis for the selection of glycosylated substrate...	MODIFY	Summary: Second IPI annotation for protein binding from PMID:17389369, this time with UniProtKB:P63208-1 (Skp1). The crystal structure showed the Skp1-Fbs1 complex architecture with the F-box domain mediating Skp1 interaction. Reason: "Protein binding" is uninformative. The interaction with Skp1 is an obligate structural interaction within the SCF complex. This is better captured by the existing SCF complex membership annotation (GO:0019005) and the substrate adaptor activity (GO:1990756). Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:17389369 we determined the crystal structures of the Skp1-Fbs1 complex and the sugar-binding domain (SBD) of the Fbs1-glycoprotein complex
GO:0005515 protein binding	IPI PMID:15809437 Activity-dependent NMDA receptor degradation mediated by ret...	MODIFY	Summary: IPI annotation for protein binding based on PMID:15809437, with interaction partner PR:P35438 (NR1/GRIN1 NMDA receptor subunit). Fbxo2 binds to high-mannose glycans of the NR1 ectodomain and promotes NR1 ubiquitination. Reason: "Protein binding" is uninformative. The binding to NR1 is glycan-mediated (Fbxo2 binds the high-mannose glycans on the NR1 ectodomain) and represents substrate recognition for ubiquitination. This is better captured by carbohydrate binding (GO:0030246) and/or ubiquitin-like ligase-substrate adaptor activity (GO:1990756). Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:15809437 the F-box protein, Fbx2, bound to high-mannose glycans of the NR1 ectodomain. F-box proteins specify ubiquitination by linking protein substrates to the terminal E3 ligase
GO:0005515 protein binding	IPI PMID:15723043 Glycoprotein-specific ubiquitin ligases recognize N-glycans ...	MODIFY	Summary: IPI annotation for protein binding from PMID:15723043, with interaction partner PR:P09055 (integrin beta-1). Fbxo2 interacts with integrin-beta1 (an ERAD substrate) in the cytosol in a manner dependent on p97 ATPase activity. Reason: "Protein binding" is uninformative. The interaction with integrin-beta1 represents glycan-mediated substrate recognition. This is better captured by the substrate adaptor activity term and the ERAD pathway annotation. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:15723043 The SCF(Fbs1) complex was associated with p97/VCP AAA ATPase and bound to integrin-beta1, one of the SCF(Fbs1) substrates, in the cytosol in a manner dependent on p97 ATPase activity
GO:0005515 protein binding	IPI PMID:15723043 Glycoprotein-specific ubiquitin ligases recognize N-glycans ...	MARK AS OVER ANNOTATED	Summary: Second IPI annotation for protein binding from PMID:15723043 (with PR:Q01853, VCP/p97). This is a separate entry from the same reference, representing the VCP/p97 interaction partner. Reason: The VCP/p97 interaction is part of ERAD machinery coordination rather than Fbxo2's substrate adaptor activity. "Protein binding" is true at the interaction level but not useful as a functional descriptor; the ERAD pathway annotation captures the biological context without implying a separate core molecular function. Supporting Evidence: PMID:15723043 The SCF(Fbs1) complex was associated with p97/VCP AAA ATPase
GO:0005737 cytoplasm	ISO GO_REF:0000119	ACCEPT	Summary: ISO annotation for cytoplasm localization, transferred from human ortholog UniProtKB:Q9UK22 (FBXO2). Redundant with IBA and IDA evidence. Reason: Correct and consistent with experimental evidence for cytoplasm/cytosol localization.
GO:0008285 negative regulation of cell population proliferation	ISO GO_REF:0000096	UNDECIDED	Summary: ISO annotation for negative regulation of cell population proliferation, transferred from rat ortholog RGD:621751. This is not a well-characterized function of Fbxo2. The core function of Fbxo2 is ERAD-linked glycoprotein degradation, not cell proliferation regulation. Reason: This annotation is based on ortholog transfer from rat and may reflect an indirect downstream consequence, but the mouse review does not establish positive support for retaining a proliferation-regulatory role.
GO:0098890 extrinsic component of postsynaptic membrane	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO annotation for extrinsic component of postsynaptic membrane, transferred from rat ortholog. This is consistent with Fbxo2's role in degrading NMDA receptor NR1 subunits at the postsynapse (PMID:15809437). Reason: This localization is supported in the neuronal NR1 substrate context, but it is context-specific rather than the primary Fbxo2 ERAD/glycoprotein-recognition role. Supporting Evidence: PMID:15809437 the F-box protein, Fbx2, bound to high-mannose glycans of the NR1 ectodomain
GO:0098978 glutamatergic synapse	ISO GO_REF:0000096	KEEP AS NON CORE	Summary: ISO annotation for glutamatergic synapse localization, transferred from rat ortholog. Redundant with IDA evidence from SynGO (PMID:15809437). Reason: Supported in the neuronal NR1 substrate context, but glutamatergic synapse localization is context-specific rather than the primary Fbxo2 ERAD/glycoprotein recognition role.
GO:0098978 glutamatergic synapse	IDA PMID:15809437 Activity-dependent NMDA receptor degradation mediated by ret...	KEEP AS NON CORE	Summary: IDA annotation from SynGO for glutamatergic synapse localization based on PMID:15809437. Kato et al. showed Fbxo2 localizes to hippocampal neurons and specifically targets NR1 at glutamatergic synapses. Multiple evidence lines (ECO:0000314, ECO:0005589, ECO:0007695, ECO:0007719) all support this. Reason: Supported by PMID:15809437 in a neuronal substrate context, but glutamatergic synapse localization is context-specific rather than the primary Fbxo2 ERAD/glycoprotein-recognition role. Supporting Evidence: PMID:15809437 When expressed in hippocampal neurons, this Fbx2 dominant-negative mutant augmented NR1 subunit levels and NMDA receptor-mediated currents in an activity-dependent fashion
GO:0098978 glutamatergic synapse	IMP PMID:15809437 Activity-dependent NMDA receptor degradation mediated by ret...	KEEP AS NON CORE	Summary: IMP annotation from SynGO for glutamatergic synapse localization based on mutant phenotype analysis (dominant-negative Fbxo2) in PMID:15809437. Reason: The dominant-negative Fbxo2 mutant supports a neuronal NR1 substrate context, but this is not the primary Fbxo2 ERAD/glycoprotein-recognition role. Supporting Evidence: PMID:15809437 this Fbx2 dominant-negative mutant augmented NR1 subunit levels and NMDA receptor-mediated currents in an activity-dependent fashion
GO:0099576 regulation of protein catabolic process at postsynapse, modulating synaptic transmission	IDA PMID:15809437 Activity-dependent NMDA receptor degradation mediated by ret...	KEEP AS NON CORE	Summary: IDA annotation from SynGO for regulation of postsynaptic protein catabolism. Fbxo2 promotes ubiquitination and degradation of NMDA receptor NR1 subunits at the postsynapse, thereby modulating synaptic transmission (PMID:15809437). Reason: This is a supported neuronal-specific substrate context, but it is not the primary Fbxo2 ERAD/glycoprotein-recognition role. Supporting Evidence: PMID:15809437 ubiquitination of NR1 was increased by Fbx2 and diminished by an Fbx2 dominant-negative mutant
GO:0099576 regulation of protein catabolic process at postsynapse, modulating synaptic transmission	IMP PMID:15809437 Activity-dependent NMDA receptor degradation mediated by ret...	KEEP AS NON CORE	Summary: IMP annotation from SynGO for postsynaptic protein catabolism regulation, based on mutant phenotype evidence. The dominant-negative Fbxo2 augmented NR1 levels and NMDA receptor currents. Reason: Supported by the dominant-negative experiment in PMID:15809437, but retained as non-core because it represents a neuronal substrate context rather than the primary Fbxo2 ERAD/glycoprotein-recognition role. Supporting Evidence: PMID:15809437 this Fbx2 dominant-negative mutant augmented NR1 subunit levels and NMDA receptor-mediated currents in an activity-dependent fashion
GO:0016567 protein ubiquitination	IEA GO_REF:0000041	ACCEPT	Summary: IEA annotation for protein ubiquitination, based on UniPathway vocabulary mapping. Fbxo2 participates in protein ubiquitination as part of the SCF(Fbxo2) complex. Reason: Correct. Fbxo2 is integral to the SCF(Fbxo2) E3 ubiquitin ligase complex that ubiquitinates glycoprotein substrates. Consistent with IDA evidence from PMID:12140560.
GO:0005515 protein binding	IPI PMID:15809437 Activity-dependent NMDA receptor degradation mediated by ret...	MODIFY	Summary: IPI annotation for protein binding from PMID:15809437, with interaction partner PR:P35438 (NR1/GRIN1). This is the MGI-curated version of the NR1 interaction. Redundant with the SynGO-curated IPI annotation from the same paper. Reason: "Protein binding" is uninformative. The NR1 interaction is glycan-mediated and represents substrate recognition for ubiquitination. Better captured by GO:1990756 ubiquitin-like ligase-substrate adaptor activity. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:15809437 the F-box protein, Fbx2, bound to high-mannose glycans of the NR1 ectodomain
GO:0005829 cytosol	IDA PMID:12140560 E3 ubiquitin ligase that recognizes sugar chains.	ACCEPT	Summary: IDA annotation for cytosol localization from the landmark paper identifying SCF(Fbxo2) (PMID:12140560). Fbxo2 interacts with its glycoprotein substrate pre-integrin beta-1 in the cytosol after proteasome inhibition. Reason: Well-supported. Yoshida et al. demonstrated cytosolic localization of Fbxo2 and its interaction with substrates in the cytosol (PMID:12140560). UniProt also lists cytoplasm and microsome membrane (cytoplasmic side) as subcellular locations. Supporting Evidence: PMID:12140560 Pre-integrin beta 1 is a target of Fbx2; these two proteins interact in the cytosol after inhibition of the proteasome
GO:0006516 glycoprotein catabolic process	IDA PMID:12140560 E3 ubiquitin ligase that recognizes sugar chains.	ACCEPT	Summary: IDA annotation for glycoprotein catabolic process from PMID:12140560. SCF(Fbxo2) ubiquitinates N-glycosylated proteins translocated from the ER, promoting their proteasomal degradation. Reason: Core function. Directly demonstrated in PMID:12140560 that Fbxo2 targets glycoproteins for degradation. Supporting Evidence: PMID:12140560 SCF(Fbx2) ubiquitinates N-glycosylated proteins that are translocated from the ER to the cytosol by the quality control mechanism
GO:0016567 protein ubiquitination	IDA PMID:12140560 E3 ubiquitin ligase that recognizes sugar chains.	ACCEPT	Summary: IDA annotation for protein ubiquitination from PMID:12140560. Fbxo2 contributes to ubiquitination of N-glycosylated proteins as part of the SCF(Fbxo2) complex. Reason: Core function. Directly demonstrated in PMID:12140560. Supporting Evidence: PMID:12140560 The F-box protein Fbx2 (ref. 4) binds specifically to proteins attached to N-linked high-mannose oligosaccharides and subsequently contributes to ubiquitination of N-glycosylated proteins
GO:0019005 SCF ubiquitin ligase complex	IDA PMID:12140560 E3 ubiquitin ligase that recognizes sugar chains.	ACCEPT	Summary: IDA annotation for SCF ubiquitin ligase complex membership from PMID:12140560. Fbxo2 was identified as the F-box protein forming the SCF(Fbxo2) complex (SKP1-CUL1-FBXO2-ROC1). Reason: Core structural annotation. The SCF(Fbxo2) complex was originally identified in PMID:12140560 and confirmed by crystal structures (PMID:17389369). Supporting Evidence: PMID:12140560 N-glycan serves as a signal for degradation by the Skp1-Cullin1-Fbx2-Roc1 (SCF(Fbx2)) ubiquitin ligase complex
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	IDA PMID:12140560 E3 ubiquitin ligase that recognizes sugar chains.	ACCEPT	Summary: IDA annotation for SCF-dependent proteasomal degradation from PMID:12140560. SCF(Fbxo2) mediates ubiquitin-dependent proteasomal degradation of glycoprotein substrates. Reason: Core function. The dominant-negative Fbxo2 Delta-F blocked ERAD substrate degradation (PMID:12140560), directly demonstrating SCF-dependent proteasomal degradation. Supporting Evidence: PMID:12140560 expression of the mutant Fbx2 Delta F, which lacks the F-box domain that is essential for forming the SCF complex, appreciably blocks degradation of typical substrates of the ER-associated degradation pathway
GO:0006511 ubiquitin-dependent protein catabolic process	IDA PMID:15723043 Glycoprotein-specific ubiquitin ligases recognize N-glycans ...	ACCEPT	Summary: IDA annotation for ubiquitin-dependent protein catabolic process from PMID:15723043. This is a parent term of the more specific SCF-dependent proteasomal degradation annotation. Fbxo2 mediates ubiquitin-dependent degradation of glycoprotein substrates. Reason: Correct, though redundant with the more specific GO:0031146 annotation. Keeping as the evidence from PMID:15723043 demonstrated ubiquitin-dependent degradation. Supporting Evidence: PMID:15723043 the SCF(Fbs1,2) ubiquitin-ligase complexes that contribute to ubiquitination of glycoproteins are involved in the ER-associated degradation pathway
GO:0031396 regulation of protein ubiquitination	IDA PMID:15809437 Activity-dependent NMDA receptor degradation mediated by ret...	ACCEPT	Summary: IDA annotation for regulation of protein ubiquitination from PMID:15809437. Fbxo2 increased NR1 ubiquitination, and the dominant-negative mutant diminished it. Reason: Well-supported. PMID:15809437 showed that Fbxo2 expression increased NR1 ubiquitination and the dominant-negative form decreased it, demonstrating regulation of ubiquitination at the synapse. Supporting Evidence: PMID:15809437 ubiquitination of NR1 was increased by Fbx2 and diminished by an Fbx2 dominant-negative mutant
GO:0043197 dendritic spine	IDA PMID:15809437 Activity-dependent NMDA receptor degradation mediated by ret...	KEEP AS NON CORE	Summary: IDA annotation for dendritic spine localization from PMID:15809437. Fbxo2 was shown to localize to hippocampal neurons including dendritic spines where it targets NMDA receptors for degradation. Reason: Consistent with the synaptic NR1 substrate context, but dendritic-spine localization is not the primary Fbxo2 localization/function. Supporting Evidence: PMID:15809437 When expressed in hippocampal neurons, this Fbx2 dominant-negative mutant augmented NR1 subunit levels and NMDA receptor-mediated currents
GO:0005515 protein binding	IPI PMID:15723043 Glycoprotein-specific ubiquitin ligases recognize N-glycans ...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding from PMID:15723043, with interaction partner PR:Q01853 (VCP/p97). This is the MGI-curated record of Fbxo2 interaction with VCP/p97 AAA ATPase. Reason: "Protein binding" is uninformative. The VCP/p97 interaction is part of the ERAD machinery coordination rather than substrate recognition. The direct interaction supports ERAD pathway placement, but it should not be retained as a separate core molecular function annotation. Supporting Evidence: PMID:15723043 The SCF(Fbs1) complex was associated with p97/VCP AAA ATPase and bound to integrin-beta1, one of the SCF(Fbs1) substrates, in the cytosol in a manner dependent on p97 ATPase activity
GO:0005829 cytosol	TAS PMID:15723043 Glycoprotein-specific ubiquitin ligases recognize N-glycans ...	ACCEPT	Summary: TAS annotation for cytosol localization from PMID:15723043. Yoshida et al. showed Fbxo2 binds integrin-beta1 in the cytosol dependent on p97 ATPase activity. Reason: Correct and consistent with IDA evidence from PMID:12140560. Redundant but valid. Supporting Evidence: PMID:15723043 The SCF(Fbs1) complex was associated with p97/VCP AAA ATPase and bound to integrin-beta1, one of the SCF(Fbs1) substrates, in the cytosol
GO:0006516 glycoprotein catabolic process	IDA PMID:15723043 Glycoprotein-specific ubiquitin ligases recognize N-glycans ...	ACCEPT	Summary: IDA annotation for glycoprotein catabolic process from PMID:15723043. Redundant with the same annotation from PMID:12140560, but independently supported by this paper which demonstrated Fbs1/Fbs2 interaction with denatured glycoproteins. Reason: Core function, independently confirmed in PMID:15723043. Supporting Evidence: PMID:15723043 the SCF(Fbs1,2) ubiquitin-ligase complexes that contribute to ubiquitination of glycoproteins are involved in the ER-associated degradation pathway
GO:0031249 denatured protein binding	IDA PMID:15723043 Glycoprotein-specific ubiquitin ligases recognize N-glycans ...	MODIFY	Summary: IDA annotation for denatured protein binding. GO:0031249 is being obsoleted. Yoshida et al. (PMID:15723043) showed that Fbs1 and Fbs2 "interacted with denatured glycoproteins...more efficiently than native proteins" and proposed that "Fbs proteins distinguish native from unfolded glycoproteins by sensing the exposed chitobiose structure." Critically, this is NOT general denatured protein binding. Fbxo2 recognizes the N-glycan (chitobiose core) that becomes exposed upon glycoprotein denaturation. It does not bind non-glycosylated denatured proteins and is not a chaperone. Reason: GO:0031249 is being obsoleted and is inaccurate for Fbxo2 regardless. Fbxo2 does not bind denatured proteins in general -- it binds the N-glycan moiety on denatured glycoproteins. The enhanced binding to denatured vs native glycoproteins is because denaturation exposes the normally protein-buried chitobiose core of N-glycans. The actual molecular function is carbohydrate/oligosaccharide binding (already annotated as GO:0030246) and ubiquitin-like ligase-substrate adaptor activity (GO:1990756). Alternatively, GO:0051787 "misfolded protein binding" could apply in a loose sense, but this also misrepresents the mechanism since Fbxo2 recognizes the glycan, not the protein moiety. The best replacement is the oligosaccharide binding term combined with the substrate adaptor activity. Proposed replacements: oligosaccharide binding ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:15723043 Both Fbs1 and Fbs2 proteins interacted with denatured glycoproteins, which were modified with not only high-mannose but also complex-type oligosaccharides, more efficiently than native proteins. Given that Fbs proteins interact with innermost chitobiose in N-glycans, we propose that Fbs proteins distinguish native from unfolded glycoproteins by sensing the exposed chitobiose structure
GO:0036503 ERAD pathway	IDA PMID:15723043 Glycoprotein-specific ubiquitin ligases recognize N-glycans ...	ACCEPT	Summary: IDA annotation for ERAD pathway from PMID:15723043. Redundant with IBA and IDA evidence from PMID:12140560, but independently confirmed. Reason: Core function. PMID:15723043 confirmed ERAD involvement and additionally demonstrated the p97/VCP interaction that links Fbxo2 to the ERAD retrotranslocation machinery. Supporting Evidence: PMID:15723043 the SCF(Fbs1,2) ubiquitin-ligase complexes that contribute to ubiquitination of glycoproteins are involved in the ER-associated degradation pathway
GO:0001540 amyloid-beta binding	IDA PMID:9173930 Identification of candidate proteins binding to prion protei...	UNDECIDED	Summary: Cannot be adjudicated here: PMID:9173930 is cached abstract-only. Prior observation, not a verdict: IDA annotation for amyloid-beta binding from PMID:9173930 (Yehiely et al. 1997). This paper screened a lambdagt11 mouse brain cDNA library using a PrP-alkaline phosphatase fusion probe to find candidate prion protein binding partners. Six clones were isolated, four of which were novel. The paper identified Fbxo2 as a candidate prion protein binding partner, not specifically as an amyloid-beta binder. The annotation appears to be a misinterpretation of the screening result. The binding was to prion protein (PrP), not to amyloid-beta peptide. Reason: PMID:9173930 is cached abstract-only, so the curator's experimental evidence cannot be inspected here; per CLAUDE.md an experimental annotation is not overruled on that basis. Recorded observation, not a verdict: PMID:9173930 was a candidate screen for PrP binding partners using a PrP-AP probe, not a specific amyloid-beta binding assay. The paper states it identified "candidate proteins binding to prion protein," not amyloid-beta. Given what is now known about Fbxo2's glycan-binding specificity, any interaction with PrP would most likely be mediated through PrP's N-glycans rather than specific amyloid-beta recognition. The annotation of "amyloid-beta binding" is not supported by the experiment. The Aplp1 clone mentioned in the paper is an APP-family fragment recovered from the screen, not evidence that Fbxo2 binds amyloid-beta peptide. Supporting Evidence: PMID:9173930 PrP-AP was used to screen a lambdagt11 mouse brain cDNA library, and six clones were isolated. Four cDNAs are novel while two clones are fragments of Nrf2 (NF-E2 related factor 2) transcription factor and Aplp1 (amyloid precursor-like protein 1)
GO:0030246 carbohydrate binding	IDA PMID:12939278 Fbs2 is a new member of the E3 ubiquitin ligase family that ...	ACCEPT	Summary: IDA annotation for carbohydrate binding from PMID:12939278 (Yoshida et al. 2003). This paper primarily characterized Fbs2 (Fbxo6b) as a new family member, but also confirmed that Fbs1 (Fbxo2) binds specifically to proteins with high-mannose oligosaccharides. The paper demonstrated that Man3-9GlcNAc2 glycans are required for efficient binding. Reason: Core molecular function. Carbohydrate binding (specifically N-glycan/oligosaccharide binding) is the primary mechanism by which Fbxo2 recognizes substrates. Well-supported by multiple papers including PMID:12140560, PMID:12939278, and structural studies (PMID:14990996, PMID:17389369). Supporting Evidence: PMID:12939278 Fbs1 (F-box protein that recognizes sugar chains; equivalent to Fbx2 or NFB42) binds specifically to proteins attached with high mannose oligosaccharides and subsequently contributes to elimination of N-glycoproteins in cytosol file:mouse/Fbxo2/Fbxo2-deep-research-falcon.md FBXO2 is a lectin-type substrate adaptor that recognizes high-mannose N-glycans, especially the Man3GlcNAc2 core, on misfolded or unassembled glycoproteins.
GO:1990756 ubiquitin-like ligase-substrate adaptor activity	IDA PMID:12140560 E3 ubiquitin ligase that recognizes sugar chains.	NEW	Summary: NEW annotation. Fbxo2 is the substrate-recognition (F-box) subunit of the SCF(Fbxo2) E3 ubiquitin ligase complex. It brings together the E3 ligase (via Skp1 binding through its F-box domain) and the glycoprotein substrate (via N-glycan binding through its FBA domain). This is the canonical function of F-box proteins. GO:1990756 is defined as "The binding activity of a molecule that brings together a ubiquitin-like ligase (including ubiquitin ligase and UFM1 ligase) and its substrate. Usually mediated by F-box BTB/POZ domain proteins" -- this precisely describes Fbxo2. That definition is quoted from the GO term record itself and is not checkable from any tracked file here: the label caches (cache/go/terms.csv, cache/ontologies/go.tsv) carry no definitions, and cache/ontologies/.obo is gitignored, so verifying it needs a GO lookup rather than a local grep. Reason:* This term is not currently annotated for Fbxo2 but is the most accurate molecular function descriptor. It captures the substrate adaptor role that is the core molecular function of Fbxo2, bridging the SCF complex catalytic machinery with glycoprotein substrates via N-glycan recognition. Supported by crystal structures (PMID:17389369) and biochemical data (PMID:12140560). Supporting Evidence: PMID:17389369 In SCF ubiquitin ligases, a diverse array of F-box proteins confers substrate specificity. Fbs1/Fbx2, a member of the F-box protein family, recognizes high-mannose oligosaccharides PMID:12140560 The F-box protein Fbx2 (ref. 4) binds specifically to proteins attached to N-linked high-mannose oligosaccharides and subsequently contributes to ubiquitination of N-glycosylated proteins file:mouse/Fbxo2/Fbxo2-deep-research-falcon.md FBXO2 is a lectin-type substrate adaptor that recognizes high-mannose N-glycans and directs their ubiquitination by SCF for proteasomal degradation.
GO:0070492 oligosaccharide binding	IDA PMID:14990996 Structural basis of sugar-recognizing ubiquitin ligase.	NEW	Summary: NEW annotation. Fbxo2 specifically binds oligosaccharides, particularly Man3GlcNAc2 (the innermost core of N-glycans). This is more specific than the existing "carbohydrate binding" annotation. The crystal structure of Fbxo2 with chitobiose (PMID:14990996) and with glycoprotein substrate (PMID:17389369) demonstrated the oligosaccharide binding specificity. Reason: GO:0070492 "oligosaccharide binding" is more specific than GO:0030246 "carbohydrate binding" and accurately describes Fbxo2's binding to N-glycan oligosaccharides. Mutagenesis of key residues (F177A, Y279A, W280A) abolished glycoprotein binding (PMID:14990996), confirming the structural basis of oligosaccharide recognition. Supporting Evidence: PMID:17389369 The structure of the SBD-glycoprotein complex indicates that the SBD primarily recognizes Man(3)GlcNAc(2), thereby explaining the broad activity of the enzyme against various glycoproteins file:mouse/Fbxo2/Fbxo2-deep-research-falcon.md The Falcon report summarizes FBXO2 substrate specificity as binding innermost N-glycan cores, with preference for high-mannose species.

Gene Description

Proposed New Ontology Terms

misfolded glycoprotein sensor activity

Existing Annotations Review

Core Functions

Substrate-recognition component of the SCF(Fbxo2) E3 ubiquitin-protein ligase complex that recognizes N-linked high-mannose oligosaccharides on misfolded glycoproteins retrotranslocated from the ER to the cytosol, promoting their ubiquitination and proteasomal degradation via the ERAD pathway.

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Falcon

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