FBXO2 (FBG1/FBX2/NFB42) is a 296-residue cytoplasmic F-box protein that serves as the substrate-recognition subunit of a Skp1-Cul1-F-box (SCF) E3 ubiquitin-protein ligase complex. It contains an N-terminal F-box domain (residues 44-91) that binds SKP1, bridging the receptor to the CUL1-RBX1 catalytic core, and a C-terminal F-box-associated (FBA) sugar-binding domain (residues 113-296) that folds as a galactose-binding-domain-like lectin and binds N-linked high-mannose oligosaccharides. The FBA domain recognizes the innermost N-glycan core (Man3GlcNAc2 / the chitobiose-proximal GlcNAc2 moiety) through a small hydrophobic pocket, a "sugar degron" that becomes exposed when a glycoprotein is misfolded, denatured, or aberrantly retrotranslocated to the cytosol. Through this lectin activity FBXO2 recognizes N-glycans on misfolded/denatured glycoproteins that have been retrotranslocated from the endoplasmic reticulum into the cytosol, recruiting them to the SCF complex for polyubiquitination and proteasomal degradation as part of the ER-associated degradation (ERAD) pathway, thereby preventing the accumulation of cytosolic aggregates of unfolded glycoproteins. Reported glycoprotein clients in the Fbs1/Fbs2 quality-control orbit include pre-integrin beta-1, the T-cell receptor alpha chain, the asialoglycoprotein receptor subunit, and the disease variant CFTR-deltaF508; in neurons FBXO2 additionally turns over APP and BACE1 to limit amyloidogenic processing. FBXO2 is most highly expressed in the nervous system, where it has additional roles in synaptic protein turnover and in clearance of damaged glycan-bearing membranes (lysophagy) and intracellular bacteria (xenophagy), recognizing GlcNAc/high- mannose glycans on these targets. The protein is a peripheral cytoplasmic-side membrane protein and is itself a glycoprotein-specific lectin, not a glycosidase.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0036503 ERAD pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of involvement in ER-associated degradation, a core biological process for the FBA/lectin F-box family. Reason: Core biological process; FBXO2 recognizes N-glycans on retrotranslocated misfolded glycoproteins and targets them for ERAD, supported by UniProt and the founding literature. The Falcon deep-research synthesis reinforces the mechanism (recognition of the innermost N-glycan core after ER retrotranslocation) and adds named ERAD clients. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt Involved in the endoplasmic reticulum-associated degradation pathway (ERAD) for misfolded lumenal proteins by recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation file:human/FBXO2/FBXO2-deep-research-falcon.md lectin-type F-box proteins such as FBXO2 are described as operating in the **nucleocytoplasmic compartment**, where they can recognize **retrotranslocated ER glycoproteins** and promote their ubiquitination as part of **ER-associated degradation (ERAD)** and broader proteostasis mechanisms |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of cytoplasmic site of action, consistent with FBXO2 acting on retrotranslocated cytosolic glycoproteins. Reason: FBXO2 is a cytoplasmic protein that acts on the cytosolic side; supported by UniProt and IDA evidence. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006516 glycoprotein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of involvement in glycoprotein catabolism, the substrate-class-defining process for this lectin F-box subfamily. Reason: Core process; FBXO2 directs ubiquitin-dependent degradation of N-glycosylated substrates recognized via its FBA lectin domain. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation |
| GO:0019005 SCF ubiquitin ligase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of FBXO2 as part of the SCF complex, its core complex context as a substrate receptor. Reason: Core; FBXO2 is the substrate-recognition subunit of SCF(FBXO2) (CUL1, RBX1, SKP1, FBXO2). Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2 |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of SCF-dependent proteasomal degradation, the core process executed by SCF(FBXO2). Reason: Core biological process; SCF(FBXO2) mediates ubiquitination and proteasomal degradation of its glycoprotein substrates. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:0061630 ubiquitin protein ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of ubiquitin ligase activity with the contributes_to qualifier, reflecting FBXO2's role as a non-catalytic receptor subunit within the SCF ligase whose catalytic activity resides in RBX1. Reason: Appropriate with contributes_to; FBXO2 is the substrate-recognition subunit and does not itself carry the catalytic RING activity (RBX1), but contributes to the complex's ligase function. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of cytoplasmic localization, consistent with the experimentally and curator-supported cytoplasmic location. Reason: Correct core localization; redundant with IDA and UniProt. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: High-throughput interactome interaction. Bare protein binding is uninformative per curation guidelines. Reason: Records a real screen-derived interaction but bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt Q9UK22; P63208: SKP1 |
| GO:0005515 protein binding | IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex... | KEEP AS NON CORE | Summary: Interaction captured in a Polycomb complexome map. Bare protein binding is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt Q9UK22; O15212: PFDN6 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Binary interactome reference map interaction. Bare protein binding is uninformative. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt Q9UK22; P63208: SKP1 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Cell-specific interactome interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt Q9UK22; P63208: SKP1 |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Multimodal cell-map interaction. Bare protein binding is uninformative. Reason: High-throughput cell-map interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt Q9UK22; P63208: SKP1 |
| GO:0001540 amyloid-beta binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic transfer of amyloid-beta binding. FBXO2 has been reported to bind/regulate APP-derived species, but this is a context-specific neuronal activity rather than the core lectin/ERAD function. Reason: Plausible secondary neuronal activity (FBXO2 regulates APP/amyloid-related substrates) but not the core carbohydrate-binding/ERAD function; retained as non-core. |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based electronic assignment of cytosolic localization, consistent with the cytoplasmic/cytosolic site of action. Reason: Correct localization; FBXO2 acts on the cytosolic side; redundant with UniProt ISS and IDA. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic assignment of protein ubiquitination, a parent process of the specific SCF-dependent catabolism FBXO2 mediates. Reason: Correct but generic; the specific SCF-dependent proteasomal catabolism and ERAD annotations better capture the role. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0019005 SCF ubiquitin ligase complex | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based electronic assignment of SCF complex membership, the core complex context. Reason: Core; redundant with IBA/ISS/NAS SCF annotations. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2 |
| GO:0030246 carbohydrate binding | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic assignment (UniProt keyword Lectin) of carbohydrate binding, the defining molecular function of the FBA domain. Reason: Core molecular function; the FBA domain is a lectin that binds N-linked high-mannose glycans (carbohydrate-binding sites at residues 210-212 and 278-279). The Falcon deep-research synthesis specifies that the bound determinant is the innermost N-glycan core (Man3GlcNAc2) engaged by a hydrophobic pocket, with preference for high-mannose glycans on denatured glycoproteins. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt Able to recognize and bind denatured glycoproteins, preferentially those of the high-mannose type file:human/FBXO2/FBXO2-deep-research-falcon.md it binds the **innermost N-glycan core** (described as **Man3GlcNAc2** / innermost GlcNAc2 moiety) using a **small hydrophobic pocket** in its SBD, with preference for **high-mannose N-glycans** and **denatured/misfolded glycoproteins** (where the core glycan becomes accessible) |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based electronic assignment of SCF-dependent proteasomal catabolism, the core process. Reason: Core biological process; redundant with IBA/ISS/NAS evidence. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:0043197 dendritic spine | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic transfer of dendritic spine localization, reflecting FBXO2's neuronal/synaptic expression and role in synaptic protein turnover. Reason: Plausible neuronal localization tied to a secondary synaptic role; not the core ERAD compartment. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic transfer of glutamatergic synapse localization/activity, reflecting a neuronal synaptic role. Reason: Secondary neuronal/synaptic context; not the core ERAD/lectin function. |
| GO:0099576 regulation of protein catabolic process at postsynapse, modulating synaptic transmission | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic transfer of a postsynaptic protein-catabolism regulatory role, reflecting FBXO2's neuronal function in synaptic protein turnover. Reason: Secondary, neuronal-context process; not the core ERAD/glycoprotein catabolism function. |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: Author-stated SCF complex membership. Core complex context. Reason: Core; consistent with the SCF(FBXO2) complex composition. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2 |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: Author-stated involvement in SCF-dependent proteasomal degradation. Core process. Reason: Core biological process; consistent with FBXO2's SCF substrate-receptor function. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:1904415 regulation of xenophagy | NAS PMID:34515398 FBXO2/SCF ubiquitin ligase complex directs xenophagy through... | KEEP AS NON CORE | Summary: FBXO2/SCF directs xenophagy against group A Streptococcus by recognizing GlcNAc side chains of the bacterial surface carbohydrate; FBXO2 knockout reduces ubiquitin accumulation and xenophagic degradation. A documented secondary (immune/autophagy) role of the lectin activity. Reason: Experimentally supported secondary role extending the lectin/glycan-recognition function to bacterial glycans; distinct from the core ERAD function. Supporting Evidence: PMID:34515398 FBXO2, a glycoprotein-specific receptor for substrate in the SKP1/CUL1/F-box protein (SCF) ubiquitin ligase complex, mediates recognition of GlcNAc side chains of the GAS surface carbohydrate structure and promotes ubiquitin-mediated xenophagy against GAS |
| GO:0005737 cytoplasm | IDA PMID:21378169 A Competitive binding mechanism between Skp1 and exportin 1 ... | ACCEPT | Summary: Direct assay placing FBXO2 in the cytoplasm in the study of Skp1/CRM1-controlled F-box protein localization. Core localization. Reason: IDA-supported cytoplasmic localization consistent with the documented site of action. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | ACCEPT | Summary: Reactome neddylation-pathway annotation of cytosolic localization for the CRL1/SCF context. Correct compartment. Reason: Correct cytosolic localization; redundant with IDA/ISS evidence. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | ACCEPT | Summary: Reactome CRL1/neddylation cytosolic localization annotation. Correct compartment. Reason: Correct cytosolic localization; redundant with other evidence. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | ACCEPT | Summary: Reactome (CAND1 binds cytosolic CRL) cytosolic localization annotation. Correct compartment. Reason: Correct cytosolic localization; redundant. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | ACCEPT | Summary: Reactome (COMMD/CAND1) cytosolic localization annotation. Correct compartment. Reason: Correct cytosolic localization; redundant. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | ACCEPT | Summary: Reactome (COP9 signalosome deneddylation) cytosolic localization annotation. Correct compartment. Reason: Correct cytosolic localization; redundant. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | ACCEPT | Summary: Reactome (DCUN1D3 binds CRL1) cytosolic localization annotation. Correct compartment. Reason: Correct cytosolic localization; redundant. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | ACCEPT | Summary: Reactome (Transfer of Ub from E2 to substrate) cytosolic localization annotation. Correct compartment. Reason: Correct cytosolic localization; redundant. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | ACCEPT | Summary: Reactome (Release of E3 from polyubiquitinated substrate) cytosolic localization annotation. Correct compartment. Reason: Correct cytosolic localization; redundant. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | ACCEPT | Summary: Reactome (Polyubiquitination of substrate) cytosolic localization annotation. Correct compartment. Reason: Correct cytosolic localization; redundant. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | ACCEPT | Summary: Reactome (Interaction of E3 with substrate and E2-Ub) cytosolic localization annotation. Correct compartment. Reason: Correct cytosolic localization; redundant. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of cytosolic localization. Correct compartment. Reason: Correct cytosolic localization; redundant with IDA. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006516 glycoprotein catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of glycoprotein catabolic process, the substrate-class-defining core process. Reason: Core process; redundant with IBA. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt recognizing and binding sugar chains on unfolded glycoproteins that are retrotranslocated into the cytosol and promoting their ubiquitination and subsequent degradation |
| GO:0016567 protein ubiquitination | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator sequence-similarity transfer of protein ubiquitination, a parent of the specific SCF-dependent catabolism. Reason: Correct but generic; specific SCF-dependent catabolism/ERAD annotations are preferred. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0019005 SCF ubiquitin ligase complex | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of SCF complex membership. Core complex context. Reason: Core; redundant with IBA/IEA/NAS. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt Component of the SCF(FBXO2) complex consisting of CUL1, RBX1, SKP1 and FBXO2 |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of SCF-dependent proteasomal catabolism. Core process. Reason: Core biological process; redundant with IBA/IEA/NAS. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:0004842 ubiquitin-protein transferase activity | TAS PMID:10531035 Identification of a family of human F-box proteins. | KEEP AS NON CORE | Summary: Author statement from the F-box family identification paper attributing ubiquitin-protein transferase activity to the SCF complex containing this F-box protein. FBXO2 itself is the substrate receptor, not the catalytic subunit. Reason: The catalytic transferase activity resides in the RBX1/CUL1 core, not the F-box receptor; this term over-attributes catalysis to FBXO2. Retained as non-core (contributes_to ligase activity is the more accurate framing). Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:0006508 proteolysis | TAS PMID:10531035 Identification of a family of human F-box proteins. | KEEP AS NON CORE | Summary: Author statement of involvement in proteolysis, a very general parent of the specific proteasomal/ERAD catabolism. Reason: Correct but overly generic; specific SCF-dependent catabolism and ERAD annotations better capture the role. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins |
| GO:0036211 protein modification process | TAS PMID:10531035 Identification of a family of human F-box proteins. | KEEP AS NON CORE | Summary: Author statement of involvement in protein modification, a very general parent of protein ubiquitination. Reason: Correct but overly generic; the specific ubiquitination/SCF-catabolism annotations are preferred. Supporting Evidence: file:human/FBXO2/FBXO2-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
Loading supporting content…
Download this section (compressed HTML)Q: What is the endogenous high-mannose glycoprotein substrate repertoire of SCF(FBXO2) in different tissues, and how is substrate selection partitioned among the FBA paralogs FBXO2, FBXO6, and FBXO27?
Q: How are FBXO2's neuronal/synaptic roles (dendritic spine, synaptic protein catabolism) and its lysophagy/xenophagy functions mechanistically related to its core ERAD lectin activity, and do they use distinct substrate pools?
Experiment: Glycan-array and ITC/SPR binding assays with purified FBXO2 FBA domain (wild type vs carbohydrate-binding-site mutants at residues 173, 210-212, 278-279) to quantify high-mannose vs GlcNAc specificity and map the binding determinants.
Experiment: Quantitative ubiquitinome/proteome profiling in FBXO2-knockout versus wild-type cells (neuronal and epithelial) under ER-stress and ERAD-substrate challenge to define the endogenous glycoprotein substrate set and assess redundancy with FBXO6/FBXO27.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)