Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniPathway vocabulary mapping
Automated transfer of experimentally-verified manual GO annotation data to mouse-rat orthologs
Electronic Gene Ontology annotations created by ARBA machine learning models
Automated transfer of experimentally-verified manual GO annotation data to mouse-human orthologs
Combined Automated Annotation using Multiple IEA Methods
E3 ubiquitin ligase that recognizes sugar chains.
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SCF(Fbxo2) ubiquitin ligase complex identified as recognizing N-glycan sugar chains on retrotranslocated glycoproteins for ERAD-mediated proteasomal degradation.
"N-glycan serves as a signal for degradation by the Skp1-Cullin1-Fbx2-Roc1 (SCF(Fbx2)) ubiquitin ligase complex"
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Pre-integrin beta-1 identified as substrate of SCF(Fbxo2); interaction occurs in cytosol after proteasome inhibition.
"Pre-integrin beta 1 is a target of Fbx2; these two proteins interact in the cytosol after inhibition of the proteasome"
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Dominant-negative Fbxo2 (lacking F-box domain) blocks typical ERAD substrate degradation.
"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"
Fbs2 is a new member of the E3 ubiquitin ligase family that recognizes sugar chains.
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Fbs2 (Fbxo6b) identified as second F-box protein recognizing N-glycans. Both Fbs1 and Fbs2 require Man3-9GlcNAc2 for binding. Fbs1 expression restricted to brain and testis while Fbs2 is ubiquitous.
"Although the expression of Fbs1 was restricted to the adult brain and testis, the Fbs2 transcript was widely expressed"
Structural basis of sugar-recognizing ubiquitin ligase.
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Crystal structure of Fbxo2 FBA domain with chitobiose at 1.7 angstroms. Mutagenesis of F177, Y279, W280 abolished glycoprotein binding.
"Efficient binding to an N-glycan requires di-N-acetylchitobiose (chitobiose). Here we report the crystal structures of the sugar-binding domain (SBD) of Fbs1 alone and in complex with chitobiose"
Glycoprotein-specific ubiquitin ligases recognize N-glycans in unfolded substrates.
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Fbs1/Fbs2 interact preferentially with denatured glycoproteins by sensing exposed chitobiose. SCF(Fbs1) associates with p97/VCP AAA ATPase.
"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"
Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination.
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Fbxo2 binds high-mannose glycans of NR1 ectodomain and promotes NR1 ubiquitination. Dominant-negative Fbxo2 augments NR1 levels and NMDA receptor currents at glutamatergic synapses in an activity-dependent manner.
"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. Indeed, ubiquitination of NR1 was increased by Fbx2 and diminished by an Fbx2 dominant-negative mutant"
A neural-specific F-box protein Fbs1 functions as a chaperone suppressing glycoprotein aggregation.
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Fbxo2 prevents formation of cytosolic aggregates of retrotranslocated unfolded glycoproteins. Functions as both ubiquitin ligase component and anti-aggregation factor. Predominantly detected as heterodimer with Skp1.
"In vitro, Fbs1 prevented the aggregation of the glycoprotein through the N-terminal unique sequence of Fbs1"
Structural basis for the selection of glycosylated substrates by SCF(Fbs1) ubiquitin ligase.
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Crystal structures of Skp1-Fbs1 complex and SBD-glycoprotein complex reveal that the sugar-binding domain primarily recognizes Man3GlcNAc2, explaining broad glycoprotein substrate specificity.
"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"
Selective cochlear degeneration in mice lacking the F-box protein, Fbx2, a glycoprotein-specific ubiquitin ligase subunit.
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Fbxo2 knockout mice develop progressive hearing loss due to degeneration of cochlear epithelial support cells, hair cells, and spiral ganglion neurons. Expression enriched in brain and cochlea.
"Mice with targeted deletion of Fbxo2 develop age-related hearing loss beginning at 2 months. Cellular degeneration begins in the epithelial support cells of the organ of Corti"
Identification of candidate proteins binding to prion protein.
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Fbxo2 (then unnamed) identified as candidate prion protein binding partner using PrP-AP probe to screen mouse brain cDNA library. Four of six isolated clones were novel and expressed preferentially in brain.
"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)"
Falcon deep research report for mouse Fbxo2
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Falcon identifies mouse Fbxo2/Fbs1 as a lectin-type F-box substrate adaptor for SCF-mediated glycoprotein ubiquitination in ERAD.
"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."
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Falcon supports high-mannose N-glycan/Man3GlcNAc2 recognition as the specific substrate-recognition mechanism.
"FBXO2 is a lectin-type substrate adaptor that recognizes high-mannose N-glycans, especially the Man3GlcNAc2 core, on misfolded or unassembled glycoproteins."
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Falcon supports the mouse in vivo cochlear degeneration phenotype as a physiological consequence, not as the primary molecular function.
"Fbxo2-/- mice exhibit early-onset, progressive hearing loss beginning around 2 months of age, with initial degeneration of organ of Corti supporting cells."