FBXO41 (F-box only protein 41; KIAA1940) is a brain/neuron-enriched member of the FBXO family of F-box proteins. F-box proteins serve as the substrate-recognition (receptor/adaptor) subunits of SCF (SKP1-CUL1-RBX1-F-box) Cullin-RING E3 ubiquitin ligase complexes: the F-box motif docks the protein onto the SKP1-CUL1 scaffold, while a separate substrate-binding region recruits target proteins for poly-ubiquitination, committing them to proteasomal degradation. FBXO41 carries a C-terminal F-box domain together with an N-terminal C2H2 zinc-finger-like region, a long predicted coiled-coil, and extensive intrinsically disordered/low-complexity regions, and by sequence similarity is predicted to assemble into an SCF complex through direct interaction with SKP1 and CUL1. FBXO41 is a neuron-specific/CNS-enriched protein (expressed from early embryogenesis, abundant postnatally in cerebellum and hippocampus; not detected in astrocytes or oligodendrocytes). It is cytoplasmic and excluded from the nucleus, with a prominent centrosomal/pericentriolar pool: in neurons FBXO41 localizes adjacent to centriole markers and co-fractionates with centrosomes, and this targeting requires both its coiled-coil and F-box domains. Functionally, increased centrosomal/centriolar accumulation of FBXO41 promotes disassembly/shortening of neuronal primary cilia and thereby modulates the cilium-dependent Sonic hedgehog (Shh) pathway; this cilia disassembly activity depends on actin-cytoskeleton remodeling and, in mitotic contexts, on Aurora A kinase. F-box deletion or an F-box point mutation (W577A) abolishes SKP1/CUL1 binding, and a centrosome-localized F-box mutant fails to drive cilia shortening, indicating that FBXO41's biological activity is coupled to SCF/CRL assembly. In vivo, loss of Fbxo41 in mice causes cerebellar granule neuron migration defects, an ataxia-like phenotype and cerebellar neurodegeneration. Its direct, broadly validated ubiquitination substrate repertoire remains unestablished; a less-replicated (thesis-level) model proposes an FBXO41-CUL7 complex mediating non-proteolytic K63-linked ubiquitination of neurofilament medium (NFM) to promote axon growth, alongside proposed interactions with DISC1 and NDEL1. A rare homozygous human variant (p.Arg317Gln) has been reported segregating with a neurologic phenotype, and FBXO41 shows altered DNA methylation in 22q11.2 deletion syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic ortholog-transfer (from mouse Q6NS60) of a generic cytoplasmic localization. Plausible for an SCF substrate adaptor that acts in the cytoplasm/cytosol, but it is generic and derives from Ensembl Compara transfer rather than direct evidence on the human protein. Reason: Generic compartment consistent with a cytoplasmic/cytosolic SCF adaptor, but derived from ortholog transfer (GO_REF:0000107) rather than experimental evidence for human FBXO41; subsumed by the more specific cytosol annotation. Supporting Evidence: file:human/FBXO41/FBXO41-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0005813 centrosome | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic ortholog-transfer (from mouse Q6NS60) of centrosome localization, now corroborated by primary full text of the two mouse/rat studies. King et al. 2019 (PMID:31160656) show by immunostaining and super-resolution dSTORM that Fbxo41 co-localizes with Pericentrin and resides adjacent to the centriole protein Cep135 in primary hippocampal neurons, and Mukherjee et al. 2015 (PMID:26063905) report FBXO41 localizes to the centrosome and cytoplasm of neurons. The centriolar pool is mechanistically central (its accumulation there drives cilia disassembly), though the human UniProt record itself does not mention a centrosomal location. Reason: The annotation rests on Ensembl Compara ortholog transfer (GO_REF:0000107), and the underlying mouse/rat evidence has now been verified from primary full text (King et al. 2019, PMID:31160656; Mukherjee et al. 2015, PMID:26063905), which directly demonstrate centriolar/centrosomal localization of the ortholog. This is a core functional location rather than merely generic compartment context because centriolar FBXO41 accumulation is the experimentally tested site of its cilium-disassembly activity. Supporting Evidence: PMID:31160656 Super-resolution stochastic optical reconstruction microscopy (STORM) revealed that Fbxo41-EGFP resides adjacent to centrosomal protein 135 (Cep135), a centriole proximal-end protein PMID:26063905 we identify FBXO41 as a novel CNS-specific F-box protein that localizes to the centrosome and the cytoplasm of neurons |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: FBXO41 is the substrate-recognition F-box subunit of an SCF (SKP1-CUL1-F-box) E3 ligase complex. ComplexPortal curates a dedicated SCF FBXO41-variant complex (CPX-7982), and UniProt states FBXO41 directly interacts with SKP1 and CUL1. This complex membership is the best-supported aspect of FBXO41's annotation. Reason: Consistent with the F-box/SCF architecture (F-box domain at 496-540) and with UniProt's statement of direct SKP1/CUL1 interaction; ComplexPortal curates the SCF FBXO41-variant complex (CPX-7982). Core cellular-component context for an F-box protein. Supporting Evidence: file:human/FBXO41/FBXO41-uniprot.txt Directly interacts with SKP1 and CUL1. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | ISO PMID:31160656 Fbxo41 Promotes Disassembly of Neuronal Primary Cilia. | NEW | Summary: FBXO41 is an F-box substrate-receptor subunit of an SCF ubiquitin ligase. The ortholog study demonstrates F-box-dependent association with SKP1 and CUL1, while the reviewed human UniProt record identifies FBXO41 as the substrate-recognition component of the complex. This supports the adaptor activity rather than catalytic ubiquitin-protein ligase activity, which resides in the SCF catalytic core. Reason: GO:1990756 is the appropriate molecular function for an F-box protein that confers substrate recognition on an SCF ligase. Proposed for human FBXO41 by orthology-supported inference because the primary experiments used rodent Fbxo41 and no human FBXO41 substrate has yet been established. The absence of an identified physiological substrate limits substrate-specific process claims but does not negate the conserved substrate-adaptor role supported by the intact F-box-dependent SCF assembly and reviewed UniProt family inference. Supporting Evidence: PMID:31160656 Generally, F-box proteins are modular substrate binding adaptors of a Skp1/Cullin1/F-box (SCF) E3-ligase complex PMID:31160656 Indeed, Fbxo41 associated with Skp1 and Cullin1, albeit less efficiently than Fbxo21 which was included as a positive control. Deleting (Fbxo41ΞF-box) or mutating (Fbxo41W577A) the F-box domain abolished these interactions file:human/FBXO41/FBXO41-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. file:human/FBXO41/FBXO41-deep-research-falcon.md Removing the F-box (Fbxo41ΞF-box) or introducing an F-box point mutation (W577A) abolishes SKP1/CUL1 interactions, indicating the F-box is required for SCF recruitment. |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | KEEP AS NON CORE | Summary: As an F-box substrate receptor of an SCF complex, FBXO41 is expected to participate in SCF-dependent proteasomal degradation of its (currently unidentified) substrates. This is a family-level inference; the cited reference (PMID:34445249) is a general SCF review and does not present FBXO41-specific substrate or degradation data, and no direct experimental evidence for a human FBXO41 substrate is available. Reason: Reasonable family-level expectation for an SCF F-box protein, but rests on NAS/general-review and similarity inference rather than direct experimental evidence for FBXO41; retained as non-core pending identification of bona fide substrates. Supporting Evidence: file:human/FBXO41/FBXO41-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0061523 cilium disassembly | ISO PMID:31160656 Fbxo41 Promotes Disassembly of Neuronal Primary Cilia. | NEW | Summary: King et al. 2019 (PMID:31160656; full text read) demonstrate in primary rat hippocampal neurons and hTERT-RPE1 cells that increased centriolar accumulation of Fbxo41 promotes disassembly/shortening of primary cilia. Centrosomal Fbxo41 levels inversely correlate with cilia length, the effect requires a functional F-box domain (SCF-assembly competence) and centriolar targeting, requires actin-cytoskeleton rearrangement, and disturbs Sonic hedgehog signaling. Annotated for human FBXO41 by orthology inference (ISO) from this mouse/rat ortholog evidence. Reason: Not currently in GOA; proposed for the human protein by orthology inference (ISO) from the mouse/rat ortholog. The primary study (King et al., Sci Rep 2019, PMID:31160656) has now been read in full and verified to assay Fbxo41 cilia-disassembly activity directly, so it is cited as the supporting reference. Remains a proposal pending human-specific confirmation. Supporting Evidence: PMID:31160656 We identify Fbxo41 as a novel Skp1/Cullin1/F-box (SCF) E3-ligase complex subunit that targets to neuronal centrioles where its accumulation promotes disassembly of primary cilia, and affects sonic hedgehog signaling, a canonical ciliary pathway. |
| GO:0001764 neuron migration | ISO PMID:26063905 Loss of the neuron-specific F-box protein FBXO41 models an a... | NEW | Summary: Mukherjee et al. 2015 (PMID:26063905; full text read) show by in vivo electroporation that cytoplasmic FBXO41 promotes neuronal migration, and that Fbxo41-knockout mice display a severely ataxic gait with delayed migration of cerebellar granule neurons in the developing cerebellum plus degeneration of the mature cerebellum. Annotated for human FBXO41 by orthology inference (ISO) from this in vivo mouse loss-of-function evidence. Reason: Not currently in GOA; proposed for the human protein by orthology inference (ISO) from in vivo mouse loss-of-function evidence. The primary study (Mukherjee et al., J Neurosci 2015, PMID:26063905) has now been read in full and verified to assay Fbxo41's role in granule-neuron migration directly, so it is cited as the supporting reference. A developmental process distinct from the core SCF-adaptor molecular function; remains a proposal pending human-specific confirmation. Supporting Evidence: PMID:26063905 we identify FBXO41 as a novel CNS-specific F-box protein that localizes to the centrosome and the cytoplasm of neurons and demonstrate that cytoplasmic FBXO41 promotes neuronal migration. Interestingly, deletion of the FBXO41 gene results in a severely ataxic gait in mice, which show delayed neuronal migration of granule neurons in the developing cerebellum |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization assigned within generic Cullin-RING ligase (CRL1/neddylation) reactions. Plausible compartment for an SCF adaptor, but reflects pathway curation of the CRL machinery rather than FBXO41-specific experimental localization. Reason: Cytosol is a plausible site for an SCF adaptor, but this annotation derives from Reactome CRL1 pathway reactions, not from direct FBXO41 evidence; retained as supporting localization context. Supporting Evidence: file:human/FBXO41/FBXO41-uniprot.txt Directly interacts with SKP1 and CUL1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization assigned within generic CRL1/neddylation reactions. Duplicate of the cytosol annotation from a related Reactome reaction. Reason: Plausible compartment for an SCF adaptor but derived from generic Reactome CRL pathway curation rather than FBXO41-specific evidence; redundant with the other cytosol annotations. Supporting Evidence: file:human/FBXO41/FBXO41-uniprot.txt Directly interacts with SKP1 and CUL1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization from the CAND1-binds-CRL reaction. Reflects generic CRL machinery curation, not FBXO41-specific localization. Reason: Plausible but pathway-derived (generic CRL reaction); redundant with the other cytosol annotations. Supporting Evidence: file:human/FBXO41/FBXO41-uniprot.txt Directly interacts with SKP1 and CUL1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization from the COMMD-displaces-CAND1 reaction. Reflects generic CRL machinery curation, not FBXO41-specific localization. Reason: Plausible but pathway-derived (generic CRL reaction); redundant with the other cytosol annotations. Supporting Evidence: file:human/FBXO41/FBXO41-uniprot.txt Directly interacts with SKP1 and CUL1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization from the COP9-signalosome-deneddylates-CRL reaction. Reflects generic CRL machinery curation, not FBXO41-specific localization. Reason: Plausible but pathway-derived (generic CRL reaction); redundant with the other cytosol annotations. Supporting Evidence: file:human/FBXO41/FBXO41-uniprot.txt Directly interacts with SKP1 and CUL1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization from the DCUN1D3-binds-CRL1 reaction. Reflects generic CRL machinery curation, not FBXO41-specific localization. Reason: Plausible but pathway-derived (generic CRL reaction); redundant with the other cytosol annotations. Supporting Evidence: file:human/FBXO41/FBXO41-uniprot.txt Directly interacts with SKP1 and CUL1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization from a generic ubiquitination reaction (transfer of Ub from E2 to substrate). Reflects generic ubiquitin-pathway curation, not FBXO41-specific localization. Reason: Plausible but pathway-derived (generic ubiquitination reaction); redundant with the other cytosol annotations. Supporting Evidence: file:human/FBXO41/FBXO41-uniprot.txt Directly interacts with SKP1 and CUL1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization from a generic ubiquitination reaction (release of E3 from polyubiquitinated substrate). Reflects generic ubiquitin-pathway curation, not FBXO41-specific localization. Reason: Plausible but pathway-derived (generic ubiquitination reaction); redundant with the other cytosol annotations. Supporting Evidence: file:human/FBXO41/FBXO41-uniprot.txt Directly interacts with SKP1 and CUL1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization from a generic ubiquitination reaction (polyubiquitination of substrate). Reflects generic ubiquitin-pathway curation, not FBXO41-specific localization. Reason: Plausible but pathway-derived (generic ubiquitination reaction); redundant with the other cytosol annotations. Supporting Evidence: file:human/FBXO41/FBXO41-uniprot.txt Directly interacts with SKP1 and CUL1. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | KEEP AS NON CORE | Summary: Reactome pathway-level cytosol localization from a generic ubiquitination reaction (interaction of E3 with substrate and E2-Ub complex). Reflects generic ubiquitin-pathway curation, not FBXO41-specific localization. Reason: Plausible but pathway-derived (generic ubiquitination reaction); redundant with the other cytosol annotations. Supporting Evidence: file:human/FBXO41/FBXO41-uniprot.txt Directly interacts with SKP1 and CUL1. |
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Download this section (compressed HTML)Q: What are the physiological substrate(s) of the SCF-FBXO41 complex, and are they neuron- or brain-specific given FBXO41's strong brain/hippocampal enrichment?
Q: Does FBXO41 function as a canonical degradative SCF substrate receptor, or does it (like some FBXO proteins) have non-degradative or SCF-independent roles in neurons?
Q: What is the role of FBXO41's N-terminal C2H2 zinc-finger-like region and long coiled-coil in substrate recognition or complex assembly, distinct from the C-terminal F-box domain?
Q: Is FBXO41-driven primary cilia disassembly mediated by SCF-dependent ubiquitination of a centriolar/ciliary substrate, and which substrate links FBXO41 to actin remodeling and Aurora A in modulating Sonic hedgehog signaling?
Q: Does FBXO41 use an alternative CUL7-based ligase context in neurons to catalyze non-proteolytic K63-linked ubiquitination of neurofilament medium (NFM), and are DISC1 and NDEL1 bona fide partners/substrates relevant to axon growth and cerebellar neuron migration?
Experiment: Affinity-purify FBXO41 (e.g. tagged or endogenous) from neuronal cells or brain tissue followed by mass spectrometry to define its SCF-complex partners (confirming SKP1/CUL1/RBX1) and to identify candidate ubiquitination substrates.
Experiment: Perform comparative ubiquitinome/proteome profiling in FBXO41-knockout versus wild-type neurons (with and without proteasome inhibition) to identify proteins that accumulate upon loss of FBXO41 and are therefore candidate substrates.
Experiment: Reconstitute the SCF-FBXO41 complex in vitro with purified SKP1, CUL1, RBX1, an E1, an E2 and candidate substrates to test for direct, F-box-dependent substrate ubiquitination and to determine ubiquitin-chain linkage type.
Experiment: In primary neurons and ciliated epithelial models, quantify primary cilium length, percent ciliation and Sonic hedgehog pathway output upon FBXO41 overexpression, knockout and F-box/centrosome-targeting mutants, with actin (e.g. cytochalasin D) and Aurora A perturbations, to define how centrosomal FBXO41 couples SCF assembly to cilia disassembly.
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