id: Q5MNV8 gene_symbol: FBXO47 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXO47 (F-box only protein 47) is a 452-residue F-box-domain-containing protein (F-box at residues 41-91, plus an FBXO47-specific armadillo-like region) belonging to the FBXO ("F-box only") subfamily of F-box proteins, which canonically act as substrate-recognition receptors that, together with SKP1, CUL1 and RBX1, assemble SCF (SKP1-cullin-F-box) E3 ubiquitin ligase complexes. FBXO47 is strongly enriched in testis (HPA testis-enriched; expressed in male germline cells) and was originally cloned from a testis library. Functional studies in mouse have established FBXO47 as a germ-cell protein essential for meiotic prophase I in spermatocytes: Fbxo47-null males are infertile with spermatocytes arresting around late zygotene/pachytene, showing incomplete homologous synapsis, persistent autosomal gamma-H2AX, and failure to form XY bodies. Mechanistically, FBXO47 acts at meiotic chromosome subcompartments through SKP1-associated regulation: it localizes to the nuclear periphery and co-localizes with the shelterin component TRF2, where it promotes telomere-inner nuclear membrane attachment by stabilizing TRF2 (impairing TRF2 ubiquitination) during the bouquet stage; FBXO47 also interacts with SKP1 and the axis protein HORMAD1, contributing to HORMAD1 turnover and meiotic double-strand-break/ recombination homeostasis, and has been proposed to act in a centromeric SCF module that preserves centromeric SKP1 to support centromere pairing. Notably, several of its documented activities involve preventing rather than promoting substrate degradation (TRF2, SKP1), so its in vivo role may diverge from a classical SCF substrate receptor that drives degradation. A curated SCF E3 ligase complex variant containing FBXO47 has been recorded (ComplexPortal CPX-8006). FBXO47 maps to 17q12; human genetics associates the locus with azoospermia, and a missense variant has been reported as a candidate in autosomal recessive intellectual disability. existing_annotations: - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:34445249 qualifier: part_of review: summary: ComplexPortal NAS assertion that FBXO47 is part of an SCF E3 ubiquitin ligase complex, consistent with its F-box domain and the curated FBXO47-variant SCF complex (CPX-8006). FBXO47's essential, experimentally established biology is in meiotic prophase, not canonical SCF catalysis, so this is retained as non-core. action: KEEP_AS_NON_CORE reason: FBXO47 has an F-box domain and a curated SCF-complex variant (CPX-8006), and UniProt states it is part of an SCF complex, but this is inferred by similarity (ECO:0000250) and asserted (NAS) from a general SCF review (PMID:34445249) rather than demonstrated for FBXO47 specifically. Falcon-sourced primary literature (Hua 2019; Ma 2024) shows FBXO47 physically interacts with the SCF core component SKP1 in germ cells, which biochemically supports SCF-machinery association; however the in vivo essential function is in meiotic prophase (telomere-INM integration via TRF2 stabilization, centromere pairing) and several activities prevent rather than promote substrate degradation, so SCF-complex membership is kept as a non-core annotation rather than promoted to a core function. This is consistent with the functional placement of FBXO47 as an F-box/SCF (CRL1) substrate-recognition module while keeping the meiotic biology central. supported_by: - reference_id: file:human/FBXO47/FBXO47-uniprot.txt supporting_text: 'Part of a SCF (SKP1-cullin-F-box) protein ligase complex.' - reference_id: file:human/FBXO47/FBXO47-deep-research-falcon.md supporting_text: Evidence from co-immunoprecipitation indicates FBXO47 **interacts with SKP1**, supporting a model in which FBXO47 can act as an F-box/SCF-associated factor - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:34445249 qualifier: involved_in review: summary: ComplexPortal NAS assertion that FBXO47 participates in SCF-dependent proteasomal protein degradation. This is inferred from F-box family membership and a general SCF review, and the UniProt FUNCTION itself is only a "Probably" statement by similarity; the experimentally documented FBXO47 function is in meiosis and may not proceed via canonical SCF-dependent degradation in vivo. action: UNDECIDED reason: >- The annotation rests on family-level inference (UniProt FUNCTION is a "Probably recognizes... promotes their ubiquitination and degradation" ECO:0000250 statement) and an NAS citation to a general SCF review (PMID:34445249) that does not characterize FBXO47. Falcon-sourced primary literature complicates rather than confirms this term: while one study reports FBXO47 can target HORMAD1 for polyubiquitination and degradation (supporting some SCF-dependent catabolic activity), the best-characterized FBXO47 activities are protective/stabilizing (impairing ubiquitination of TRF2 and of SKP1), i.e. opposing degradation. The functionally validated in vivo role of FBXO47 (mouse knockouts) is in meiotic prophase / telomere-INM integration / centromere pairing; whether FBXO47's essential function proceeds via canonical SCF-dependent proteasomal degradation of substrates in vivo is not established. Marked UNDECIDED rather than ACCEPT/REMOVE because the underlying biochemical claim cannot be verified from the available evidence and the gene's documented activities point in both directions. supported_by: - reference_id: file:human/FBXO47/FBXO47-uniprot.txt supporting_text: Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation. - reference_id: file:human/FBXO47/FBXO47-deep-research-falcon.md supporting_text: FBXO47 interacts with SKP1 and HORMAD1 and targets HORMAD1 for polyubiquitination and degradation in HEK293T cells references: - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: - statement: General review of the 69 SCF E3 ubiquitin ligase complexes, in which variable F-box proteins determine substrate specificity and target substrates for proteasomal degradation; does not specifically characterize FBXO47. reference_section_type: ABSTRACT reference_review: relevance: LOW correctness: LOW_QUALITY review_notes: >- PubMed-verified (Int J Mol Sci 2021;22(16):8544, PMC8395177); abstract-only in cache (full_text_available: false). This is a general SCF-family review and does not establish FBXO47-specific function. It is the NAS source used by ComplexPortal for both FBXO47 SCF annotations, but it provides only family-level support, not direct evidence for FBXO47 acting as a canonical SCF substrate receptor. - id: file:human/FBXO47/FBXO47-uniprot.txt title: UniProt entry Q5MNV8 (FBX47_HUMAN), F-box only protein 47 findings: - statement: UniProt FUNCTION and SUBUNIT for FBXO47 are inferred by similarity (ECO:0000250); FBXO47 is testis-enriched and contains an F-box domain (residues 41-91). reference_section_type: OTHER reference_review: relevance: HIGH correctness: VERIFIED review_notes: >- Source of the SCF complex membership and substrate-receptor function statements, both flagged by UniProt as "by similarity" (ECO:0000250). Also documents testis tissue specificity and the F-box domain, supporting the germ-cell/meiotic context. - id: file:human/FBXO47/FBXO47-deep-research-falcon.md title: Falcon deep research report for human FBXO47 findings: - statement: FBXO47 is a meiosis-associated F-box protein that interacts with the SCF core component SKP1 and regulates meiotic chromosomal proteins (TRF2, HORMAD1) during meiotic prophase I. supporting_text: 'Most supported primary function: FBXO47 is a meiosis-associated F‑box protein that interacts with SCF machinery (via SKP1) and regulates key meiotic chromosomal proteins to ensure proper meiotic prophase progression.' - statement: In the meiotic context FBXO47 stabilizes the shelterin protein TRF2 (impairing its ubiquitination) at the telomere-inner nuclear membrane interface, rather than promoting TRF2 degradation. supporting_text: 'Ubiquitination assays indicate FBXO47 overexpression can **impair TRF2 ubiquitination** (without similarly affecting TRF1), consistent with **TRF2 stabilization**' - statement: FBXO47 interacts with SKP1 and HORMAD1 and can target HORMAD1 for polyubiquitination/degradation, linking SCF activity to control of meiotic DSB homeostasis. supporting_text: FBXO47 interacts with SKP1 and HORMAD1 and targets HORMAD1 for polyubiquitination and degradation in HEK293T cells - statement: A 2024 model proposes FBXO47 acts in a centromeric SCF module that suppresses SKP1 ubiquitination to preserve centromeric SKP1 and promote centromere pairing and pachytene progression. supporting_text: FBXO47 is a component of a **centromeric SCF E3 ligase** and that FBXO47 can **reduce SKP1 ubiquitination**, helping preserve SKP1 levels at centromeres/chromosome axes reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: >- Falcon synthesis of FBXO47 meiotic biology, anchored on Hua et al. 2019 (Nucleic Acids Research, doi:10.1093/nar/gkz992; telomere-INM/TRF2), Guan et al. 2022 (NAR, doi:10.1093/nar/gkac304; SKP1/HORMAD1), and Ma et al. 2024 (Communications Biology, doi:10.1038/s42003-024-06782-6; centromeric SCF). These are real, citable primary studies cross-consistent with the UniProt/HPA testis-enriched, F-box framing, but Falcon cites author-year/DOIs not PMIDs and the underlying papers are not in the local cache, so the molecular claims are treated as leads (UNVERIFIED) rather than independently verified here. core_functions: - description: >- F-box-domain protein expressed in male germ cells that is essential for meiotic prophase I. FBXO47 acts at meiotic chromosome subcompartments through SKP1-associated regulation: it localizes to the nuclear periphery, co-localizes with the shelterin protein TRF2, and promotes telomere-inner nuclear membrane attachment (bouquet formation) by stabilizing TRF2 (impairing its ubiquitination); it also engages SKP1 and the axis protein HORMAD1 and is implicated in HORMAD1 turnover, homologous synapsis, and meiotic double-strand-break/recombination homeostasis. FBXO47 carries the F-box motif characteristic of SCF substrate-recognition receptors and is recorded as part of a curated FBXO47-variant SCF E3 ligase complex, but several of its documented activities prevent rather than promote substrate degradation, so its essential meiotic role may be partly distinct from canonical SCF-mediated proteasomal degradation; a direct in vivo SCF substrate-receptor catalytic role for FBXO47 has not been firmly established. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity directly_involved_in: - id: GO:0007129 label: homologous chromosome pairing at meiosis locations: - id: GO:0000794 label: condensed nuclear chromosome supported_by: - reference_id: file:human/FBXO47/FBXO47-uniprot.txt supporting_text: Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation. - reference_id: file:human/FBXO47/FBXO47-uniprot.txt supporting_text: 'DOMAIN 41..91' - reference_id: file:human/FBXO47/FBXO47-deep-research-falcon.md supporting_text: 'Most supported primary function: FBXO47 is a meiosis-associated F‑box protein that interacts with SCF machinery (via SKP1) and regulates key meiotic chromosomal proteins to ensure proper meiotic prophase progression.' proposed_new_terms: - proposed_name: telomere attachment to nuclear envelope involved in meiotic telomere clustering (bouquet formation) proposed_definition: >- A meiotic-prophase-I biological process in which telomeres become tethered to and cluster at the inner nuclear membrane (the bouquet stage), facilitating homologous chromosome pairing and recombination. FBXO47's best-supported in vivo role is promoting this telomere-inner-nuclear-membrane attachment via stabilization of the shelterin protein TRF2; no existing FBXO47 annotation captures this specific telomere-INM/bouquet process. Proposed label and definition only; no GO ID invented. suggested_questions: - question: Does FBXO47 assemble a canonical SCF (SKP1-CUL1-RBX1) E3 ligase complex in germ cells and ubiquitinate substrates for proteasomal degradation, or does its essential meiotic function (telomere-INM integration, centromere pairing) operate via non-degradative, stabilizing activities (e.g. shielding TRF2 and SKP1 from ubiquitination)? - question: Are the telomere-centric (TRF2/bouquet) and centromere-centric (SKP1/centromere pairing) models of FBXO47 reconcilable as a single SKP1-dependent meiotic surveillance activity, or do they reflect distinct chromosome-subcompartment functions and/or antibody/knockout-method artefacts? - question: Is the human FBXO47 azoospermia association causal, and does the reported intellectual-disability missense variant (R182G) affect FBXO47 function or reflect linkage at 17q12? suggested_experiments: - description: Generate F-box-deletion or F-box point-mutant FBXO47 alleles (disrupting SKP1 binding) in a germ-cell or mouse model and assess whether SKP1/SCF association is required for telomere-INM integration, TRF2 stabilization, and centromere pairing, distinguishing degradative SCF function from non-degradative stabilizing roles. - description: Perform affinity-purification mass spectrometry of FBXO47 from testis across meiotic stages to define its complex composition (SKP1/CUL1/RBX1 versus shelterin/axis partners such as TRF2 and HORMAD1) and candidate ubiquitination substrates, followed by in vitro reconstitution and ubiquitination/deubiquitination assays to test whether FBXO47 promotes or restrains substrate ubiquitination. - description: Use super-resolution and electron microscopy of Fbxo47 wild-type versus knockout spermatocytes to map FBXO47 localization at telomere-INM versus centromeric/axis sites and directly test the telomere-centric versus centromere-centric models.