FBXO5 PN Consistency Notes
- Generated: 2026-06-18
- Project: PROTEOSTASIS
- Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
- UniProt: Q9UKT4
- AIGR review status: COMPLETE
- Review batch: proteostasis-batch-2026-06-13
- Batch change status: added
Source Files Checked
Deep Research Files
AIGR Review Snapshot
- Description: FBXO5 (Early mitotic inhibitor 1, EMI1) is a cell-cycle regulatory protein that, despite containing an F-box, functions principally as a direct inhibitor of the anaphase-promoting complex/cyclosome (APC/C), the multisubunit E3 ubiquitin ligase that drives mitotic and cell-cycle progression. EMI1 accumulates from late G1 through S and G2 phase under E2F transcriptional control and binds tightly to the APC/C and its coactivators FZR1/CDH1 and CDC20. It acts as a pseudosubstrate/multimodal inhibitor: a conserved C-terminal D-box, linker, and tail together with a structured zinc-binding region (ZBR) engage distinct sites on APC/C to block substrate access at the D-box coreceptor (FZR1-ANAPC10) and to suppress ubiquitin-chain elongation by the APC/C E2 enzymes UBE2C/UBCH10 and UBE2S. By restraining APC/C during interphase, EMI1 stabilizes APC/C substrates such as cyclin A (CCNA2) and geminin (GMNN), thereby coupling DNA replication with mitosis, preventing rereplication, and protecting against DNA-damage-induced senescence. EMI1 levels are sharply controlled: at the G1/S transition it switches from being a substrate of APC/C(CDH1) to its inhibitor, and at the onset of mitosis it is phosphorylated by CDK1/2 and PLK1 to generate a DSGxxS phosphodegron recognized by the SCF(beta-TrCP/BTRC) ubiquitin ligase, leading to its degradation and APC/C activation. In oocyte meiosis the EMI1/EMI2 family provides cytostatic-factor activity that arrests cells through APC/C inhibition. EMI1 levels are dosage-sensitive for genome stability: reduced EMI1 causes chromosome instability, micronucleation, and DNA damage and is associated with cellular transformation, while EMI1 abundance is also shaped by post-transcriptional control (METTL16-mediated m6A mRNA stabilization and PTBP1-dependent exon-3 splicing), and FBXO5 is frequently dysregulated in cancers. EMI1 localizes to the nucleus and cytoplasm in interphase and to the spindle in mitosis.
- Existing/core annotation action counts: ACCEPT: 28; KEEP_AS_NON_CORE: 35; MARK_AS_OVER_ANNOTATED: 2
PN Consistency Summary
- Consistency: CONTRADICTION (substantive, by design). The PN places EMI1 in the SCF substrate-receptor group and projects GO:1990756 adaptor activity. The review (correctly per the SPECIAL CASE) treats EMI1 as a non-canonical F-box whose dominant function is APC/C INHIBITION, not productive SCF substrate reception: core MF = GO:1990948 ubiquitin ligase inhibitor activity (verified real; ACCEPT, IDA PMID:15148369). Review explicitly demotes the ComplexPortal SCF-receptor NAS to non-core and MARK_AS_OVER_ANNOTATED for SCF-dependent catabolism / protein ubiquitination (EMI1 is a SCF^BTRC substrate, not a productive receptor). Falcon DR ↔ review agree; both diverge from the PN node framing.
- PN story / NEW pressure: The PN role (generic SCF receptor → GO:1990756) is NOT supported as core for this gene and is contradicted by the well-documented inhibitor biology. No new term needed: the accurate MFs (GO:1990948 inhibitor activity; GO:0010997 anaphase-promoting complex binding; GO:1904667/GO:0051444 negative regulation of ligase/transferase) are already in GOA and accepted. A single 2024 report frames SCF^EMI1/RAD51, but the review rightly does not let it overturn the inhibitor role. Conclude: PN adaptor projection over-reaches for FBXO5.
- Evidence alignment: PN reference only "15340381 / rev". Review uses gene-specific primary literature: PMID:15148369 (inhibitor activity, IDA), 23708605 (DisProt IDR inhibition), 15148369/15469984-class APC/C-binding, 17875940 (genome-stability IMP), plus Falcon DR. No overlap with PN; review evidence is far richer and on-point.
- Verdict: PN node placement is misleading for EMI1 — adaptor projection (GO:1990756) should NOT propagate; review correctly anchors on GO:1990948 inhibitor activity (in GOA). Over-reach on the PN side.
Full Consistency Review
- UniProt: Q9UKT4 (FBXO5/EMI1) · batch: proteostasis-batch-2026-06-13 (Falcon DR) · review status: COMPLETE
- PN placement:
UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|ZBR-type ZnF ; PN-node mapping: group Cul1 substrate receptor=mapped/ok_for_propagation→GO:1990756; F-box/ZBR subtype+type=no_mapping; class=context_only/too_broad→GO:0061630.
- Consistency: CONTRADICTION (substantive, by design). The PN places EMI1 in the SCF substrate-receptor group and projects GO:1990756 adaptor activity. The review (correctly per the SPECIAL CASE) treats EMI1 as a non-canonical F-box whose dominant function is APC/C INHIBITION, not productive SCF substrate reception: core MF = GO:1990948 ubiquitin ligase inhibitor activity (verified real; ACCEPT, IDA PMID:15148369). Review explicitly demotes the ComplexPortal SCF-receptor NAS to non-core and MARK_AS_OVER_ANNOTATED for SCF-dependent catabolism / protein ubiquitination (EMI1 is a SCF^BTRC substrate, not a productive receptor). Falcon DR ↔ review agree; both diverge from the PN node framing.
- PN story / NEW pressure: The PN role (generic SCF receptor → GO:1990756) is NOT supported as core for this gene and is contradicted by the well-documented inhibitor biology. No new term needed: the accurate MFs (GO:1990948 inhibitor activity; GO:0010997 anaphase-promoting complex binding; GO:1904667/GO:0051444 negative regulation of ligase/transferase) are already in GOA and accepted. A single 2024 report frames SCF^EMI1/RAD51, but the review rightly does not let it overturn the inhibitor role. Conclude: PN adaptor projection over-reaches for FBXO5.
- Mapping strategy: This gene SHOULD change/qualify the node. Like FBXO2/FBXO6 (lectin) but more strongly, EMI1 is an exception to the Cul1-substrate-receptor → GO:1990756 default. Recommend marking FBXO5/EMI1 (and ZBR-type-ZnF F-box) so the GO:1990756 projection is suppressed or flagged "non-canonical / APC-C inhibitor" rather than propagated as a productive adaptor.
- Evidence alignment: PN reference only "15340381 / rev". Review uses gene-specific primary literature: PMID:15148369 (inhibitor activity, IDA), 23708605 (DisProt IDR inhibition), 15148369/15469984-class APC/C-binding, 17875940 (genome-stability IMP), plus Falcon DR. No overlap with PN; review evidence is far richer and on-point.
- Verdict: PN node placement is misleading for EMI1 — adaptor projection (GO:1990756) should NOT propagate; review correctly anchors on GO:1990948 inhibitor activity (in GOA). Over-reach on the PN side.
- Recommended edits: none to FBXO5-ai-review.yaml (review is correct). [MAP] Flag FBXO5/EMI1 as a non-canonical F-box (APC/C inhibitor) so GO:1990756 is NOT propagated to it; its core MF is GO:1990948 ubiquitin ligase inhibitor activity.
PN Dossier Context
- review_batch: proteostasis-batch-2026-06-13
- review_yaml: genes/human/FBXO5/FBXO5-ai-review.yaml
- PN workbook rows: 1
PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | ZBR-type ZnF
- UniProt: Q9UKT4
- In branches: UPS
- Signature domains: IPR001810
- Auxiliary domains: IPR044064
- PN references (titles):
- PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|ZBR-type ZnF
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box
status=no_mapping scope= GO=[]
rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
status=no_mapping scope= GO=[]
rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.
Projected GO annotations (1)
- GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
Note
This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.