FBXW10

UniProt ID: Q5XX13
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

FBXW10 (ubiquitin ligase-specificity factor) is a large (1052 aa) member of the F-box/WD40 (FBXW) family, containing an F-box motif and WD40 repeats together with coiled-coil regions. F-box proteins act as the interchangeable substrate-recognition subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase complexes, in which the F-box motif docks onto SKP1/CUL1 and the WD40 propeller recruits substrates for ubiquitination by the RBX1-bound E2, committing them to proteasomal degradation; the F-box protein itself is the substrate adaptor and is not catalytic. Curated interactome resources classify FBXW10 as an E3 cullin-RING-ligase (CRL) adaptor with F-box plus WD40 repeats. FBXW10 is testis-enriched in expression. Functional data are limited: in a study of laminopathy-associated lamin A rod-domain mutants, FBXW10 transcript was induced several-fold in cells expressing these mutants, and ectopic FBXW10 expression depleted heterochromatin protein 1 isoforms HP1-alpha (CBX5) and HP1-beta (CBX1) but not HP1-gamma in a proteasome-dependent manner, implicating FBXW10 in turnover of these chromatin proteins under conditions of nuclear stress. FBXW10 has been reported mutated (missense, nonsense and frameshift) in T-cell prolymphocytic leukemia and was nominated as a candidate susceptibility gene (an in-frame WD-propeller deletion, p.Ile440del) in familial non-medullary thyroid cancer, and it shows tumor-type-specific expression changes in pan-cancer analyses. Its direct, physiological ubiquitination substrates and its assembly into a defined SCF complex have not been biochemically demonstrated; the HP1 isoforms are best regarded as candidate/affected substrates rather than validated direct targets.

Proposed New Ontology Terms

ubiquitin-like ligase-substrate adaptor activity

Definition: Bridging a substrate to a ubiquitin-like protein ligase, as performed by an SCF F-box substrate-recognition subunit that binds both SKP1/the ligase scaffold and the substrate to facilitate the substrate's ubiquitination. This corresponds to the existing GO term GO:1990756, which is not currently in FBXW10's annotation set.

Justification: FBXW10 is classified as an E3 CRL adaptor with an F-box and WD40 propeller and, when induced, promotes proteasome-dependent depletion of HP1-alpha/beta, consistent with a substrate-adaptor molecular function rather than catalysis (which is RBX1's). Adding GO:1990756 would give FBXW10 an informative molecular-function term, currently absent from its annotation set.

Parent term: ubiquitin-like ligase-substrate adaptor activity

Supporting Evidence:

Existing Annotations Review

GO Term Evidence Action Reason
GO:0019005 SCF ubiquitin ligase complex
NAS
PMID:20498703
Lamin A rod domain mutants target heterochromatin protein 1a... 		ACCEPT
Summary: ComplexPortal/family-based assignment of SCF complex membership (CPX-7786, SCF complex FBXW10 variant), consistent with the F-box motif and with curated interactome classification of FBXW10 as an E3 CRL adaptor; the cited study links FBXW10 to SCF-mediated proteasomal degradation of HP1 isoforms.
Reason: Core assembly annotation for an F-box protein; supported by the F-box domain, the UniProt function statement describing FBXW10 as a probable SCF substrate-recognition component, and interactome-level annotation as an E3 CRL adaptor. Direct biochemical reconstitution of an SCF(FBXW10) complex has not been shown.
Supporting Evidence:
file:human/FBXW10/FBXW10-uniprot.txt
Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
file:human/FBXW10/FBXW10-deep-research-falcon.md
FBXW10 is explicitly categorized as an **E3 CRL adaptor** with **F-box + WD repeats**
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
NAS
PMID:20498703
Lamin A rod domain mutants target heterochromatin protein 1a... 		ACCEPT
Summary: Assignment of involvement in SCF-dependent proteasomal degradation; ectopic FBXW10 depletes HP1-alpha/beta via the proteasome in cells expressing lamin A mutants, and proteasome inhibitors (MG132/lactacystin) rescue HP1 levels.
Reason: Core biological process for an SCF substrate receptor; supported by the experimental observation that FBXW10 expression drives proteasome-dependent depletion of HP1 isoforms. Direct in vitro ubiquitination of HP1 by reconstituted SCF(FBXW10) was not demonstrated, so HP1-alpha/beta are best treated as candidate/affected substrates.
Supporting Evidence:
PMID:20498703
ectopic expression of FBXW10 in HeLa cells led to depletion of HP1alpha and beta without alteration of HP1gamma levels
file:human/FBXW10/FBXW10-deep-research-falcon.md
ectopic FBXW10 is sufficient to deplete HP1α and HP1β, but not HP1γ, supporting a role in selective ubiquitin-proteasome-mediated turnover of HP1 isoforms
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952618 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (AcM-UBE2M transfers NEDD8 to CRL1) propagated to FBXW10 as an SCF subunit.
Reason: Generic CRL pathway-derived localization; plausible for an SCF subunit but not FBXW10-specific, and the one functional study implicates a nuclear/heterochromatin context.
Supporting Evidence:
file:human/FBXW10/FBXW10-uniprot.txt
Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8952620 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (NEDD8:AcM-UBE2M binds CRL1) propagated to FBXW10.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
Supporting Evidence:
file:human/FBXW10/FBXW10-uniprot.txt
Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955241 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (CAND1 binds cytosolic CRL ligases) propagated to FBXW10.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
Supporting Evidence:
file:human/FBXW10/FBXW10-uniprot.txt
Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8955289 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (COMMDs displace CAND1) propagated to FBXW10.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
Supporting Evidence:
file:human/FBXW10/FBXW10-uniprot.txt
Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956040 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (COP9 signalosome deneddylates CRLs) propagated to FBXW10.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
Supporting Evidence:
file:human/FBXW10/FBXW10-uniprot.txt
Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-8956200 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (MyrG-DCUN1D3 binds CRL1) propagated to FBXW10.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
Supporting Evidence:
file:human/FBXW10/FBXW10-uniprot.txt
Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-983140 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (transfer of Ub from E2 to substrate) propagated to FBXW10.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
Supporting Evidence:
file:human/FBXW10/FBXW10-uniprot.txt
Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-983147 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (release of E3 from polyubiquitinated substrate) propagated to FBXW10.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
Supporting Evidence:
file:human/FBXW10/FBXW10-uniprot.txt
Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-983156 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (polyubiquitination of substrate) propagated to FBXW10.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
Supporting Evidence:
file:human/FBXW10/FBXW10-uniprot.txt
Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
GO:0005829 cytosol
TAS
Reactome:R-HSA-983157 		KEEP AS NON CORE
Summary: Reactome pathway-level cytosol localization (interaction of E3 with substrate and E2-Ub complex) propagated to FBXW10.
Reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
Supporting Evidence:
file:human/FBXW10/FBXW10-uniprot.txt
Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex

Core Functions

Probable substrate-recognition (substrate-adaptor) subunit of an SCF (SKP1-CUL1-F-box) cullin-RING E3 ubiquitin ligase complex that, when induced, promotes proteasome-dependent depletion of the heterochromatin proteins HP1-alpha (CBX5) and HP1-beta (CBX1) under conditions of nuclear/lamin stress. FBXW10 is non-catalytic (ubiquitin transfer is RBX1's), and direct reconstituted ubiquitination of HP1 has not been shown, so HP1 isoforms remain candidate/affected substrates.

Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/FBXW10/FBXW10-uniprot.txt
    Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins
  • PMID:20498703
    ectopic expression of FBXW10 in HeLa cells led to depletion of HP1alpha and beta without alteration of HP1gamma levels

References

PMID:20498703
Lamin A rod domain mutants target heterochromatin protein 1alpha and beta for proteasomal degradation by activation of F-box protein, FBXW10.
  • In HeLa cells, lamin A rod-domain mutants induced FBXW10 transcript several-fold and triggered proteasomal degradation of HP1-alpha (CBX5) and HP1-beta (CBX1) but not HP1-gamma; ectopic FBXW10 expression alone depleted HP1-alpha/beta, implicating FBXW10 (an F-box protein involved in E3 ubiquitin ligase activity) in this turnover.
Reactome:R-HSA-8952618
AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
Reactome:R-HSA-8952620
NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
Reactome:R-HSA-8955241
CAND1 binds cytosolic CRL E3 ubiquitin ligases
Reactome:R-HSA-8955289
COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
Reactome:R-HSA-8956040
COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
Reactome:R-HSA-8956200
MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
Reactome:R-HSA-983140
Transfer of Ub from E2 to substrate and release of E2
Reactome:R-HSA-983147
Release of E3 from polyubiquitinated substrate
Reactome:R-HSA-983156
Polyubiquitination of substrate
Reactome:R-HSA-983157
Interaction of E3 with substrate and E2-Ub complex
file:human/FBXW10/FBXW10-deep-research-falcon.md
Falcon deep research report for human FBXW10
  • Curated interactome/UPS resources classify FBXW10 (Q5XX13, 1052 aa) as an E3 cullin-RING-ligase adaptor with F-box plus WD40 repeats, consistent with an SCF-type substrate-receptor architecture rather than an enzyme.
    "FBXW10 is explicitly categorized as an **E3 CRL adaptor** with **F-box + WD repeats**"
  • The strongest functional evidence is that lamin A rod-domain mutants induce FBXW10 and ectopic FBXW10 is sufficient to deplete HP1-alpha/HP1-beta but not HP1-gamma in a proteasome-dependent manner, though direct in vitro ubiquitination of HP1 by purified SCF(FBXW10) was not shown.
    "ectopic FBXW10 is sufficient to deplete HP1α and HP1β, but not HP1γ, supporting a role in selective ubiquitin-proteasome-mediated turnover of HP1 isoforms"
  • FBXW10 has been reported mutated (missense, nonsense, frameshift) in T-cell prolymphocytic leukemia, and the function/substrates remain largely unknown.
    "FBXW10 harbors **missense, nonsense, and frameshift mutations** in **T-cell prolymphocytic leukemia (T-PLL)**"
  • A candidate familial non-medullary thyroid cancer variant (p.Ile440del) maps to a beta-hairpin within a WD-propeller blade, implicating the WD40 substrate-binding region, though FBXW10 was ranked a second-priority candidate.
    "Ile440 is evolutionarily conserved down to placental mammals and lies in a **β-hairpin of a WD-propeller blade**"

Suggested Questions for Experts

Q: Does FBXW10 directly ubiquitinate HP1-alpha (CBX5) and HP1-beta (CBX1) within a reconstituted SCF complex, or is the observed depletion indirect?

Q: Given testis-enriched expression, what is FBXW10's physiological role and substrate repertoire in spermatogenesis, distinct from the lamin-stress-induced HP1 turnover?

Q: Are the T-PLL mutations and the familial thyroid-cancer WD-propeller variant (p.Ile440del) loss-of-function for substrate recognition, and what substrate do they affect?

Suggested Experiments

Experiment: Reconstitute SCF(FBXW10) with SKP1, CUL1, RBX1 and an E2 in vitro and test direct ubiquitination of CBX5/CBX1, with F-box-deletion FBXW10 as a negative control.

Experiment: Co-immunoprecipitation of endogenous FBXW10 with SKP1/CUL1 and with CBX5/CBX1 in testis-derived cells, plus FBXW10 knockdown to assess effects on endogenous HP1 isoform stability.

Experiment: Express the WD-propeller variant p.Ile440del and T-PLL truncating alleles and assay SCF assembly (SKP1/CUL1 binding) and HP1-alpha/beta turnover relative to wild-type FBXW10.

Deep Research

Falcon

(FBXW10-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 22 citations 2 artifacts 2026-06-13T07:08:51.386590
Edison artifact artifact-00 (text/markdown)
## Context ID: pqac-00000009 The requested information regarding FBXW10 induction and HP1α/β depletion is presented in the following figures and tables: - **HP1 (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human FBXW10 (UniProt Q5XX13) — Functional Annotation, Evidence, and Current Understanding

1) Target verification (gene/protein identity)

The literature evidence retrieved matches the specified target: human FBXW10 encoding F-box/WD repeat-containing protein 10, UniProt Q5XX13. A curated interactome/UPS resource explicitly lists FBXW10 as UniProt Q5XX13, 1052 aa, annotated as an E3 CRL adaptor with F-box domain + WD repeats, consistent with an SCF-type substrate receptor architecture (Poirson et al., 2017-10, FEBS J; https://doi.org/10.1111/febs.14193) (poirson2017mappingtheinteractome pages 23-23). Review literature also classifies FBXW10 as a WD40-repeat F-box (FBXW-class) protein (Sahasrabuddhe & Elenitoba-Johnson, 2015-01, Immunol Rev; https://doi.org/10.1111/imr.12236) (sahasrabuddhe2015roleofthe pages 4-5).

2) Key concepts and definitions (current understanding)

2.1 SCF E3 ubiquitin ligases and F-box proteins

F-box proteins are best understood as substrate-recognition subunits of SCF (SKP1–CUL1–F-box) cullin-RING E3 ubiquitin ligase complexes, where the F-box motif supports binding to Skp1 and additional domains (e.g., WD40 repeats) support substrate recruitment. In the UPS interactome mapping paper, FBXW10 is explicitly categorized as an E3 CRL adaptor with F-box + WD repeats (poirson2017mappingtheinteractome pages 23-23). In a hematologic malignancy review, FBXW10 is described as a WD40-repeat F-box protein (FBXW class) and discussed in the context of substrate specificity in SCF E3 ligases (sahasrabuddhe2015roleofthe pages 4-5).

2.2 Domain architecture and inferred biochemical role

FBXW10’s F-box plus WD40/β-propeller domain architecture is typical of F-box substrate receptors, in which WD40 repeats form a propeller-like scaffold enabling selective protein–protein interactions. Consistent with this, a 2023 hereditary thyroid cancer genetics study interpreted a disease-candidate variant (p.Ile440del) within the WD-repeat propeller, using an AlphaFold model for human FBXW10 (Q5XX13) and noting high model confidence (pLDDT > 90) near the affected region (Majdalani et al., 2023-05, IJMS; https://doi.org/10.3390/ijms24098233) (majdalani2023novelsusceptibilitygenes pages 5-7).

3) Experimentally supported functional evidence (what FBXW10 does)

A central mechanistic study (Chaturvedi & Parnaik, 2010-05, PLoS ONE; https://doi.org/10.1371/journal.pone.0010620) reports that lamin A rod-domain disease mutants in HeLa cells are associated with proteasomal depletion of heterochromatin protein 1 (HP1) isoforms and that FBXW10 is induced and sufficient to drive depletion of specific HP1 isoforms (chaturvedi2010laminarod pages 1-2).

Key findings:
- FBXW10 induction: qRT-PCR (Table 3) shows FBXW10 transcript levels increased in lamin-mutant contexts (e.g., G232E: 5.64 ± 0.49 vs GFP control 1.71 ± 0.43; R386K: 2.35 ± 0.44), consistent with several-fold induction (chaturvedi2010laminarod pages 5-7).
- Isoform specificity: Ectopic expression of FBXW10 caused depletion of HP1α and HP1β but not HP1γ (HP1c) (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7).
- Cell-level penetrance: FBXW10 overexpression depleted HP1α/β in ~80–90% of cells (chaturvedi2010laminarod pages 5-7).
- Proteasome dependence / pharmacologic rescue: Proteasome inhibitors restored HP1 and partially corrected lamin mutant phenotypes. For example, MG132 increased nuclear rim localization of lamin mutants from 19.6% ± 6.09 → 83.2% ± 6.11 (G232E) and 15.4% ± 5.11 → 61.0% ± 6.40 (R386K); lactacystin also improved rim localization (G232E 73.2% ± 9.07; R386K 39.8% ± 8.57) (chaturvedi2010laminarod pages 5-7). In the same work, HP1-positive-cell frequencies (immunofluorescence) were markedly restored by MG132/lactacystin for multiple lamin mutants (chaturvedi2010laminarod pages 2-4).

Interpretation for functional annotation:
- These results support FBXW10 as an E3-ligase adaptor/substrate receptor that can promote (directly or indirectly via SCF) the ubiquitin–proteasome-dependent turnover of HP1α/HP1β under specific cellular conditions (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7, chaturvedi2010laminarod pages 2-4).
- However, the study does not establish purified-complex biochemistry (e.g., reconstituted SCF-FBXW10 ubiquitination of HP1 in vitro) and is largely based on induction/overexpression and proteasome-inhibitor phenotypic rescue; thus, HP1 isoforms are best treated as supported candidate substrates/affected proteins rather than definitively validated direct substrates of SCF-FBXW10 (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7).

Visual evidence (figures/tables): The paper contains Western blot and tabular qRT-PCR evidence of HP1 depletion/FBXW10 induction and the ability of FBXW10 overexpression to deplete HP1α/β (chaturvedi2010laminarod media 9af6f79a, chaturvedi2010laminarod media 7bc1e356, chaturvedi2010laminarod media 2d73f981).

3.2 Subcellular localization and cellular compartment context

The functional evidence above places the FBXW10-associated phenotype in nuclear organization/heterochromatin maintenance pathways, via effects on HP1α/β and lamin mutant nuclear morphology in cultured cells (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 2-4). While the provided excerpts do not directly map FBXW10 itself to a specific subcellular compartment by microscopy under endogenous expression, the implicated pathway is nuclear: HP1 proteins are heterochromatin-associated and lamin A mutants perturb nuclear architecture (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 2-4).

4) Human genetics and disease associations (2023–2024 emphasis where possible)

4.1 Familial non-medullary thyroid cancer (FNMTC) candidate variant (2023)

A 2023 whole-exome sequencing study of a large consanguineous kindred with FNMTC nominated FBXW10 among candidate susceptibility genes (Majdalani et al., 2023-05; https://doi.org/10.3390/ijms24098233) (majdalani2023novelsusceptibilitygenes pages 4-5).

  • Variant: FBXW10 c.1317_1319delCAT (p.Ile440del; chr17:18661699), heterozygous in multiple family members and discussed as a candidate with incomplete penetrance (majdalani2023novelsusceptibilitygenes pages 5-7, majdalani2023novelsusceptibilitygenes pages 4-5).
  • Structural interpretation: Ile440 is evolutionarily conserved down to placental mammals and lies in a β-hairpin of a WD-propeller blade; deletion was predicted to disrupt local hydrogen-bond networks; AlphaFold confidence around the region was reported as pLDDT > 90 (majdalani2023novelsusceptibilitygenes pages 5-7).
  • Importantly, the authors ranked FBXW10 as a second-priority candidate relative to ARHGEF28, noting low normal thyroid expression and lack of a connected PPI network to known thyroid pathways in their analysis (majdalani2023novelsusceptibilitygenes pages 9-10).

This constitutes recent genetics evidence suggesting potential involvement in thyroid cancer predisposition, but not causal proof (majdalani2023novelsusceptibilitygenes pages 5-7, majdalani2023novelsusceptibilitygenes pages 9-10).

4.2 Hematologic malignancy genetics: mutations reported in T-PLL (reviewed)

A 2015 review of the ubiquitin-proteasome system in hematologic malignancies reports that FBXW10 harbors missense, nonsense, and frameshift mutations in T-cell prolymphocytic leukemia (T-PLL) (e.g., R318N, R416*, K966fs) (Sahasrabuddhe & Elenitoba-Johnson, 2015-01; https://doi.org/10.1111/imr.12236) (sahasrabuddhe2015roleofthe pages 4-5). The review emphasizes that very little is known about FBXW10’s function and that identifying substrates would be critical to understand consequences of inactivation in T-PLL (sahasrabuddhe2015roleofthe pages 4-5).

5) Recent developments and latest research (prioritizing 2023–2024)

5.1 Pan-cancer bioinformatics: expression/prognosis associations (2024)

A 2024 pan-cancer analysis of the FBXW family reports that FBXW10 shows tumor-type-specific expression differences (Huang et al., 2024-12, Front Immunol; https://doi.org/10.3389/fimmu.2022.1084339) (huang2024pancanceranalysisof pages 5-7).

  • Expression: FBXW10 is reported as higher in several cancers (e.g., LUAD, LUSC, LIHC, PRAD, STAD) and reduced in KICH, KIRC, THCA versus normal tissues (huang2024pancanceranalysisof pages 5-7).
  • Prognosis statements in the excerpt: FBXW10 is described as a “dangerous factor in KIRC” and high FBXW10 expression associated with worse prognosis in KIRP, THCA, THYM (huang2024pancanceranalysisof pages 7-10).
  • Stemness metrics: FBXW10 expression was negatively related with DNAss in OV and negatively related with RNAss in THYM (huang2024pancanceranalysisof pages 7-10).

Limitations: The accessible text excerpt does not provide hazard ratios, coefficients, or p-values; those may be contained in the figures or supplementary material (huang2024pancanceranalysisof pages 7-10, huang2024pancanceranalysisof pages 5-7).

5.2 Human genetics + protein structure inference (2023)

Majdalani et al. (2023) exemplifies a current trend in functional annotation that combines human genetics with AlphaFold-based structural reasoning to prioritize candidate variants in less-characterized proteins, here mapping p.Ile440del to a WD-propeller structural element with high confidence (majdalani2023novelsusceptibilitygenes pages 5-7).

6) Current applications and real-world implementations

6.1 Biomarker-style applications in oncology and human genetics

Based on the evidence available in this run, current “applications” of FBXW10 are primarily:
- Candidate-gene prioritization in hereditary cancer studies using WES plus segregation and structural prediction (e.g., FNMTC candidate p.Ile440del) (majdalani2023novelsusceptibilitygenes pages 5-7, majdalani2023novelsusceptibilitygenes pages 4-5).
- Pan-cancer transcriptomic association analyses to identify cancer types where FBXW10 expression correlates with stage/prognosis features, potentially motivating future validation as a biomarker or mechanistic node (huang2024pancanceranalysisof pages 7-10, huang2024pancanceranalysisof pages 5-7).

6.2 Mechanistic inference for nuclear architecture/heterochromatin biology

Chaturvedi & Parnaik (2010) provide a conceptual application in cell biology: using lamin mutant phenotypes and proteasome modulation to infer that FBXW10 is part of a pathway connecting nuclear lamina disruption to proteasome-dependent loss of heterochromatin regulators (HP1α/β) (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7, chaturvedi2010laminarod pages 2-4). While not a “clinical implementation,” it is a real-world experimental implementation informing laminopathy-related hypotheses.

7) Expert opinions and authoritative analysis (from retrieved sources)

A key expert/authoritative assessment comes from the Immunological Reviews article, which notes reported FBXW10 mutations in T-PLL but explicitly states that “very little is known” about FBXW10 function and that substrate identification would be important for understanding disease consequences (sahasrabuddhe2015roleofthe pages 4-5). This aligns with the evidence landscape in this run: strong domain-based inference and one direct cellular study, but limited substrate-validated biochemistry.

8) Summary of quantitative/statistical evidence (from recent/available studies)

  • FBXW10 induction (qRT-PCR) in lamin-mutant contexts: values ranging from ~1.7 (controls) to 5.64 ± 0.49 (G232E), and 2.35 ± 0.44 (R386K) (chaturvedi2010laminarod pages 5-7).
  • Phenotype penetrance: FBXW10 overexpression depleted HP1α/β in ~80–90% of cells (chaturvedi2010laminarod pages 5-7).
  • Proteasome inhibitor rescue: MG132 increased rim localization for lamin mutants (e.g., 19.6% → 83.2% for G232E), with additional rescue by lactacystin (chaturvedi2010laminarod pages 5-7). HP1-positive-cell frequencies in lamin mutant-expressing cells increased substantially with MG132/lactacystin across multiple mutants (chaturvedi2010laminarod pages 2-4).
  • Human genetics: a specific 2023 candidate variant p.Ile440del with genomic coordinate (chr17:18661699) and conservation/structural interpretation using AlphaFold confidence (pLDDT > 90) (majdalani2023novelsusceptibilitygenes pages 5-7).

9) Evidence table

The following table consolidates the evidence types, assays, key quantitative results, and limitations.

Evidence type Key finding System/assay Quantitative/statistical detail Source (authors, year, journal) URL/DOI Notes/limitations
Domain/complex Human FBXW10 is identified as UniProt Q5XX13, a 1052-aa F-box/WD-repeat protein annotated as an “E3 CRL adaptor,” consistent with an SCF-type substrate receptor architecture. (poirson2017mappingtheinteractome pages 23-23) Proteome/interactome annotation table Length reported as 1052 aa; row annotated with F-box domain and WD repeats. (poirson2017mappingtheinteractome pages 23-23) Poirson et al., 2017, The FEBS Journal https://doi.org/10.1111/febs.14193 Classification/annotation evidence rather than direct biochemical demonstration of SCF assembly or substrate binding.
Substrate/function Lamin A rod-domain mutants induce FBXW10, and ectopic FBXW10 is sufficient to deplete HP1α and HP1β, but not HP1γ, supporting a role in selective ubiquitin-proteasome-mediated turnover of HP1 isoforms. (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7) HeLa cell expression studies; immunofluorescence; western blot; qRT-PCR FBXW10 qRT-PCR: GFP 1.71 ± 0.43, WT lamin A 1.66 ± 0.70, G232E 5.64 ± 0.49, R386K 2.35 ± 0.44; ectopic FBXW10 depleted HP1α/β in 80–90% of cells. (chaturvedi2010laminarod pages 5-7) Chaturvedi & Parnaik, 2010, PLoS ONE https://doi.org/10.1371/journal.pone.0010620 Evidence is from overexpression/mutant-lamin context; direct ubiquitination of HP1 by purified SCF-FBXW10 was not shown.
Substrate/rescue HP1α/β loss in lamin-mutant cells is proteasome-dependent, and proteasome inhibition restores HP1 and partially rescues lamin/emerin nuclear-rim localization, linking FBXW10-associated phenotype to proteasomal degradation. (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7, chaturvedi2010laminarod pages 2-4) HeLa cells treated with MG132 or lactacystin; immunofluorescence; western blot MG132 restored G232E rim localization from 19.6% ± 6.09 to 83.2% ± 6.11 and R386K from 15.4% ± 5.11 to 61.0% ± 6.40; lactacystin restored G232E to 73.2% ± 9.07 and R386K to 39.8% ± 8.57; HP1-positive cells also increased markedly with inhibitors. (chaturvedi2010laminarod pages 5-7, chaturvedi2010laminarod pages 2-4) Chaturvedi & Parnaik, 2010, PLoS ONE https://doi.org/10.1371/journal.pone.0010620 Rescue implicates the proteasome but does not by itself prove FBXW10 is the only E3 responsible.
Disease/genetics FBXW10 has been reported mutated in T-cell prolymphocytic leukemia (T-PLL), supporting possible disease relevance of loss/alteration of function. (sahasrabuddhe2015roleofthe pages 4-5) Literature review of hematologic malignancy genetics Reported variants include missense, nonsense, and frameshift changes such as R318N, R416*, and K966fs. (sahasrabuddhe2015roleofthe pages 4-5) Sahasrabuddhe & Elenitoba-Johnson, 2015, Immunological Reviews https://doi.org/10.1111/imr.12236 Review explicitly states that very little is known about FBXW10 biology and substrates; mutation significance remains uncertain.
Disease/variant interpretation In familial non-medullary thyroid cancer (FNMTC), FBXW10 was nominated as a candidate susceptibility gene carrying a heterozygous in-frame deletion p.Ile440del. (majdalani2023novelsusceptibilitygenes pages 5-7, majdalani2023novelsusceptibilitygenes pages 4-5) Whole-exome sequencing and pedigree segregation analysis Variant: c.1317_1319delCAT; p.Ile440del; chr17:18661699; segregated in heterozygous state in multiple family members with incomplete penetrance. (majdalani2023novelsusceptibilitygenes pages 5-7, majdalani2023novelsusceptibilitygenes pages 4-5) Majdalani et al., 2023, International Journal of Molecular Sciences https://doi.org/10.3390/ijms24098233 Candidate-gene evidence only; authors prioritized ARHGEF28 over FBXW10 as the strongest causal candidate.
Domain/structure The p.Ile440del candidate variant lies in the WD-repeat propeller region, where structural modeling predicts disruption of a beta-hairpin within a propeller blade. (majdalani2023novelsusceptibilitygenes pages 5-7) Conservation analysis and AlphaFold-based structural interpretation Ile440 conserved down to placental mammals; AlphaFold model around site reported with pLDDT > 90; ACMG evidence listed as PM2, PM4. (majdalani2023novelsusceptibilitygenes pages 5-7) Majdalani et al., 2023, International Journal of Molecular Sciences https://doi.org/10.3390/ijms24098233 Inference is structural/computational, not functional validation in cells or animals.
Expression/cancer association FBXW10 shows differential expression across cancers in pan-cancer analysis, with higher expression in several tumor types and lower expression in some kidney cancers and thyroid cancer. (huang2024pancanceranalysisof pages 5-7) TCGA-based pan-cancer expression analysis Higher in LUAD, LUSC, LIHC, PRAD, STAD; reduced in KICH, KIRC, THCA versus normal tissues. (huang2024pancanceranalysisof pages 5-7) Huang et al., 2024, Frontiers in Immunology https://doi.org/10.3389/fimmu.2022.1084339 Expression correlations do not establish mechanism, substrate specificity, or causal function in these cancers.

Table: This table summarizes the main published evidence supporting functional annotation of human FBXW10/Q5XX13, including domain architecture, experimentally supported substrate-linked effects, disease-associated variants, and cancer-expression findings. It is useful for distinguishing direct evidence from inference and highlighting the major limitations of the current literature.

10) Practical functional annotation (evidence-weighted)

Most defensible annotation (supported by evidence): FBXW10 is an F-box/WD-repeat cullin-RING E3 ligase adaptor/substrate receptor (consistent with SCF-type E3 complexes) and can promote proteasome-dependent depletion of HP1α/HP1β in a lamin-mutant nuclear stress context (poirson2017mappingtheinteractome pages 23-23, chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7).

Likely cellular role (inference plus context): Through protein–protein interactions mediated by its WD-repeat propeller, FBXW10 likely contributes to selective ubiquitination pathways affecting nuclear/heterochromatin proteins, but direct substrate validation beyond the HP1-linked cellular evidence remains limited in the retrieved corpus (chaturvedi2010laminarod pages 1-2, sahasrabuddhe2015roleofthe pages 4-5).

Disease relevance (current status): FBXW10 has (i) reported mutations in T-PLL (reviewed) (sahasrabuddhe2015roleofthe pages 4-5), (ii) a 2023 candidate hereditary thyroid cancer variant with structural rationale but not definitive causality (majdalani2023novelsusceptibilitygenes pages 5-7, majdalani2023novelsusceptibilitygenes pages 9-10), and (iii) pan-cancer expression/prognostic associations without mechanistic resolution in the accessible excerpt (huang2024pancanceranalysisof pages 7-10, huang2024pancanceranalysisof pages 5-7).

11) External authoritative database URLs (for reference; not used as primary evidence here)

These database pages can be consulted for curated annotations, isoforms, and cross-references:
- UniProt Q5XX13 (FBXW10): https://www.uniprot.org/uniprotkb/Q5XX13
- InterPro (domain signatures; e.g., F-box-like, WD40 repeats): https://www.ebi.ac.uk/interpro/

12) Key limitations and evidence gaps

  • The strongest mechanistic evidence in the retrieved corpus is from 2010, and it is largely cellular/phenotypic; direct biochemical demonstration of SCF-FBXW10 ubiquitination of specific substrates (including HP1 isoforms) was not available in the retrieved texts (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7).
  • Recent (2023–2024) evidence accessible here is primarily human genetics/structure inference and TCGA-scale expression/prognosis association, which are valuable for hypothesis generation but do not substitute for substrate validation and pathway dissection (majdalani2023novelsusceptibilitygenes pages 5-7, huang2024pancanceranalysisof pages 7-10).

References (retrieved and cited)

  • Chaturvedi P, Parnaik VK. 2010-05. PLoS ONE. “Lamin A Rod Domain Mutants Target Heterochromatin Protein 1α and β for Proteasomal Degradation by Activation of F-Box Protein, FBXW10.” https://doi.org/10.1371/journal.pone.0010620 (chaturvedi2010laminarod pages 1-2, chaturvedi2010laminarod pages 5-7, chaturvedi2010laminarod pages 2-4).
  • Poirson J, et al. 2017-10. The FEBS Journal. “Mapping the interactome of HPV E6 and E7 oncoproteins with the ubiquitin-proteasome system.” https://doi.org/10.1111/febs.14193 (poirson2017mappingtheinteractome pages 23-23).
  • Sahasrabuddhe AA, Elenitoba-Johnson KSJ. 2015-01. Immunological Reviews. “Role of the ubiquitin proteasome system in hematologic malignancies.” https://doi.org/10.1111/imr.12236 (sahasrabuddhe2015roleofthe pages 4-5).
  • Majdalani P, et al. 2023-05. International Journal of Molecular Sciences. “Novel Susceptibility Genes Drive Familial Non-Medullary Thyroid Cancer in a Large Consanguineous Kindred.” https://doi.org/10.3390/ijms24098233 (majdalani2023novelsusceptibilitygenes pages 5-7, majdalani2023novelsusceptibilitygenes pages 4-5, majdalani2023novelsusceptibilitygenes pages 9-10).
  • Huang T, et al. 2024-12. Frontiers in Immunology. “Pan-cancer analysis of FBXW family with potential implications in prognosis and immune infiltration.” https://doi.org/10.3389/fimmu.2022.1084339 (huang2024pancanceranalysisof pages 7-10, huang2024pancanceranalysisof pages 5-7).

References

  1. (poirson2017mappingtheinteractome pages 23-23): Juline Poirson, Elise Biquand, Marie‐Laure Straub, Patricia Cassonnet, Yves Nominé, Louis Jones, Sylvie van der Werf, Gilles Travé, Katia Zanier, Yves Jacob, Caroline Demeret, and Murielle Masson. Mapping the interactome of hpv e6 and e7 oncoproteins with the ubiquitin‐proteasome system. The FEBS Journal, 284:3171-3201, Oct 2017. URL: https://doi.org/10.1111/febs.14193, doi:10.1111/febs.14193. This article has 74 citations.

  2. (sahasrabuddhe2015roleofthe pages 4-5): Anagh A. Sahasrabuddhe and Kojo S. J. Elenitoba‐Johnson. Role of the ubiquitin proteasome system in hematologic malignancies. Immunological Reviews, 263:224-239, Jan 2015. URL: https://doi.org/10.1111/imr.12236, doi:10.1111/imr.12236. This article has 45 citations and is from a domain leading peer-reviewed journal.

  3. (majdalani2023novelsusceptibilitygenes pages 5-7): Pierre Majdalani, Uri Yoel, Tayseer Nasasra, Merav Fraenkel, Alon Haim, Neta Loewenthal, Raz Zarivach, Eli Hershkovitz, and Ruti Parvari. Novel susceptibility genes drive familial non-medullary thyroid cancer in a large consanguineous kindred. International Journal of Molecular Sciences, 24:8233, May 2023. URL: https://doi.org/10.3390/ijms24098233, doi:10.3390/ijms24098233. This article has 4 citations.

  4. (chaturvedi2010laminarod pages 1-2): Pankaj Chaturvedi and Veena K. Parnaik. Lamin a rod domain mutants target heterochromatin protein 1α and β for proteasomal degradation by activation of f-box protein, fbxw10. PLoS ONE, 5:e10620, May 2010. URL: https://doi.org/10.1371/journal.pone.0010620, doi:10.1371/journal.pone.0010620. This article has 59 citations and is from a peer-reviewed journal.

  5. (chaturvedi2010laminarod pages 5-7): Pankaj Chaturvedi and Veena K. Parnaik. Lamin a rod domain mutants target heterochromatin protein 1α and β for proteasomal degradation by activation of f-box protein, fbxw10. PLoS ONE, 5:e10620, May 2010. URL: https://doi.org/10.1371/journal.pone.0010620, doi:10.1371/journal.pone.0010620. This article has 59 citations and is from a peer-reviewed journal.

  6. (chaturvedi2010laminarod pages 2-4): Pankaj Chaturvedi and Veena K. Parnaik. Lamin a rod domain mutants target heterochromatin protein 1α and β for proteasomal degradation by activation of f-box protein, fbxw10. PLoS ONE, 5:e10620, May 2010. URL: https://doi.org/10.1371/journal.pone.0010620, doi:10.1371/journal.pone.0010620. This article has 59 citations and is from a peer-reviewed journal.

  7. (chaturvedi2010laminarod media 9af6f79a): Pankaj Chaturvedi and Veena K. Parnaik. Lamin a rod domain mutants target heterochromatin protein 1α and β for proteasomal degradation by activation of f-box protein, fbxw10. PLoS ONE, 5:e10620, May 2010. URL: https://doi.org/10.1371/journal.pone.0010620, doi:10.1371/journal.pone.0010620. This article has 59 citations and is from a peer-reviewed journal.

  8. (chaturvedi2010laminarod media 7bc1e356): Pankaj Chaturvedi and Veena K. Parnaik. Lamin a rod domain mutants target heterochromatin protein 1α and β for proteasomal degradation by activation of f-box protein, fbxw10. PLoS ONE, 5:e10620, May 2010. URL: https://doi.org/10.1371/journal.pone.0010620, doi:10.1371/journal.pone.0010620. This article has 59 citations and is from a peer-reviewed journal.

  9. (chaturvedi2010laminarod media 2d73f981): Pankaj Chaturvedi and Veena K. Parnaik. Lamin a rod domain mutants target heterochromatin protein 1α and β for proteasomal degradation by activation of f-box protein, fbxw10. PLoS ONE, 5:e10620, May 2010. URL: https://doi.org/10.1371/journal.pone.0010620, doi:10.1371/journal.pone.0010620. This article has 59 citations and is from a peer-reviewed journal.

  10. (majdalani2023novelsusceptibilitygenes pages 4-5): Pierre Majdalani, Uri Yoel, Tayseer Nasasra, Merav Fraenkel, Alon Haim, Neta Loewenthal, Raz Zarivach, Eli Hershkovitz, and Ruti Parvari. Novel susceptibility genes drive familial non-medullary thyroid cancer in a large consanguineous kindred. International Journal of Molecular Sciences, 24:8233, May 2023. URL: https://doi.org/10.3390/ijms24098233, doi:10.3390/ijms24098233. This article has 4 citations.

  11. (majdalani2023novelsusceptibilitygenes pages 9-10): Pierre Majdalani, Uri Yoel, Tayseer Nasasra, Merav Fraenkel, Alon Haim, Neta Loewenthal, Raz Zarivach, Eli Hershkovitz, and Ruti Parvari. Novel susceptibility genes drive familial non-medullary thyroid cancer in a large consanguineous kindred. International Journal of Molecular Sciences, 24:8233, May 2023. URL: https://doi.org/10.3390/ijms24098233, doi:10.3390/ijms24098233. This article has 4 citations.

  12. (huang2024pancanceranalysisof pages 5-7): Tingting Huang, XIaoxiao OuYang, Jiwei Li, Bingbing Shi, Zhengda Shan, Zhiyuan Shi, and Zhangru Yang. Pan-cancer analysis of fbxw family with potential implications in prognosis and immune infiltration. Frontiers in Immunology, Dec 2024. URL: https://doi.org/10.3389/fimmu.2022.1084339, doi:10.3389/fimmu.2022.1084339. This article has 6 citations and is from a peer-reviewed journal.

  13. (huang2024pancanceranalysisof pages 7-10): Tingting Huang, XIaoxiao OuYang, Jiwei Li, Bingbing Shi, Zhengda Shan, Zhiyuan Shi, and Zhangru Yang. Pan-cancer analysis of fbxw family with potential implications in prognosis and immune infiltration. Frontiers in Immunology, Dec 2024. URL: https://doi.org/10.3389/fimmu.2022.1084339, doi:10.3389/fimmu.2022.1084339. This article has 6 citations and is from a peer-reviewed journal.

Artifacts

Citations

  1. poirson2017mappingtheinteractome pages 23-23
  2. sahasrabuddhe2015roleofthe pages 4-5
  3. majdalani2023novelsusceptibilitygenes pages 5-7
  4. chaturvedi2010laminarod pages 1-2
  5. chaturvedi2010laminarod pages 5-7
  6. chaturvedi2010laminarod pages 2-4
  7. majdalani2023novelsusceptibilitygenes pages 4-5
  8. majdalani2023novelsusceptibilitygenes pages 9-10
  9. huang2024pancanceranalysisof pages 5-7
  10. huang2024pancanceranalysisof pages 7-10
  11. https://doi.org/10.1111/febs.14193
  12. https://doi.org/10.1111/imr.12236
  13. https://doi.org/10.3390/ijms24098233
  14. https://doi.org/10.1371/journal.pone.0010620
  15. https://doi.org/10.3389/fimmu.2022.1084339
  16. https://www.uniprot.org/uniprotkb/Q5XX13
  17. https://www.ebi.ac.uk/interpro/
  18. https://doi.org/10.1111/febs.14193,
  19. https://doi.org/10.1111/imr.12236,
  20. https://doi.org/10.3390/ijms24098233,
  21. https://doi.org/10.1371/journal.pone.0010620,
  22. https://doi.org/10.3389/fimmu.2022.1084339,

📚 Additional Documentation

Pn Notes

(FBXW10-pn-notes.md)

FBXW10 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q5XX13
  • 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: FBXW10 (ubiquitin ligase-specificity factor) is a large (1052 aa) member of the F-box/WD40 (FBXW) family, containing an F-box motif and WD40 repeats together with coiled-coil regions. F-box proteins act as the interchangeable substrate-recognition subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3 ubiquitin ligase complexes, in which the F-box motif docks onto SKP1/CUL1 and the WD40 propeller recruits substrates for ubiquitination by the RBX1-bound E2, committing them to proteasomal degradation; the F-box protein itself is the substrate adaptor and is not catalytic. Curated interactome resources classify FBXW10 as an E3 cullin-RING-ligase (CRL) adaptor with F-box plus WD40 repeats. FBXW10 is testis-enriched in expression. Functional data are limited: in a study of laminopathy-associated lamin A rod-domain mutants, FBXW10 transcript was induced several-fold in cells expressing these mutants, and ectopic FBXW10 expression depleted heterochromatin protein 1 isoforms HP1-alpha (CBX5) and HP1-beta (CBX1) but not HP1-gamma in a proteasome-dependent manner, implicating FBXW10 in turnover of these chromatin proteins under conditions of nuclear stress. FBXW10 has been reported mutated (missense, nonsense and frameshift) in T-cell prolymphocytic leukemia and was nominated as a candidate susceptibility gene (an in-frame WD-propeller deletion, p.Ile440del) in familial non-medullary thyroid cancer, and it shows tumor-type-specific expression changes in pan-cancer analyses. Its direct, physiological ubiquitination substrates and its assembly into a defined SCF complex have not been biochemically demonstrated; the HP1 isoforms are best regarded as candidate/affected substrates rather than validated direct targets.
  • Existing/core annotation action counts: ACCEPT: 2; KEEP_AS_NON_CORE: 10

PN Consistency Summary

  • Consistency: Fully consistent. Deep research (falcon), review YAML, PN annotation and PN-node mapping all describe FBXW10 as a poorly characterized SCF F-box/WD40 substrate receptor (non-catalytic adaptor). The review's proposed_new_terms explicitly proposes GO:1990756, exactly matching the PN projection. No contradictions.
  • PN story / NEW pressure: PN asserts the substrate-adaptor MF (GO:1990756) which is NOT in FBXW10's GOA (no MF adaptor/scaffold term present — confirmed in goa.tsv). GO:1990756 is real (OLS verified: "brings together a ubiquitin-like ligase and its substrate... F-box/BTB/POZ proteins") and is the canonical F-box receptor MF. Verdict: ADD GO:1990756 — already independently proposed in the review.
  • Evidence alignment: Aligned. PN ref 15340381 = PMID:20498703 (lamin A mutants target HP1 via FBXW10), which is the review's sole experimental PMID and is marked relevance HIGH / correctness VERIFIED. Falcon adds interactome (Poirson 2017) and disease genetics; no divergence.
  • Verdict: Consistent; PN GO:1990756 add is defensible and already mirrored in the review. No changes needed.

Full Consistency Review

  • UniProt: Q5XX13 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE
  • PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|WD40 ; PN-node mapping: group=mapped, ok_for_propagation_to_go, GO:1990756 (substrate-adaptor MF); subtype/type=no_mapping; projected GO:1990756 goa_status=new_to_goa.
  • Consistency: Fully consistent. Deep research (falcon), review YAML, PN annotation and PN-node mapping all describe FBXW10 as a poorly characterized SCF F-box/WD40 substrate receptor (non-catalytic adaptor). The review's proposed_new_terms explicitly proposes GO:1990756, exactly matching the PN projection. No contradictions.
  • PN story / NEW pressure: PN asserts the substrate-adaptor MF (GO:1990756) which is NOT in FBXW10's GOA (no MF adaptor/scaffold term present — confirmed in goa.tsv). GO:1990756 is real (OLS verified: "brings together a ubiquitin-like ligase and its substrate... F-box/BTB/POZ proteins") and is the canonical F-box receptor MF. Verdict: ADD GO:1990756 — already independently proposed in the review.
  • Mapping strategy: Correct. FBXW10 is a Cul1/SCF F-box WD40 receptor; catalysis is RBX1's. GO:1990756 (receptor/adaptor) is the right category, not scaffold (GO:0160072) and not catalytic (GO:0061630). Scope ok_for_propagation. The class-level GO:0061630 is correctly held as too_broad context_only.
  • Evidence alignment: Aligned. PN ref 15340381 = PMID:20498703 (lamin A mutants target HP1 via FBXW10), which is the review's sole experimental PMID and is marked relevance HIGH / correctness VERIFIED. Falcon adds interactome (Poirson 2017) and disease genetics; no divergence.
  • Verdict: Consistent; PN GO:1990756 add is defensible and already mirrored in the review. No changes needed.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/FBXW10/FBXW10-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | WD40

  • UniProt: Q5XX13
  • In branches: UPS
  • Signature domains: IPR036047
  • Auxiliary domains: IPR001680
  • PN references (titles):
    • 15340381 / rev
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|WD40
      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.

📄 View Raw YAML

 
id: Q5XX13
gene_symbol: FBXW10
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXW10 (ubiquitin ligase-specificity factor) is a large (1052 aa) member of the
  F-box/WD40 (FBXW) family, containing an F-box motif and WD40 repeats together
  with coiled-coil regions. F-box proteins act as the interchangeable
  substrate-recognition subunits of SCF (SKP1-CUL1-F-box)-type cullin-RING E3
  ubiquitin ligase complexes, in which the F-box motif docks onto SKP1/CUL1 and
  the WD40 propeller recruits substrates for ubiquitination by the RBX1-bound E2,
  committing them to proteasomal degradation; the F-box protein itself is the
  substrate adaptor and is not catalytic. Curated interactome resources classify
  FBXW10 as an E3 cullin-RING-ligase (CRL) adaptor with F-box plus WD40 repeats.
  FBXW10 is testis-enriched in expression. Functional data are limited: in a study
  of laminopathy-associated lamin A rod-domain mutants, FBXW10 transcript was
  induced several-fold in cells expressing these mutants, and ectopic FBXW10
  expression depleted heterochromatin protein 1 isoforms HP1-alpha (CBX5) and
  HP1-beta (CBX1) but not HP1-gamma in a proteasome-dependent manner, implicating
  FBXW10 in turnover of these chromatin proteins under conditions of nuclear
  stress. FBXW10 has been reported mutated (missense, nonsense and frameshift) in
  T-cell prolymphocytic leukemia and was nominated as a candidate susceptibility
  gene (an in-frame WD-propeller deletion, p.Ile440del) in familial non-medullary
  thyroid cancer, and it shows tumor-type-specific expression changes in
  pan-cancer analyses. Its direct, physiological ubiquitination substrates and its
  assembly into a defined SCF complex have not been biochemically demonstrated;
  the HP1 isoforms are best regarded as candidate/affected substrates rather than
  validated direct targets.
existing_annotations:
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:20498703
  qualifier: part_of
  review:
    summary: ComplexPortal/family-based assignment of SCF complex membership (CPX-7786, SCF complex FBXW10 variant), consistent with the F-box motif and with curated interactome classification of FBXW10 as an E3 CRL adaptor; the cited study links FBXW10 to SCF-mediated proteasomal degradation of HP1 isoforms.
    action: ACCEPT
    reason: Core assembly annotation for an F-box protein; supported by the F-box domain, the UniProt function statement describing FBXW10 as a probable SCF substrate-recognition component, and interactome-level annotation as an E3 CRL adaptor. Direct biochemical reconstitution of an SCF(FBXW10) complex has not been shown.
    additional_reference_ids:
    - file:human/FBXW10/FBXW10-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/FBXW10/FBXW10-uniprot.txt
      supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
    - reference_id: file:human/FBXW10/FBXW10-deep-research-falcon.md
      supporting_text: FBXW10 is explicitly categorized as an **E3 CRL adaptor** with **F-box + WD repeats**
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: NAS
  original_reference_id: PMID:20498703
  qualifier: involved_in
  review:
    summary: Assignment of involvement in SCF-dependent proteasomal degradation; ectopic FBXW10 depletes HP1-alpha/beta via the proteasome in cells expressing lamin A mutants, and proteasome inhibitors (MG132/lactacystin) rescue HP1 levels.
    action: ACCEPT
    reason: Core biological process for an SCF substrate receptor; supported by the experimental observation that FBXW10 expression drives proteasome-dependent depletion of HP1 isoforms. Direct in vitro ubiquitination of HP1 by reconstituted SCF(FBXW10) was not demonstrated, so HP1-alpha/beta are best treated as candidate/affected substrates.
    additional_reference_ids:
    - file:human/FBXW10/FBXW10-deep-research-falcon.md
    supported_by:
    - reference_id: PMID:20498703
      supporting_text: ectopic expression of FBXW10 in HeLa cells led to depletion of HP1alpha and beta without alteration of HP1gamma levels
    - reference_id: file:human/FBXW10/FBXW10-deep-research-falcon.md
      supporting_text: ectopic FBXW10 is sufficient to deplete HP1α and HP1β, but not HP1γ, supporting a role in selective ubiquitin-proteasome-mediated turnover of HP1 isoforms
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (AcM-UBE2M transfers NEDD8 to CRL1) propagated to FBXW10 as an SCF subunit.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible for an SCF subunit but not FBXW10-specific, and the one functional study implicates a nuclear/heterochromatin context.
    supported_by:
    - reference_id: file:human/FBXW10/FBXW10-uniprot.txt
      supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (NEDD8:AcM-UBE2M binds CRL1) propagated to FBXW10.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
    supported_by:
    - reference_id: file:human/FBXW10/FBXW10-uniprot.txt
      supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (CAND1 binds cytosolic CRL ligases) propagated to FBXW10.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
    supported_by:
    - reference_id: file:human/FBXW10/FBXW10-uniprot.txt
      supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (COMMDs displace CAND1) propagated to FBXW10.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
    supported_by:
    - reference_id: file:human/FBXW10/FBXW10-uniprot.txt
      supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (COP9 signalosome deneddylates CRLs) propagated to FBXW10.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
    supported_by:
    - reference_id: file:human/FBXW10/FBXW10-uniprot.txt
      supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (MyrG-DCUN1D3 binds CRL1) propagated to FBXW10.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
    supported_by:
    - reference_id: file:human/FBXW10/FBXW10-uniprot.txt
      supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (transfer of Ub from E2 to substrate) propagated to FBXW10.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
    supported_by:
    - reference_id: file:human/FBXW10/FBXW10-uniprot.txt
      supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (release of E3 from polyubiquitinated substrate) propagated to FBXW10.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
    supported_by:
    - reference_id: file:human/FBXW10/FBXW10-uniprot.txt
      supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (polyubiquitination of substrate) propagated to FBXW10.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
    supported_by:
    - reference_id: file:human/FBXW10/FBXW10-uniprot.txt
      supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome pathway-level cytosol localization (interaction of E3 with substrate and E2-Ub complex) propagated to FBXW10.
    action: KEEP_AS_NON_CORE
    reason: Generic CRL pathway-derived localization; plausible but not FBXW10-specific.
    supported_by:
    - reference_id: file:human/FBXW10/FBXW10-uniprot.txt
      supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex
references:
- id: PMID:20498703
  title: Lamin A rod domain mutants target heterochromatin protein 1alpha and beta
    for proteasomal degradation by activation of F-box protein, FBXW10.
  findings:
  - statement: In HeLa cells, lamin A rod-domain mutants induced FBXW10 transcript several-fold and triggered proteasomal degradation of HP1-alpha (CBX5) and HP1-beta (CBX1) but not HP1-gamma; ectopic FBXW10 expression alone depleted HP1-alpha/beta, implicating FBXW10 (an F-box protein involved in E3 ubiquitin ligase activity) in this turnover.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; sole functional study of FBXW10. Supports SCF-dependent proteasomal degradation involvement and the CBX5/CBX1 substrate link, though direct in vitro ubiquitination by FBXW10 was not demonstrated.
- id: Reactome:R-HSA-8952618
  title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8952620
  title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8955241
  title: CAND1 binds cytosolic CRL E3 ubiquitin ligases
  findings: []
- id: Reactome:R-HSA-8955289
  title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956040
  title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956200
  title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-983140
  title: Transfer of Ub from E2 to substrate and release of E2
  findings: []
- id: Reactome:R-HSA-983147
  title: Release of E3 from polyubiquitinated substrate
  findings: []
- id: Reactome:R-HSA-983156
  title: Polyubiquitination of substrate
  findings: []
- id: Reactome:R-HSA-983157
  title: Interaction of E3 with substrate and E2-Ub complex
  findings: []
- id: file:human/FBXW10/FBXW10-deep-research-falcon.md
  title: Falcon deep research report for human FBXW10
  findings:
  - statement: Curated interactome/UPS resources classify FBXW10 (Q5XX13, 1052 aa) as an E3 cullin-RING-ligase adaptor with F-box plus WD40 repeats, consistent with an SCF-type substrate-receptor architecture rather than an enzyme.
    supporting_text: FBXW10 is explicitly categorized as an **E3 CRL adaptor** with **F-box + WD repeats**
  - statement: The strongest functional evidence is that lamin A rod-domain mutants induce FBXW10 and ectopic FBXW10 is sufficient to deplete HP1-alpha/HP1-beta but not HP1-gamma in a proteasome-dependent manner, though direct in vitro ubiquitination of HP1 by purified SCF(FBXW10) was not shown.
    supporting_text: ectopic FBXW10 is sufficient to deplete HP1α and HP1β, but not HP1γ, supporting a role in selective ubiquitin-proteasome-mediated turnover of HP1 isoforms
  - statement: FBXW10 has been reported mutated (missense, nonsense, frameshift) in T-cell prolymphocytic leukemia, and the function/substrates remain largely unknown.
    supporting_text: FBXW10 harbors **missense, nonsense, and frameshift mutations** in **T-cell prolymphocytic leukemia (T-PLL)**
  - statement: A candidate familial non-medullary thyroid cancer variant (p.Ile440del) maps to a beta-hairpin within a WD-propeller blade, implicating the WD40 substrate-binding region, though FBXW10 was ranked a second-priority candidate.
    supporting_text: Ile440 is evolutionarily conserved down to placental mammals and lies in a **β-hairpin of a WD-propeller blade**
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Falcon synthesis grounded chiefly in Chaturvedi & Parnaik 2010 (PLoS ONE, doi:10.1371/journal.pone.0010620; the sole functional study, already cited here as PMID:20498703) plus Poirson et al. 2017 (FEBS J, doi:10.1111/febs.14193; interactome classification as E3 CRL adaptor), Sahasrabuddhe & Elenitoba-Johnson 2015 (Immunol Rev, doi:10.1111/imr.12236; T-PLL mutations), and Majdalani et al. 2023 (IJMS, doi:10.3390/ijms24098233; FNMTC candidate variant p.Ile440del). Cross-checked against UniProt Q5XX13 FUNCTION/INDUCTION statements and ComplexPortal CPX-7786. The disease/genetics findings are hypothesis-generating and do not alter the existing annotation calls; the HP1 link is supported but not biochemically reconstituted.
core_functions:
- description: Probable substrate-recognition (substrate-adaptor) subunit of an SCF (SKP1-CUL1-F-box) cullin-RING E3 ubiquitin ligase complex that, when induced, promotes proteasome-dependent depletion of the heterochromatin proteins HP1-alpha (CBX5) and HP1-beta (CBX1) under conditions of nuclear/lamin stress. FBXW10 is non-catalytic (ubiquitin transfer is RBX1's), and direct reconstituted ubiquitination of HP1 has not been shown, so HP1 isoforms remain candidate/affected substrates.
  supported_by:
  - reference_id: file:human/FBXW10/FBXW10-uniprot.txt
    supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins
  - reference_id: PMID:20498703
    supporting_text: ectopic expression of FBXW10 in HeLa cells led to depletion of HP1alpha and beta without alteration of HP1gamma levels
  locations:
  - id: GO:0005829
    label: cytosol
  directly_involved_in:
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms:
- proposed_name: ubiquitin-like ligase-substrate adaptor activity
  proposed_definition: Bridging a substrate to a ubiquitin-like protein ligase, as performed by an SCF F-box substrate-recognition subunit that binds both SKP1/the ligase scaffold and the substrate to facilitate the substrate's ubiquitination. This corresponds to the existing GO term GO:1990756, which is not currently in FBXW10's annotation set.
  justification: FBXW10 is classified as an E3 CRL adaptor with an F-box and WD40 propeller and, when induced, promotes proteasome-dependent depletion of HP1-alpha/beta, consistent with a substrate-adaptor molecular function rather than catalysis (which is RBX1's). Adding GO:1990756 would give FBXW10 an informative molecular-function term, currently absent from its annotation set.
  proposed_parent:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  supported_by:
  - reference_id: file:human/FBXW10/FBXW10-uniprot.txt
    supporting_text: Probable substrate-recognition component of a SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins
  - reference_id: file:human/FBXW10/FBXW10-deep-research-falcon.md
    supporting_text: FBXW10 is explicitly categorized as an **E3 CRL adaptor** with **F-box + WD repeats**
suggested_questions:
- question: Does FBXW10 directly ubiquitinate HP1-alpha (CBX5) and HP1-beta (CBX1) within a reconstituted SCF complex, or is the observed depletion indirect?
- question: Given testis-enriched expression, what is FBXW10's physiological role and substrate repertoire in spermatogenesis, distinct from the lamin-stress-induced HP1 turnover?
- question: Are the T-PLL mutations and the familial thyroid-cancer WD-propeller variant (p.Ile440del) loss-of-function for substrate recognition, and what substrate do they affect?
suggested_experiments:
- description: Reconstitute SCF(FBXW10) with SKP1, CUL1, RBX1 and an E2 in vitro and test direct ubiquitination of CBX5/CBX1, with F-box-deletion FBXW10 as a negative control.
- description: Co-immunoprecipitation of endogenous FBXW10 with SKP1/CUL1 and with CBX5/CBX1 in testis-derived cells, plus FBXW10 knockdown to assess effects on endogenous HP1 isoform stability.
- description: Express the WD-propeller variant p.Ile440del and T-PLL truncating alleles and assay SCF assembly (SKP1/CUL1 binding) and HP1-alpha/beta turnover relative to wild-type FBXW10.