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.
AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
CAND1 binds cytosolic CRL E3 ubiquitin ligases
COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
Transfer of Ub from E2 to substrate and release of E2
Release of E3 from polyubiquitinated substrate
Polyubiquitination of substrate
Interaction of E3 with substrate and E2-Ub complex
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**"