FEM1C

FEM1C is a substrate-recognition receptor of the CRL2 (Cullin2-RING) E3 ubiquitin ligase that targets proteins bearing C-terminal arginine degrons (Arg/C-degrons) for proteasomal degradation (PMID:33398170). Crystal structures of FEM1C bound to its degron, together with biochemical and mutagenesis studies, established that the receptor uses a semi-open binding pocket in which the extreme C-terminal arginine is the principal recognition determinant, and that the pocket extends to accept R/K-X-R and R/K-X-X-R C-terminal motifs (PMID:33398170, PMID:37339537). The conserved Asp126 residue is required for substrate engagement, as a de novo missense variant at this position impairs substrate binding in vitro and produces synaptic dysfunction in a C. elegans model, linking FEM1C activity to neuronal function (PMID:36336956). Loss of FEM1C by knockdown in colorectal cancer cells drives migration, invasion, proliferation, and an epithelial-to-mesenchymal transition phenotype with enhanced metastasis in vivo, identifying it as a suppressor of EMT-related pathways (PMID:34733943). The specific physiological substrates degraded through FEM1C in these neuronal and cancer contexts have not been identified in the available corpus.

1. 2003 Low

   Before any function was known, it was unclear how vertebrate FEM1C related to the broader FEM1 family; sequence analysis showed it uniquely terminates in a C-terminal arginine, a feature later central to its mechanism.

   Evidence comparative genomics, cDNA cloning, chromosomal mapping in human/mouse/zebrafish

   PMID:14527725

   Open questions at the time

   • no functional mechanism established
   • no link to ubiquitin ligase activity at this stage
   • expression profiling does not define cellular role
2. 2009 Low

   The subcellular compartment in which FEM1C acts was undefined; localization studies placed the protein in the cytoplasm, consistent across species.

   Evidence immunofluorescence in zebra finch fibroblasts

   PMID:19139913

   Open questions at the time

   • single localization experiment
   • no functional consequence tied to localization
   • human FEM1C localization not directly tested
3. 2021 High

   The molecular function of FEM1C was unknown until structures showed it is a CRL2 substrate receptor that captures C-terminal arginine degrons through a semi-open pocket, defining how it selects substrates for degradation.

   Evidence X-ray crystallography of FEM1C–Arg/C-degron complex with biochemical and mutagenesis validation

   PMID:33398170

   Open questions at the time

   • physiological substrates not identified
   • in vivo CRL2 assembly with FEM1C not characterized in this work
   • scope of degron motifs beyond Arg terminus not fully mapped
4. 2023 Medium

   It was unclear whether the FEM1C pocket tolerated extended degron motifs or could be chemically targeted; biophysical work mapped recognition of R/K-X-R and R/K-X-X-R C-terminal motifs and showed the pocket is druggable.

   Evidence fluorescence polarization competition and ITC with synthetic probe ES148 (Ki = 1.6 µM)

   PMID:37339537

   Open questions at the time

   • single-lab biophysical characterization
   • no cellular degradation demonstrated with the probe
   • endogenous substrates bearing these motifs not enumerated
5. 2023 Medium

   Whether a disease-associated variant disrupts FEM1C function was unknown; an Asp126 missense variant impaired substrate binding and caused synaptic, not muscle, dysfunction, placing FEM1C activity at the neuronal synapse.

   Evidence in vitro Asp126Ala functional assay and C. elegans aldicarb/levamisole pharmacological epistasis

   PMID:36336956

   Open questions at the time

   • synaptic substrate of FEM1C not identified
   • single animal model
   • no formal Mendelian disease gene assignment established in this entry
6. 2021 Medium

   The cellular role of FEM1C in cancer was undefined; knockdown promoted EMT, migration, invasion, and metastasis, identifying it as a suppressor of EMT-related pathways.

   Evidence siRNA knockdown with proliferation, migration/invasion assays, in vivo metastasis models, and GSEA in colorectal cancer cells

   PMID:34733943

   Open questions at the time

   • no degradation substrate linking FEM1C to EMT identified
   • single lab
   • mechanistic connection between ligase activity and EMT not established

• The endogenous physiological substrates degraded by FEM1C-CRL2 in neuronal and cancer contexts remain unidentified, leaving the link between its degron-recognition activity and its synaptic and EMT-suppressive phenotypes mechanistically incomplete.
• no validated cellular substrate reported
• substrate connecting FEM1C to EMT suppression unknown
• substrate underlying synaptic dysfunction unknown