Affinage

FEM1C

Protein fem-1 homolog C · UniProt Q96JP0

Round 2 corrected
Length
617 aa
Mass
68.7 kDa
Annotated
2026-04-28
38 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FEM1C is a substrate-recognition subunit of the CRL2 (Cullin 2–RING) E3 ubiquitin ligase complex that selectively targets proteins bearing C-terminal arginine degrons (Arg/C-degrons) for proteasomal degradation. Crystal structures show FEM1C uses a semi-open binding pocket to capture the extreme C-terminal arginine residue, and global protein stability profiling demonstrates that FEM1C and FEM1A share a substrate specificity distinct from FEM1B within the Arg/C-degron pathway (PMID:33398170, PMID:33398168, PMID:29779948). Endogenous substrates include the histone mRNA regulator SLBP and truncated selenoproteins, linking FEM1C to protein quality control and histone mRNA metabolism (PMID:28118078, PMID:29775578). A de novo missense variant (p.Asp126His) that disrupts substrate binding causes a neurodevelopmental disorder with absent speech, pyramidal signs, and limb ataxia, and the equivalent mutation in C. elegans FEM-1 produces synaptic dysfunction (PMID:36336956).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2003 Medium

    Identification and molecular cloning of FEM1C established it as a conserved vertebrate member of the FEM1 family, notable for its unique C-terminal arginine residue, setting the stage for later functional studies.

    Evidence cDNA cloning, genomic mapping, and expression profiling in human, mouse, and zebrafish

    PMID:14527725

    Open questions at the time
    • No biochemical function assigned at this stage
    • Expression data limited to RT-PCR without protein-level confirmation
  2. 2004 Medium

    A gene-trap knockout mouse revealed that Fem1c is dispensable for sexual development, fertility, and neuronal cell death in isolation, suggesting functional redundancy among FEM1 family members.

    Evidence Fem1c gene-trap homozygous mice with histological and phenotypic analysis

    PMID:15082774

    Open questions at the time
    • Potential compensation by FEM1A or FEM1B not tested
    • No proteomic or ubiquitin-substrate analysis performed
  3. 2017 Medium

    Identification of SLBP as a conserved substrate of FEM1C linked the E3 ligase to histone mRNA metabolism, revealing a degron distinct from cyclin F–mediated degradation.

    Evidence Co-immunoprecipitation, degradation assays, and epistasis analysis in C. elegans and Drosophila

    PMID:28118078

    Open questions at the time
    • Single-lab study; independent replication not reported
    • The precise degron motif in SLBP recognized by FEM1C was not structurally defined
  4. 2018 High

    Genome-wide CRISPR screens and synthetic peptidome profiling established that FEM1C functions as a CRL2 substrate adaptor within the C-end degron (DesCEND) pathway, recognizing C-terminal arginine-ending sequences on aberrant proteins including truncated selenoproteins.

    Evidence CRISPR screening, global protein stability profiling, and biochemical reconstitution with defined substrates

    PMID:29775578 PMID:29779948

    Open questions at the time
    • Full repertoire of endogenous substrates remains undefined
    • Relative contributions of FEM1A versus FEM1C to shared Arg/C-degron substrates not resolved
  5. 2021 High

    Crystal structures of FEM1C bound to Arg/C-degron peptides defined the semi-open binding pocket architecture and showed that FEM1A/C recognize a distinct Arg/C-degron subset from FEM1B, providing a structural basis for substrate selectivity within the family.

    Evidence X-ray crystallography, mutagenesis, and global protein stability profiling

    PMID:33398168 PMID:33398170

    Open questions at the time
    • No full-length substrate-bound structure available
    • Structural basis for FEM1C versus FEM1A discrimination among overlapping substrates not determined
  6. 2023 Medium

    A human de novo variant (Asp126His) at the substrate-binding pocket was shown to cause neurodevelopmental disease, and the equivalent C. elegans mutation produced synaptic dysfunction, establishing a direct genotype–phenotype link for FEM1C in the nervous system.

    Evidence Exome sequencing, in vitro binding assay (Asp126Ala), C. elegans locomotion and pharmacological (aldicarb/levamisole) assays

    PMID:36336956

    Open questions at the time
    • Single affected individual; additional cases needed to confirm genotype–phenotype spectrum
    • The synaptic substrate(s) of FEM1C relevant to neurodevelopment are unidentified
  7. 2023 Medium

    Development of a fluorescent chemical probe for the FEM1C C-degron pocket validated the R/K-X-R and R/K-X-X-R recognition motifs biochemically and enabled small-molecule ligand discovery for potential PROTAC applications.

    Evidence Fluorescence polarization and isothermal titration calorimetry with competitive binding assays

    PMID:37339537

    Open questions at the time
    • No cellular target degradation via PROTAC demonstrated
    • Selectivity over FEM1A pocket not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full endogenous substrate repertoire of FEM1C, the structural basis for its discrimination from FEM1A, and the identity of neuronal substrates underlying neurodevelopmental disease remain to be determined.
  • Comprehensive endogenous substrate identification by proteomics not yet performed
  • No high-resolution structure of FEM1C in complex with a full-length physiological substrate
  • Mechanism linking FEM1C loss-of-function to synaptic defects is molecularly undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0060090 molecular adaptor activity 2
Pathway
R-HSA-392499 Metabolism of proteins 5
Partners
CUL2ELOBELOCSLBP
Complex memberships
CRL2 (Cullin 2-RING E3 ubiquitin ligase)

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 Crystal structures of FEM1C in complex with Arg/C-degron peptides revealed that FEM1C uses a semi-open binding pocket to capture the C-terminal arginine residue, with the extreme C-terminal arginine being the major structural determinant for recognition. Biochemical and mutagenesis studies confirmed this mechanism of substrate recognition. X-ray crystallography, biochemical binding assays, mutagenesis Nature chemical biology High 33398170
2021 FEM1A/C and FEM1B selectively target distinct classes of Arg/C-degrons: FEM1A and FEM1C recognize one subset of arginine-terminated C-degrons while FEM1B targets a distinct subset, as demonstrated by structural studies and global protein stability (GPS) analyses. X-ray crystallography, binding assays, global protein stability (GPS) profiling Nature chemical biology High 33398168
2018 FEM1C was identified as one of eight CRL2 substrate adaptors that recognize C-terminal degrons (C-degrons), specifically those ending in arginine, using CRISPR screening and global protein stability profiling of a synthetic human peptidome. CRISPR screening, global protein stability (GPS) profiling, synthetic peptidome Cell High 29779948
2018 CRL2 ubiquitin ligase complexes using interchangeable substrate receptors (including FEM1C) recognize unusual C termini of abnormal proteins (C-end degrons) via the DesCEND mechanism; C-terminal end position is essential for degron function, and substrates include truncated selenoproteins and the USP1 N-terminal fragment. Genetic and biochemical assays, protein degradation assays, mutagenesis Molecular cell High 29775578
2017 FEM1C (along with FEM1A and FEM1B) interacts with and mediates the ubiquitin-dependent degradation of Stem-Loop Binding Protein (SLBP), a conserved regulator of histone mRNA processing. FEM1 proteins interact with an N-terminal region of SLBP using a distinct degron from that used by cyclin F, and this regulation is evolutionarily conserved from C. elegans and Drosophila to mammals. Co-immunoprecipitation, protein degradation assays, epistasis in C. elegans and Drosophila Cell cycle Medium 28118078
2003 Human, mouse, and zebrafish FEM1C proteins are encoded by a conserved gene family member that uniquely terminates with a C-terminal arginine residue (distinguishing them from FEM1A and FEM1B), with >99% amino acid identity between human and mouse and conserved intron-exon structure and expression pattern. cDNA cloning, sequence analysis, genomic mapping, RT-PCR expression profiling Gene Medium 14527725
2004 Insertion of the beta-Geo gene trap into the first intron of mouse Fem1c disrupts normal Fem1c transcript processing in homozygous ROSA3 mice; Fem1c(R3/R3) mice show no adverse effects in sexual development, fertility, or neuronal cell death, suggesting Fem1c is not individually required for these processes in mice. Gene trap mouse model, RT-PCR, histological and phenotypic analysis Molecular and cellular biology Medium 15082774
2023 A de novo missense variant p.(Asp126His) in FEM1C causes a neurodevelopmental disorder with absent speech, pyramidal signs, and limb ataxia. The equivalent variant FEM1C(Asp126Ala) is functionally compromised in vitro for substrate binding. In C. elegans, the homologous FEM-1(Asp133His) variant causes impaired mobility due to synaptic abnormalities (sensitivity to aldicarb but not levamisole), placing FEM1C function at the synapse. Exome sequencing, in vitro binding assay, C. elegans locomotion assay, aldicarb/levamisole pharmacological assays Human molecular genetics Medium 36336956
2023 A fluorescent probe (ES148, Ki = 1.6 µM) targeting the C-degron binding pocket of FEM1C was developed and validated by fluorescence polarization and isothermal titration calorimetry, establishing that FEM1C recognizes proteins with an R/K-X-R or R/K-X-X-R motif at the C-terminus and enabling small-molecule ligand discovery for PROTAC applications. Fluorescence polarization assay, isothermal titration calorimetry, competitive binding assay Bioorganic & medicinal chemistry Medium 37339537
2021 FEM1C knockdown in colorectal cancer cells significantly promotes migration, invasion, and proliferation in vitro and enhances liver and lung metastasis in vivo; knockdown cells shift from epithelial to fibroblast-like morphology, and GSEA analysis indicates enrichment of epithelial-to-mesenchymal transition (EMT) signatures, implicating FEM1C as a suppressor of EMT. siRNA knockdown, CCK-8 proliferation assay, colony formation assay, transwell invasion assay, in vivo metastasis models, GSEA Annals of translational medicine Low 34733943

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2018 The Eukaryotic Proteome Is Shaped by E3 Ubiquitin Ligases Targeting C-Terminal Degrons. Cell 270 29779948
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2016 Two Distinct Types of E3 Ligases Work in Unison to Regulate Substrate Ubiquitylation. Cell 188 27565346
2018 C-Terminal End-Directed Protein Elimination by CRL2 Ubiquitin Ligases. Molecular cell 150 29775578
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
2001 Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 123 11347906
2020 Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. Molecular cell 88 32707033
2015 SELENOPROTEINS. CRL2 aids elimination of truncated selenoproteins produced by failed UGA/Sec decoding. Science (New York, N.Y.) 62 26138980
2019 ARIH2 Is a Vif-Dependent Regulator of CUL5-Mediated APOBEC3G Degradation in HIV Infection. Cell host & microbe 57 31253590
2017 Mapping the interactome of HPV E6 and E7 oncoproteins with the ubiquitin-proteasome system. The FEBS journal 56 28786561
2021 Molecular basis for arginine C-terminal degron recognition by Cul2FEM1 E3 ligase. Nature chemical biology 50 33398168
2022 NUDT21 limits CD19 levels through alternative mRNA polyadenylation in B cell acute lymphoblastic leukemia. Nature immunology 46 36138187
2021 Molecular basis for ubiquitin ligase CRL2FEM1C-mediated recognition of C-degron. Nature chemical biology 32 33398170
2017 FEM1 proteins are ancient regulators of SLBP degradation. Cell cycle (Georgetown, Tex.) 31 28118078
2003 The Fem1c genes: conserved members of the Fem1 gene family in vertebrates. Gene 23 14527725
2008 FEM1A and FEM1B: novel candidate genes for polycystic ovary syndrome. Human reproduction (Oxford, England) 21 18757445
2001 Identification of human FEM1A, the ortholog of a C. elegans sex-differentiation gene. Gene 19 11733146
2019 Tolerance Biomarkers in Liver Transplantation: Independent External Validation of the Predictive Strength of SENP6 and FEM1C Gene Expression. Transplantation 15 30720688
2005 FEM1A is a candidate gene for polycystic ovary syndrome. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 11 16390781
2004 Insertion of the beta Geo promoter trap into the Fem1c gene of ROSA3 mice. Molecular and cellular biology 11 15082774
2005 The Fem1a gene is downregulated in Rhabdomyosarcoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 9 16254458
2009 Fem1a is a mitochondrial protein up-regulated upon ischemia-reperfusion injury. FEBS letters 8 19406122
2023 Design and synthesis of a fluorescent probe to develop a fluorescence polarization assay for the E3 ligase FEM1C. Bioorganic & medicinal chemistry 7 37339537
2009 Disruption of FEM1C-W gene in zebra finch: evolutionary insights on avian ZW genes. Chromosoma 7 19139913
2021 Downregulation of FEM1C enhances metastasis and proliferation in colorectal cancer. Annals of translational medicine 4 34733943
2025 Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluids. Nature communications 2 40593736
2023 Eriocheir sinensis feminization-1c (Fem-1c) and Its Predicted miRNAs Involved in Sexual Development and Regulation. Animals : an open access journal from MDPI 2 37889731
2023 A novel de novo FEM1C variant is linked to neurodevelopmental disorder with absent speech, pyramidal signs and limb ataxia. Human molecular genetics 1 36336956
2012 [Polymorphisms of FEM1A gene in patients with polycystic ovary syndrome]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 22678803
2025 Fluorescence polarization binding assays for the E3 ligase FEM1C. Methods in enzymology 0 40992847