Affinage

FCHO2

F-BAR domain only protein 2 · UniProt Q0JRZ9

Length
810 aa
Mass
88.9 kDa
Annotated
2026-04-28
10 papers in source corpus 7 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FCHO2 is a membrane-sculpting F-BAR domain protein that initiates clathrin-mediated endocytosis by generating membrane curvature, clustering PI(4,5)P2, and scaffolding early endocytic machinery. Its F-BAR domain forms an intrinsically curved antiparallel dimer that tubulates phosphoinositide-enriched membranes and recruits the autoinhibited ubiquitin ligase Nedd4L, whose C2 domain senses FCHO2-generated curvature to relieve C2–HECT autoinhibition and ubiquitinate cargo such as ENaC (PMID:17540576, PMID:39402328). FCHO2 self-assembles into ring-like patches on PI(4,5)P2 domains to promote clathrin nucleation, binds the endocytic adaptor Eps15, and its depletion impairs transferrin uptake (PMID:35044298, PMID:21762413). Beyond endocytosis, FCHO2 bundles septin filaments through its intrinsically disordered region independently of the F-BAR domain and directly binds the integrin β5 cytoplasmic tail HDRRE motif to inside-out activate αvβ5 at curved adhesions (PMID:36476870, PMID:41651837).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2007 High

    Determining how F-BAR proteins generate membrane curvature: the FCHO2 F-BAR domain crystal structure revealed a curved antiparallel dimer whose concave face binds and tubulates liposomes, establishing the first structural basis for curvature sensing and generation by this protein family.

    Evidence Crystal structure, pulse EPR (DEER), liposome tubulation, site-directed mutagenesis

    PMID:17540576

    Open questions at the time
    • Lipid specificity of membrane binding not resolved
    • Cellular context of curvature generation not addressed
    • Relationship to clathrin coat assembly unknown
  2. 2011 High

    Connecting FCHO2's membrane-deforming activity to a specific cellular process: FCHO2 localizes to clathrin-coated pits, binds Eps15, and its knockdown reduces transferrin endocytosis, establishing it as a functional component of clathrin-mediated endocytosis.

    Evidence Lipid-binding assays, liposome tubulation, co-immunoprecipitation with Eps15, siRNA knockdown with transferrin uptake assay, fluorescence microscopy

    PMID:21762413

    Open questions at the time
    • Mechanism by which FCHO2 initiates coat assembly not defined
    • Functional consequence of FCHO2 monoubiquitination and oligomerization unclear
    • Whether FCHO2 acts upstream or in parallel with other nucleation factors not resolved
  3. 2022 High

    Revealing how FCHO2 nucleates clathrin assembly: reconstitution showed FCHO2 self-assembles into ring-like patches on PI(4,5)P2 domains, clustering lipids at cargo-receptor boundaries to enhance clathrin recruitment, providing a mechanistic framework for endocytic site initiation.

    Evidence In vitro reconstitution on supported lipid bilayers combined with cellular imaging

    PMID:35044298

    Open questions at the time
    • Role of Eps15 and other adaptors in patch formation not dissected
    • How ring-like patches transition to invaginated pits not shown
    • Contribution of phase separation to patch assembly not addressed
  4. 2022 High

    Uncovering a non-endocytic function: FCHO2 bundles septin filaments into flat sheets via its intrinsically disordered region, independent of the F-BAR domain, revealing a conserved cytoskeletal organizing activity distinct from membrane remodeling.

    Evidence In vitro reconstitution, electron microscopy, advanced fluorescence microscopy; conservation shown with yeast ortholog Syp1

    PMID:36476870

    Open questions at the time
    • Physiological consequence of septin bundling in mammalian cells not demonstrated
    • Whether septin bundling occurs at endocytic sites or other cellular locations unknown
    • Structural basis of IDR–septin interaction not determined
  5. 2024 High

    Explaining how membrane curvature is transduced into cargo-selective ubiquitination: FCHO2-generated tubule curvature recruits Nedd4L by engaging its C2 domain, relieving C2–HECT autoinhibition to ubiquitinate ENaC, linking geometric membrane information to E3 ligase activation.

    Evidence In vitro reconstitution on FCHO2-tubulated membranes, domain mutagenesis, siRNA knockdown, ubiquitination assay

    PMID:39402328

    Open questions at the time
    • Whether other E3 ligases are similarly curvature-activated at FCHO2 sites unknown
    • Range of cargo substrates beyond ENaC not defined
    • Quantitative curvature threshold for Nedd4L activation not precisely measured
  6. 2026 High

    Establishing FCHO2 as a curvature-dependent integrin activator: FCHO2 directly binds the HDRRE motif of the integrin β5 cytoplasmic tail and inside-out activates αvβ5 specifically at curved adhesions, with Y766 phosphorylation governing adhesion-type selectivity.

    Evidence Binding assays, Trp→Tyr mutagenesis, domain truncations, integrin activation assays, curved-adhesion imaging in cells

    PMID:41651837

    Open questions at the time
    • Whether FCHO2-mediated integrin activation is linked to its endocytic function not resolved
    • Structural basis of FCHO2–β5 tail interaction not determined
    • Upstream regulation of Y766 phosphorylation unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FCHO2's multiple activities — endocytic nucleation, Nedd4L activation, septin bundling, integrin activation, and Golgi maintenance — are spatiotemporally coordinated within a single cell remains undefined.
  • No integrated model linking FCHO2's distinct functions through shared or competing domain usage
  • In vivo phenotype of FCHO2 knockout in mammals not reported in the timeline
  • Role of phase separation in coordinating FCHO2 functions awaits peer-reviewed validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 3 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-162582 Signal Transduction 2 R-HSA-1500931 Cell-Cell communication 1
Partners
EPS15ITGB5MON1ANEDD4L

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 The FCHo2 F-BAR domain forms an intrinsically curved all-helical antiparallel dimer (Kd ~2.5 µM), binds liposomes via its concave face, and deforms them into tubules up to 130 nm in diameter; mutation of a phenylalanine on the N-terminal helix partially attenuated narrow tubule formation and conferred curvature sensitivity, establishing the structural basis for membrane curvature generation. Crystal structure, pulse EPR (DEER), liposome tubulation assay, site-directed mutagenesis Structure High 17540576
2011 FCHO2's EFC/F-BAR domain binds phosphatidylserine and phosphoinositides and deforms plasma membrane and liposomes into narrow tubes; FCHO2 localizes to clathrin-coated pits, binds the endocytic adaptor Eps15, and its knockdown reduces transferrin endocytosis, establishing its role in clathrin-mediated endocytosis. Lipid-binding assay, liposome tubulation, co-immunoprecipitation, siRNA knockdown with transferrin uptake assay, fluorescence microscopy Genes to Cells High 21762413
2011 FCHO2 undergoes monoubiquitination and forms oligomers as determined by gel filtration, properties that may contribute to its role in clathrin-mediated endocytosis. Gel filtration chromatography, ubiquitination assay Genes to Cells Medium 21762413
2022 FCHo2 self-assembles on PI(4,5)P2-enriched membrane domains into ring-like protein patches; its membrane binding promotes PI(4,5)P2 clustering at the boundary of cargo receptors, which in turn enhances clathrin assembly, providing a mechanistic framework for FCHo2-driven CME initiation. In vitro reconstitution on supported lipid bilayers, cellular imaging, minimal reconstituted and cellular systems combined eLife High 35044298
2022 FCHo2 (and its yeast ortholog Syp1) bundles septin filaments into flat sheets via its intrinsically disordered region (IDR), independent of the F-BAR domain, revealing an IDR-dependent septin-organizing activity conserved between yeast and mammals. In vitro reconstitution, electron microscopy, advanced fluorescence microscopy Cell Reports High 36476870
2024 FCHO2-generated membrane curvature recruits and activates the autoinhibited ubiquitin ligase Nedd4L at clathrin-coated pits: the Nedd4L C2 domain senses a specific degree of membrane curvature produced by the FCHO2 F-BAR domain, relieving the intramolecular C2–HECT autoinhibition, thereby enabling Nedd4L-mediated ubiquitination and endocytosis of ENaC cargo. In vitro reconstitution on FCHO2-tubulated membranes, co-localization, siRNA knockdown, ubiquitination assay, domain mutagenesis The EMBO Journal High 39402328
2023 FCHO2 interacts with Mon1a (identified by yeast two-hybrid and co-immunoprecipitation), and siRNA depletion of FCHO2 causes Golgi fragmentation, disrupted uniform distribution of Golgi enzymes, and loss of inter-ministack membrane protein exchange (by FRAP); the effect is partially cell-cycle dependent, requiring mitosis-dependent Golgi fragmentation, implicating FCHO2 in maintaining Golgi ribbon architecture. Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, FRAP, fluorescence microscopy bioRxivpreprint Medium 37461455
2026 FCHo2 binds directly to the HDRRE motif in the cytoplasmic tail of integrin β5 (but not β3) and inside-out activates integrin αvβ5 specifically in curved adhesions; a conserved Trp→Tyr substitution at position 766 in β5 (absent in other β isoforms) is required for curved-adhesion formation, and the phosphorylation state of Y766 governs whether αvβ5 engages curved adhesions versus focal adhesions. Binding assays, mutagenesis (Y766W and domain truncations), loss-of-function/replacement experiments, integrin activation assays, curved-adhesion imaging Nature Communications High 41651837
2025 FCHo2 participates in phase-separated protein condensates at nascent endocytic sites that provide a platform for clathrin triskelion recruitment and assembly; clathrin assembly in turn restricts condensate growth through surfactant-like behavior, establishing reciprocal regulation between condensates and the clathrin coat. In vitro reconstitution, NMR spectroscopy, fluorescence microscopy bioRxivpreprint Medium

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Structure and analysis of FCHo2 F-BAR domain: a dimerizing and membrane recruitment module that effects membrane curvature. Structure (London, England : 1993) 242 17540576
2011 Characterization of the EFC/F-BAR domain protein, FCHO2. Genes to cells : devoted to molecular & cellular mechanisms 29 21762413
2004 Identification and characterization of human FCHO2 and mouse Fcho2 genes in silico. International journal of molecular medicine 15 15254787
2022 Structural organization and dynamics of FCHo2 docking on membranes. eLife 14 35044298
2022 The Syp1/FCHo2 protein induces septin filament bundling through its intrinsically disordered domain. Cell reports 8 36476870
2024 The Nedd4L ubiquitin ligase is activated by FCHO2-generated membrane curvature. The EMBO journal 3 39402328
2026 FCHo2, not talin, enables inside-out activation of integrin ɑvβ5 in curved adhesions. Nature communications 0 41651837
2025 Circular RNA FCHO2 promotes airway remodeling in COPD via regulating nuclear translocation of PTBP1 to repress the splicing of GRN pre-mRNA. Cell death & disease 0 41184265
2025 FCHo2, instead of talin, enables inside-out activation of integrin ɑvβ5 in curved adhesions. bioRxiv : the preprint server for biology 0 41383757
2023 Mon1a and FCHO2 are required for maintenance of Golgi architecture. bioRxiv : the preprint server for biology 0 37461455