Affinage

VCF2

Protein VCF2 · UniProt Q5XKR9

Length
115 aa
Mass
13.1 kDa
Annotated
2026-04-28
2 papers in source corpus 1 papers cited in narrative 3 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VCF2 is a nuclear cofactor of the AAA-ATPase p97/VCP that directly binds p97 through a novel alpha-helical motif and associates with p97-UFD1-NPL4 and p97-UBXN2B complexes (PMID:37713320). VCF2 localizes to the nucleus and promotes nuclear import of p97; loss of VCF2 (and its paralog VCF1) reduces nuclear p97 levels, causes slow growth, and confers hypersensitivity to p97 chemical inhibition and DNA damage, establishing VCF2 as a critical regulator of nuclear p97 functions (PMID:37713320).

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2023 High

    Establishing how VCF2 engages p97/VCP: direct binding through a novel alpha-helical motif and co-complex formation with p97-UFD1-NPL4 and p97-UBXN2B resolved the molecular basis of VCF2-p97 interaction and placed VCF2 within the p97 cofactor network.

    Evidence Direct pulldown binding assays, reciprocal co-immunoprecipitation, and motif characterization in human cells (eLife)

    PMID:37713320

    Open questions at the time
    • No structural model of the VCF2 alpha-helical motif bound to p97
    • Whether VCF2 and VCF1 bind p97 competitively or cooperatively is unresolved
    • Stoichiometry of VCF2 within p97-UFD1-NPL4 and p97-UBXN2B complexes is unknown
  2. 2023 High

    Defining VCF2's cellular function: demonstration that VCF2 promotes nuclear import of p97, with its loss reducing nuclear p97 levels and causing slow growth and hypersensitivity to p97 inhibition and DNA damage, established VCF2 as a gatekeeper of nuclear p97 availability.

    Evidence Subcellular fractionation, live-cell imaging, and knockout/knockdown growth and drug-sensitivity assays in human cells (eLife)

    PMID:37713320

    Open questions at the time
    • Mechanism of nuclear import facilitation (carrier-dependent vs. direct escort) is uncharacterized
    • Specific nuclear p97 substrates affected by VCF2 loss remain unidentified
    • Pathway placement relies on inhibitor sensitivity rather than direct epistasis with known p97-dependent nuclear pathways

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular mechanism by which VCF2 promotes p97 nuclear import, the identity of nuclear p97 substrates dependent on VCF2, and the division of labor between VCF1 and VCF2 remain open questions.
  • No import receptor or NLS-dependent mechanism identified for VCF2-mediated p97 nuclear entry
  • Functional redundancy versus specialization of VCF1 and VCF2 not dissected
  • In vivo physiological roles (organism-level phenotype) are unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-9609507 Protein localization 1
Partners
NPLOC4UBXN2BUFD1VCP

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 VCF2 (FAM104 family member) directly binds p97/VCP via a novel alpha-helical motif and associates with p97-UFD1-NPL4 and p97-UBXN2B complexes in cells Direct binding assay (pulldown), Co-immunoprecipitation, identification of novel alpha-helical binding motif eLife High 37713320
2023 VCF2 localizes to the nucleus and promotes nuclear import of p97/VCP; loss of VCF1/2 results in reduced nuclear p97 levels Subcellular fractionation, live-cell imaging, loss-of-function (knockout/knockdown) with quantification of nuclear p97 levels eLife High 37713320
2023 Loss of VCF1/2 causes slow growth and hypersensitivity to p97 chemical inhibition in the absence and presence of DNA damage, indicating FAM104 proteins are critical regulators of nuclear p97 functions Loss-of-function (knockout) with growth assays and chemical inhibitor sensitivity assays under basal and DNA-damage conditions eLife Medium 37713320

Source papers

Stage 0 corpus · 2 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Pulmonary embolus after vena cava filter placement. The American surgeon 20 10190360
2023 The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCP. eLife 6 37713320