Affinage

ACBD4

Acyl-CoA-binding domain-containing protein 4 · UniProt Q8NC06

Length
268 aa
Mass
30.3 kDa
Annotated
2026-06-09
13 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACBD4 is a tail-anchored peroxisomal membrane protein that helps organize peroxisome-endoplasmic reticulum membrane contact sites and modulates peroxisomal lipid metabolism (PMID:28463579, PMID:37414147). It uses an FFAT motif to bind the ER-resident protein VAPB, and overexpression or loss of ACBD4 alters the extent of peroxisome-ER associations (PMID:28463579, PMID:39271061). This FFAT-VAP tethering function is evolutionarily conserved, being retained in the Drosophila ACBD4/5-like protein but lost in the fungal Ustilago maydis ortholog, which lacks a functional FFAT motif (PMID:39271061). Functionally, ACBD4 plays a regulatory rather than primary tethering role: its loss does not reduce peroxisome-ER connections or cause very long-chain fatty acid accumulation but instead increases the rate of peroxisomal β-oxidation of VLCFAs, distinguishing it mechanistically from its paralog ACBD5 (PMID:37414147). ACBD4 also interacts directly with ACBD5 independently of VAPB binding (PMID:37414147). Beyond these contact-site and metabolic regulatory roles, no further mechanistic detail has been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2017 High

    Established ACBD4 as a peroxisomal membrane protein and assigned it a role in inter-organelle contact, answering whether it physically links peroxisomes to another compartment.

    Evidence Characterization as a tail-anchored peroxisomal protein with demonstrated VAPB interaction and altered peroxisome-ER associations on manipulation

    PMID:28463579

    Open questions at the time
    • Did not distinguish whether ACBD4 is a primary tether or a regulatory factor
    • No functional consequence for lipid metabolism established
  2. 2019 Medium

    Quantified the contact-site tethering activity of ACBD4 and linked peroxisome-ER contacts to lipid exchange, addressing the functional output of these junctions.

    Evidence Proximity ligation and split-superfolder-GFP reporter assays with tether-level manipulation

    PMID:31198905

    Open questions at the time
    • Single-lab fluorescence assays
    • Did not separate ACBD4-specific from ACBD5-specific contributions
  3. 2023 High

    Distinguished ACBD4 from ACBD5 by showing ACBD4 loss does not impair tethering or cause VLCFA accumulation but accelerates β-oxidation, establishing a regulatory rather than tethering role and a VAPB-independent ACBD5 interaction.

    Evidence ACBD4 knockout in HEK293 cells with lipidomics, biochemical assays, and co-immunoprecipitation

    PMID:37414147

    Open questions at the time
    • Molecular basis for accelerated β-oxidation upon ACBD4 loss unresolved
    • Functional consequence of ACBD4-ACBD5 interaction unknown
  4. 2023 Medium

    Identified interaction determinants, including phosphorylation sites, as candidate regulators of ACBD4-VAPB binding.

    Evidence Immunoprecipitation with domain deletion and mutagenesis (methods paper context)

    PMID:36952197

    Open questions at the time
    • Functional impact of specific phosphorylation sites not demonstrated
    • Kinase and regulatory context unknown
  5. 2024 Medium

    Mapped the FFAT motif as the VAP-binding element and traced its evolutionary conservation, clarifying the structural basis and phylogenetic distribution of ACBD4-mediated tethering.

    Evidence Phylogenetic analysis with FFAT functional assays and interaction/depletion studies in Drosophila and Ustilago maydis

    PMID:39271061

    Open questions at the time
    • Mechanistic validation primarily in non-human model organisms
    • Structural model of the FFAT-VAP interface not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ACBD4 mechanistically restrains the rate of peroxisomal VLCFA β-oxidation, and how its VAPB-independent association with ACBD5 fits into contact-site assembly, remain unresolved.
  • No molecular mechanism linking ACBD4 to β-oxidation rate control
  • Role of the ACBD4-ACBD5 complex undefined
  • No structural data on the contact-site assembly

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005777 peroxisome 2 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-1430728 Metabolism 1
Partners
ACBD5VAPB
Complex memberships
peroxisome-ER membrane contact site

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 ACBD4 is a tail-anchored peroxisomal membrane protein that interacts with the ER protein VAPB (vesicle-associated membrane protein-associated protein B) to promote peroxisome-ER membrane contact site associations. Molecular cell biology characterization of ACBD4 as tail-anchored peroxisomal membrane protein; interaction with VAPB demonstrated; overexpression/loss-of-function showing altered peroxisome-ER associations Cell cycle (Georgetown, Tex.) High 28463579
2023 Loss of ACBD4 does not reduce peroxisome-ER connections or result in accumulation of very long-chain fatty acids (VLCFAs); instead, loss of ACBD4 increases the rate of peroxisomal β-oxidation of VLCFAs, suggesting a regulatory rather than primary tethering role at the peroxisome-ER interface. Additionally, ACBD4 interacts with ACBD5 independently of VAPB binding. Loss-of-function (ACBD4 knockout in HEK293 cells) combined with molecular cell biology, biochemical assays, and lipidomics; co-immunoprecipitation for ACBD4-ACBD5 interaction The Journal of biological chemistry High 37414147
2019 ACBD4 and ACBD5 function as peroxisomal tethering components that physically interact with ER-resident VAPB to form peroxisome-ER membrane contact sites; overexpression or loss of these tether proteins alters the extent of peroxisome-ER interactions and impacts lipid exchange between the two compartments. Proximity ligation assay and split superfolder GFP reporter system to monitor peroxisome-ER interactions; manipulation of tether protein levels with quantification of contact site changes Contact (Thousand Oaks (Ventura County, Calif.)) Medium 31198905
2024 The FFAT motif in ACBD4 mediates interaction with ER-resident VAP proteins to tether peroxisomes to the ER; this FFAT-VAP tethering function is conserved in Drosophila ACBD4/5-like protein (which has a functional FFAT motif tethering peroxisomes to the ER via Dm_Vap33), while the fungal Ustilago maydis ACBD4/5-like protein lacks a functional FFAT motif and does not interact with Um_Vap33. Phylogenetic analysis combined with experimental validation: FFAT motif functional assays, co-localization and interaction studies in Drosophila and fungal model organisms, depletion experiments showing peroxisome redistribution Biochimica et biophysica acta. Molecular cell research Medium 39271061
2023 ACBD4 (and its paralog ACBD5) bind ER membrane protein VAPB to mediate peroxisome-ER contacts; immunoprecipitation can be used to identify residues important for regulation of this interaction, including phosphorylation sites. Immunoprecipitation with antibody-conjugated beads followed by western blot analysis; domain deletion and mutagenesis to identify interaction determinants including phosphorylation Methods in molecular biology (Clifton, N.J.) Medium 36952197

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Peroxisomal ACBD4 interacts with VAPB and promotes ER-peroxisome associations. Cell cycle (Georgetown, Tex.) 67 28463579
2012 Brain transcriptome variation among behaviorally distinct strains of zebrafish (Danio rerio). BMC genomics 41 22817472
2012 Global effect of inauhzin on human p53-responsive transcriptome. PloS one 20 23284922
2018 Systems Genetics Approaches in Rat Identify Novel Genes and Gene Networks Associated With Cardiac Conduction. Journal of the American Heart Association 19 30608189
2019 Fluorescent tools to analyse peroxisome-ER interactions in mammalian cells. Contact (Thousand Oaks (Ventura County, Calif.)) 16 31198905
2023 Differential roles for ACBD4 and ACBD5 in peroxisome-ER interactions and lipid metabolism. The Journal of biological chemistry 11 37414147
2017 Peroxisome Motility Measurement and Quantification Assay. Bio-protocol 9 28936467
2024 New insights into the functions of ACBD4/5-like proteins using a combined phylogenetic and experimental approach across model organisms. Biochimica et biophysica acta. Molecular cell research 7 39271061
2024 Genetic architectures of the human hippocampus and those involved in neuropsychiatric traits. BMC medicine 4 39394562
2025 Acyl-coA binding protein AcbdA regulates peroxisome hitchhiking on early endosomes. bioRxiv : the preprint server for biology 1 40873809
2023 Assessing Peroxisomal Protein Interaction by Immunoprecipitation. Methods in molecular biology (Clifton, N.J.) 1 36952197
2025 Multi-omics analysis provides new insights into molecular mechanisms for waterfowl fatty liver formation. Poultry science 0 40570459
2025 Acyl-CoA-binding protein AcbdA is required for peroxisome hitchhiking on early endosomes in Aspergillus nidulans. Molecular biology of the cell 0 40901736

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