Affinage

FHIP1A

FHF complex subunit HOOK-interacting protein 1A · UniProt Q05DH4

Round 2 corrected
Length
1040 aa
Mass
116.6 kDa
Annotated
2026-04-28
24 papers in source corpus 3 papers cited in narrative 3 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FHIP1A is a subunit of the FTS-Hook-FHIP (FHF) cargo adaptor complex that links cytoplasmic dynein-1 and dynactin to specific intracellular cargos for retrograde microtubule-based transport (PMID:34882091). Proteomic interactome mapping demonstrates that FHIP1A-containing FHF complexes associate with a distinct set of motile cargos compared to complexes containing other FHIP paralogs, and single-molecule reconstitution confirms that FHIP1A-FHF complexes move processively with dynein-dynactin in vitro (PMID:34882091). The FHF complex also physically interacts with the AP-4 adaptor protein coat, and knockdown of FHF subunits disperses AP-4 and its autophagy cargo ATG9A from the perinuclear region, indicating that FHF-dynein coupling maintains perinuclear organelle positioning (PMID:32073997).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2017 Medium

    Establishing the physical proximity of the FHF complex to the dynein-dynactin machinery in living cells placed FHIP1A within the dynein transport system, but its precise role was undefined.

    Evidence BioID proximity labeling on dynein and dynactin subunits in human cells, followed by mass spectrometry

    PMID:28718761

    Open questions at the time
    • Proximity labeling does not distinguish direct from indirect interactions
    • No functional data on the consequence of FHIP1A loss
    • Identity of cargos linked specifically through FHIP1A unknown
  2. 2020 Medium

    Demonstrating that the FHF complex directly binds the AP-4 coat and that FHF knockdown disperses AP-4 and ATG9A from the perinuclear region established a functional role for the complex in dynein-driven retrograde positioning of AP-4-coated organelles.

    Evidence AP-MS, direct biochemical binding assays between AP-4 μ4 and Hook1/Hook2, siRNA knockdown with fluorescence microscopy in human cells

    PMID:32073997

    Open questions at the time
    • FHIP1A was not individually distinguished from other FHIP paralogs in this study
    • Whether FHIP1A specifically mediates the AP-4 interaction or another FHIP paralog is the relevant subunit remains unresolved
    • Mechanism by which FHF activates dynein motility on AP-4 vesicles not determined
  3. 2021 High

    Systematic interactome mapping of individual FHIP proteins revealed that FHIP1A-containing FHF complexes engage a cargo repertoire distinct from FHIP1B- and FHIP2A-containing complexes, and in vitro reconstitution proved FHIP1A-FHF activates processive dynein-dynactin motility, establishing FHIP1A as a bona fide dynein cargo adaptor.

    Evidence AP-MS of each FHIP protein, live-cell imaging, and single-molecule in vitro motility assays in a single integrated study

    PMID:34882091

    Open questions at the time
    • Specific cargo identities uniquely requiring FHIP1A in vivo remain incompletely cataloged
    • Structural basis for FHIP1A incorporation into the FHF complex and cargo selectivity is unknown
    • In vivo loss-of-function phenotype of FHIP1A alone (not other FHF subunits) not yet characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Open questions include the identity of the specific vesicular cargos that require FHIP1A (as opposed to other FHIP paralogs) for dynein-mediated transport, the structural determinants that confer cargo selectivity on FHIP1A-FHF, and the physiological consequences of FHIP1A loss in organismal models.
  • No structural model of the FHIP1A-FHF complex exists
  • No genetic or animal model phenotype reported for FHIP1A loss
  • Regulation of FHIP1A incorporation into FHF complexes is unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9612973 Autophagy 1
Partners
AP4M1DCTN1DYNC1H1FTSHOOK1HOOK2
Complex memberships
FTS-Hook-FHIP (FHF) complex

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 FHIP1A is a component of the FTS-Hook-FHIP (FHF) cargo adaptor complex that links cytoplasmic dynein-1 to cargo. Proteomic interactome mapping of each FHIP protein revealed that FHIP1A-containing FHF complexes have a distinct protein interactome compared to FHIP1B- and FHIP2A-containing complexes, and associate with distinct motile cargos. FHIP1A-FHF complexes move with dynein and dynactin in single-molecule in vitro reconstitution assays, establishing FHIP1A as a dynein cargo adaptor. Affinity purification mass spectrometry (interactome mapping), live-cell imaging, single-molecule in vitro reconstitution assays eLife High 34882091
2020 The FTS-Hook-FHIP (FHF) complex interacts with the heterotetrameric adaptor protein complex AP-4, with the interaction mediated by direct binding of the AP-4 μ4 subunit to coiled-coil domains in Hook1 and Hook2 subunits. Knockdown of FHF subunits (including FHIP proteins) results in dispersal of AP-4 and its cargo ATG9A from the perinuclear region, consistent with FHF coupling organelles to the dynein-dynactin retrograde motor on microtubules. Affinity purification-mass spectrometry, biochemical binding assays (direct binding), siRNA knockdown with fluorescence microscopy readout Molecular biology of the cell Medium 32073997
2017 FHIP1A (as part of the FTS-Hook-FHIP complex) was identified in the human cytoplasmic dynein-1 interactome by BioID proximity labeling attached to dynein and dynactin subunits, placing the FHF complex in spatial proximity to the dynein/dynactin machinery in living cells. Proximity-dependent biotinylation (BioID) coupled to mass spectrometry eLife Medium 28718761

Source papers

Stage 0 corpus · 24 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
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Generation and analysis of 280,000 human expressed sequence tags. Genome research 376 8889549
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2000 Shotgun sequencing of the human transcriptome with ORF expressed sequence tags. Proceedings of the National Academy of Sciences of the United States of America 135 10737800
2017 The human cytoplasmic dynein interactome reveals novel activators of motility. eLife 118 28718761
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2022 Proteome-scale mapping of binding sites in the unstructured regions of the human proteome. Molecular systems biology 61 35044719
2018 The MYO6 interactome reveals adaptor complexes coordinating early endosome and cytoskeletal dynamics. EMBO reports 44 29467281
2021 Cytoplasmic dynein-1 cargo diversity is mediated by the combinatorial assembly of FTS-Hook-FHIP complexes. eLife 37 34882091
2022 Meta-analysis of sub-Saharan African studies provides insights into genetic architecture of lipid traits. Nature communications 36 35546142
2019 The RNA-mediated estrogen receptor α interactome of hormone-dependent human breast cancer cell nuclei. Scientific data 32 31527615
2020 The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear distribution of AP-4 and its cargo ATG9A. Molecular biology of the cell 27 32073997
2023 Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability. Cell 23 37827155
2018 Identification of nine genes as novel susceptibility loci for early-onset ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Biomedical reports 15 29930801
2023 Pulse-SILAC and Interactomics Reveal Distinct DDB1-CUL4-Associated Factors, Cellular Functions, and Protein Substrates. Molecular & cellular proteomics : MCP 8 37689310
2018 Whole exome sequencing identifies recessive germline mutations in FAM160A1 in familial NK/T cell lymphoma. Blood cancer journal 6 30420729
2026 Identifying genes and pathways in familial lymphoid cancers using whole exome sequencing. Leukemia & lymphoma 0 41652927
2026 Coexistence of Rheumatoid Arthritis, Cerebrovascular Disease, and Alzheimer's Disease: A Case Study With Genetic Insights. Cureus 0 41913828