Affinage

KIF1A

Kinesin-like protein KIF1A · UniProt Q12756

Length
1690 aa
Mass
191.1 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KIF1A is a neuron-enriched kinesin-3 family motor that drives anterograde axonal transport of synaptic vesicle precursors, dense-core vesicles, TrkA, BACE1, and ATG-9, and is essential for synapse formation, synaptic transmission, and experience-dependent neuroplasticity (PMID:7539720, PMID:9548721, PMID:21256924, PMID:27263974, PMID:27396362, PMID:22365548). The motor achieves superprocessive plus-end-directed movement through a biased Brownian-motion mechanism in which the positively charged K-loop (loop 12) electrostatically tethers the one-head-bound (ADP) state to tubulin C-terminal tails, while ATP hydrolysis alternately engages loops L11 and L12 to drive stepping; dimerization upon cargo engagement converts the autoinhibited monomer—held by an intramolecular FHA-CC2/motor-CC1 interaction—into a processive dimer (PMID:10024239, PMID:10660047, PMID:15286375, PMID:38956021, PMID:15014437, PMID:34843479, PMID:38206323). Cargo selectivity is conferred by the PH domain binding PI(4,5)P₂ on vesicle membranes and by adaptors including liprin-α/SYD-2, DENN/MADD–GTP-Rab3, CASK/LIN-2, and calcium/calmodulin, while motor activity is further tuned by α-tubulin polyglutamylation, GSK3β phosphorylation, and Huntingtin phosphorylation state (PMID:15155810, PMID:19880746, PMID:18849981, PMID:27172328, PMID:30021165, PMID:17360631, PMID:37431882). De novo dominant mutations in KIF1A cause KIF1A-associated neurological disorder (KAND), where heterodimers of mutant and wild-type motor are functionally impaired, and distinct mutation classes—reduced microtubule binding, reduced velocity, or rigor binding—correlate with clinical severity (PMID:35917346, PMID:33880452, PMID:35132656).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 1991 High

    Identification of the C. elegans ortholog UNC-104 as the dedicated motor for synaptic vesicle axonal transport established that a single kinesin is selectively required for delivering synaptic vesicles to terminals.

    Evidence Genetic null mutant analysis with electron microscopy in C. elegans

    PMID:1710172

    Open questions at the time
    • Mammalian homolog not yet identified
    • Cargo-binding mechanism unknown
    • Motor mechanism (monomer vs. dimer) unresolved
  2. 1995 High

    Cloning of mammalian KIF1A revealed it as a neuron-specific monomeric kinesin that transports a defined subset of synaptic vesicle precursor proteins at high velocity, establishing it as the vertebrate UNC-104 ortholog.

    Evidence Molecular cloning, organelle isolation, co-immunoprecipitation with synaptic vesicle markers, velocity measurements

    PMID:7539720

    Open questions at the time
    • Mechanism of monomeric processivity unknown
    • How cargo specificity is achieved unknown
  3. 1998 High

    KIF1A knockout mice demonstrated that loss of KIF1A causes synaptic vesicle depletion at terminals, neuronal degeneration, and death, proving KIF1A is essential and non-redundant for synaptic vesicle precursor transport in mammals.

    Evidence Gene knockout mice, electron microscopy, primary neuronal culture with rescue

    PMID:9548721

    Open questions at the time
    • Molecular basis of neuronal death not fully resolved
    • Whether other cargoes are affected unknown
  4. 1999 High

    Single-molecule assays showed that a monomeric KIF1A motor domain moves processively along microtubules via biased Brownian motion, overturning the assumption that two motor heads are required for processivity.

    Evidence Single-molecule in vitro motility assay with monomeric motor domain construct

    PMID:10024239

    Open questions at the time
    • Structural basis of one-headed processivity unknown
    • Force generation capacity uncharacterized
  5. 2000 High

    Identification of the K-loop (loop 12) as an auxiliary microtubule-binding site that tethers KIF1A to tubulin C-terminal tails explained how a single motor head maintains processivity through electrostatic anchorage.

    Evidence Cryo-EM at 15 Å, site-specific cross-linking, mutant analysis

    PMID:10660047

    Open questions at the time
    • Atomic-resolution structure of K-loop–tubulin interaction lacking
    • Role of tubulin post-translational modifications unexplored
  6. 2003 High

    Multiple advances resolved the stepping mechanism, autoinhibition, and cargo adaptor linkage: optical trapping showed ~8 nm steps with one ATP per step; cryo-EM of UNC-104 revealed monomeric (autoinhibited) and dimeric conformations; and liprin-α was identified as a cargo receptor linking KIF1A to synaptic cargoes.

    Evidence Optical trapping/single-molecule force spectroscopy; cryo-EM with deletion mutagenesis and in vivo C. elegans assays; co-immunoprecipitation and nerve ligation accumulation

    PMID:12522103 PMID:12891363 PMID:14638858

    Open questions at the time
    • Structural details of autoinhibitory interface incomplete
    • How liprin-α binding activates the motor unknown
    • Relationship between dimerization and cargo binding unresolved
  7. 2004 High

    Three key regulatory principles were established: crystal structures across nucleotide states showed L11/L12 alternate as microtubule-binding elements during the ATPase cycle; the PH domain's PI(4,5)P₂ binding was shown essential for cargo attachment and motor function in vivo; and the FHA–CC2 intramolecular interaction was identified as the autoinhibitory switch.

    Evidence X-ray crystallography with transition-state analogs; PH domain mutagenesis with in vitro lipid binding and C. elegans rescue; point mutagenesis with live-cell imaging in neurons

    PMID:15014437 PMID:15155810 PMID:15286375

    Open questions at the time
    • How PI(4,5)P₂ binding triggers dimerization not shown
    • No structure of the full-length autoinhibited motor
  8. 2007 High

    α-Tubulin polyglutamylation was identified as a track-level regulator specifically required for KIF1A microtubule binding and neurite targeting, explaining how post-translational tubulin modifications selectively control kinesin-3 transport.

    Evidence ROSA22 knockout mice lacking PGs1, microtubule binding assays, immunofluorescence, electrophysiology

    PMID:17360631

    Open questions at the time
    • Direct structural mechanism of polyglutamylation–K-loop interaction not resolved
    • Whether other tubulin modifications similarly regulate KIF1A unknown
  9. 2008 High

    DENN/MADD was identified as a Rab3-GEP that directly links GTP-Rab3 vesicles to the KIF1A stalk, establishing a nucleotide-state-dependent cargo-sorting mechanism for synaptic vesicle precursors.

    Evidence Co-immunoprecipitation, sequential RNAi/KO, GTP/GDP-Rab3 binding assays, in vivo transport assays

    PMID:18849981

    Open questions at the time
    • Structural basis of DENN/MADD–KIF1A stalk interaction unknown
    • Whether DENN/MADD promotes dimerization not tested
  10. 2009 High

    SYD-2/liprin-α was shown to promote UNC-104 clustering and anterograde motor activity in vivo, establishing it as an activating scaffold rather than merely a static cargo linker.

    Evidence FRET/FLIM, FRAP, kymograph analysis in living C. elegans

    PMID:19880746

    Open questions at the time
    • Mechanism by which SYD-2 promotes motor clustering not defined at molecular level
    • Relationship between clustering and dimerization unclear
  11. 2010 High

    Discovery that UNC-104 is degraded at synapses via the ubiquitin-proteasome pathway and that PI(4,5)P₂ cargo binding protects it from degradation revealed a cargo-dependent motor stability mechanism controlling motor levels in vivo.

    Evidence Genetic analysis with PH domain mutants and intragenic suppressors, ubiquitin pathway inhibition in C. elegans

    PMID:21079789

    Open questions at the time
    • Identity of the E3 ubiquitin ligase unknown
    • Whether mammalian KIF1A undergoes similar synaptic degradation not tested
  12. 2011 High

    KIF1A's cargo repertoire was expanded beyond synaptic vesicle precursors to include dense-core vesicles in mammalian neurons, and tau was identified as a physical interactor affecting retrograde motility parameters.

    Evidence Two-color live-cell imaging with shRNA knockdown; co-immunoprecipitation and BiFC in C. elegans

    PMID:21256924 PMID:21569846

    Open questions at the time
    • How KIF1A distinguishes DCV from SVP cargo unknown
    • Functional significance of tau interaction for anterograde transport unresolved
  13. 2012 High

    Placing KIF1A downstream of BDNF signaling in experience-dependent synaptogenesis showed that KIF1A is not merely a housekeeping motor but a regulated effector of neuroplasticity.

    Evidence Kif1a+/− and Bdnf+/− mice, enriched environment paradigm, synapse counting, behavioral tests

    PMID:22365548

    Open questions at the time
    • Mechanism of BDNF-dependent KIF1A upregulation at transcriptional vs. post-transcriptional level unresolved
  14. 2016 High

    KIF1A's biological roles were broadened to include transport of TrkA (via Rab3 adaptor) in sensory neurons, ATG-9 delivery to synapses enabling local autophagosome biogenesis, BACE1 transport, interkinetic nuclear migration in radial glia, and regulation by CASK/LIN-2.

    Evidence Co-immunoprecipitation, live imaging, Kif1a+/− mice, C. elegans genetics, rat in vivo RNAi, yeast two-hybrid/BiFC

    PMID:26752160 PMID:27172328 PMID:27263974 PMID:27396362 PMID:27484852

    Open questions at the time
    • How KIF1A is recruited to nuclear envelope for INM unknown
    • Whether CASK and liprin-α binding are competitive or sequential not resolved
  15. 2018 High

    Calcium/calmodulin was identified as a positive regulator of KIF1A-DCV binding, and TANC2 was shown to capture DCVs at dendritic spines rather than serving as a cargo adaptor during transport.

    Evidence KIF1A interactome (AP-MS), co-immunoprecipitation, live-cell imaging, mutagenesis

    PMID:30021165

    Open questions at the time
    • CaM binding site on KIF1A not mapped
    • Whether CaM regulation affects autoinhibition or cargo affinity specifically not determined
  16. 2020 Medium

    GSK3β was shown to phosphorylate KIF1A and impair its transport in the context of amyloid-β pathology, though the functionally relevant phosphosite remains unidentified.

    Evidence Live-cell imaging, pharmacological GSK3β inhibition, mass spectrometry, phosphomimetic mutagenesis

    PMID:33067366

    Open questions at the time
    • Functionally relevant GSK3β phosphosite on KIF1A not identified
    • No in vivo validation of GSK3β-KIF1A regulation
  17. 2021 High

    Systematic characterization of KAND mutations revealed three mechanistic classes of motor dysfunction—reduced MT binding, reduced velocity, and rigor binding—with rigor mutations correlating to the most severe clinical outcomes, establishing a genotype-mechanism-phenotype framework for KIF1A disease.

    Evidence Single-molecule TIRF microscopy with multiple recombinant variants, neurite tip accumulation assay, clinical severity scoring

    PMID:33880452

    Open questions at the time
    • How rigor mutations affect cargo delivery vs. microtubule blockade in vivo not resolved
    • No therapeutic interventions tested
  18. 2021 High

    In vivo genetic analysis demonstrated that CC1-mediated autoinhibition of the motor domain is the primary regulatory mechanism controlling UNC-104/KIF1A activity, with gain-of-function mutations in either domain causing hyperactive transport.

    Evidence Genetic gain-of-function alleles, engineered mutations, live imaging in C. elegans

    PMID:34843479

    Open questions at the time
    • No structure of the motor-CC1 inhibitory interface
    • How cargo binding relieves CC1 autoinhibition at the molecular level unknown
  19. 2022 High

    Dominant-negative disease mechanism was established: KAND mutant KIF1A poisons wild-type motor through heterodimerization, and a suppressor mutation in the motor domain can restore activity, providing proof-of-concept for allele-specific rescue.

    Evidence CRISPR C. elegans models, suppressor screen, in vitro heterodimer motility assays

    PMID:35917346

    Open questions at the time
    • Whether suppressor mutations are therapeutically feasible in mammals not tested
    • Extent of dominant-negative poisoning across different KAND variants not systematically assessed
  20. 2022 High

    K-loop charge was shown to be linearly correlated with run length through systematic mutagenesis, and a disease mutation (E239K) was shown to hyper-stabilize the motor-neck interaction, providing atomic-level explanations for pathogenic gain-of-function.

    Evidence Loop-swap and charge-substitution mutants with single-molecule TIRF; X-ray crystallography with quantitative mass spectrometry and ATPase assays

    PMID:35132656 PMID:36549649

    Open questions at the time
    • How neck-linker hyper-stabilization translates to cellular transport defects not fully modeled
  21. 2023 High

    Huntingtin phosphorylation was shown to recruit KIF1A for enhanced SVP transport and synaptic glutamate release; KIF1A silencing rescued the synaptic and behavioral deficits caused by constitutive HTT phosphorylation, placing KIF1A as the effector motor in HTT-regulated synaptic vesicle dynamics.

    Evidence Microfluidic devices, in vivo mouse genetics with KIF1A silencing, behavioral testing

    PMID:37431882

    Open questions at the time
    • Molecular mechanism of HTT-KIF1A recruitment unknown
    • Whether this pathway is relevant to Huntington's disease pathology not established
  22. 2024 High

    Near-atomic cryo-EM structures of dimeric KIF1A on microtubules across nucleotide states revealed head-head coordination and K-loop interactions with both α- and β-tubulin C-terminal tails, providing the structural basis for superprocessivity and explaining how the P305L pathogenic mutation impairs strong MT binding.

    Evidence Cryo-EM at 2.7–3.5 Å resolution, structure-function analysis with P305L variant

    PMID:38956021

    Open questions at the time
    • Full-length structure including stalk and cargo-binding domains still lacking
    • How head-head coordination changes under load not tested
  23. 2024 High

    KIF1A's role in synaptic vesicle delivery was validated in a non-neuronal sensory system: zebrafish hair cell ribbon synapses require KIF1A for vesicle enrichment, evoked release, and sensory behavior.

    Evidence Zebrafish kif1aa mutants, electron microscopy, in vivo calcium imaging, electrophysiology, behavioral testing

    PMID:39505875

    Open questions at the time
    • Whether ribbon synapse-specific cargoes differ from CNS SVPs unknown
    • Adaptor proteins linking KIF1A to ribbon synapse vesicles not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of autoinhibited and cargo-bound KIF1A, the molecular mechanism by which cargo binding triggers dimerization and relieves CC1 autoinhibition, identification of the E3 ligase mediating synaptic KIF1A degradation, and whether therapeutic correction of dominant-negative KAND mutations is achievable in mammalian systems.
  • No full-length structure available
  • Cargo-induced dimerization mechanism not reconstituted biochemically
  • Therapeutically actionable targets for KAND not validated in mammals

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003774 cytoskeletal motor activity 5 GO:0140657 ATP-dependent activity 5 GO:0008092 cytoskeletal protein binding 4 GO:0008289 lipid binding 2
Localization
GO:0005856 cytoskeleton 4 GO:0031410 cytoplasmic vesicle 4 GO:0005829 cytosol 2
Pathway
R-HSA-9609507 Protein localization 7 R-HSA-112316 Neuronal System 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1266738 Developmental Biology 1 R-HSA-9612973 Autophagy 1
Partners
CASKDENN/MADDHTTLPHN1MAPTRAB3ATANC2

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 KIF1A is a neuron-specific, monomeric kinesin superfamily motor protein that performs anterograde axonal transport of synaptic vesicle precursors (containing synaptotagmin, synaptophysin, and Rab3A but not SV2, syntaxin 1A, or SNAP-25) at 1.2 µm/s, distinct from other anterograde motors such as conventional kinesin and KIF3. Molecular cloning, organelle isolation from axons, co-immunoprecipitation with synaptic vesicle protein markers, velocity measurements Cell High 7539720
1991 The C. elegans KIF1A ortholog UNC-104 is required for anterograde axonal transport of synaptic vesicles; unc-104 null mutants lack axonal synaptic vesicles but accumulate vesicle clusters in neuronal cell bodies, while other organelles are transported normally. Genetic null mutant analysis, electron microscopy of neuronal ultrastructure, behavioral phenotyping Cell High 1710172
1998 KIF1A gene knockout in mice causes specific reduction of synaptic vesicle precursor transport, dramatic decrease in synaptic vesicle density at terminals, accumulation of clear vesicle clusters in cell bodies, and neuronal degeneration/death; neuronal death in culture is rescued by co-culture with wild-type neurons or low-concentration glutamate, implicating insufficient afferent stimulation as the cause. Gene knockout (KIF1A−/−) mice, electron microscopy, immunohistochemistry, primary neuronal culture The Journal of cell biology High 9548721
1999 The monomeric motor domain construct of KIF1A moves processively along microtubules for >1 µm before detaching, exhibiting stochastic movement fitted by a biased Brownian-motion model, demonstrating that two motor heads are not required for processivity. Single-molecule motility assay, in vitro microtubule gliding assay with monomeric motor domain construct Science High 10024239
2000 KIF1A possesses a positively charged 'K-loop' (loop 12) that acts as an extra microtubule-binding domain by interacting with the C-terminus of tubulin; this K-loop is essential for single-headed processivity, as shown by cryo-EM at 15 Å resolution docked with atomic models and confirmed by site-specific cross-linking and mutant analysis. Cryo-electron microscopy (15 Å resolution), mutant analysis, site-specific cross-linking Cell High 10660047
2003 Single KIF1A monomers move with step sizes distributed around multiples of 8 nm (with ~3 nm net plus-end bias per ATP hydrolysis), driven by preferential binding to tubulin on the plus-end side of the microtubule; optical trapping demonstrates one ATP hydrolysis per stepping event and directional movement against loads up to 0.15 pN. Optical trapping (single-molecule force spectroscopy), fluorescence microscopy Nature High 12891363
2004 Crystal structures of KIF1A with transition-state analogs (AMP-PNP, ADP-vanadate, ADP-AlFx) reveal that KIF1A uses two microtubule-binding loops (L11 and L12) alternately during the ATP hydrolysis cycle: L11 is extended in the AMP-PNP state and L12 in the ADP state; ADP-vanadate represents an intermediate state where both loops are raised, actively detaching kinesin from microtubules. X-ray crystallography with transition-state analogs, structural comparison across nucleotide states Science High 15286375
2003 KIF1A interacts with the scaffolding protein liprin-α, co-localizes in neuronal subcellular compartments, co-accumulates with liprin-α at ligated sciatic nerves, and co-immunoprecipitates with liprin-α-associated proteins including AMPA receptors, GRIP/ABP, RIM, GIT1, and βPIX, suggesting liprin-α functions as a KIF1A cargo receptor. Co-immunoprecipitation, nerve ligation accumulation assay, co-localization by immunofluorescence The Journal of biological chemistry High 12522103
2004 The pleckstrin homology (PH) domain of UNC-104/KIF1A binds specifically to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) in vitro, and PH domain point mutations that abolish PI(4,5)P2 binding in vitro also abolish synaptic vesicle transport in living C. elegans; this lipid-binding interaction also regulates motor velocity and processivity in vivo. PH domain mutagenesis, in vitro lipid-binding assay, in vivo rescue assay in C. elegans, real-time live imaging of UNC-104::GFP Molecular biology of the cell High 15155810
2004 An intramolecular interaction between the forkhead-associated (FHA) domain and coiled-coil domain 2 (CC2) of KIF1A negatively regulates motor activity; disrupting this interaction by point mutations causes dramatic accumulation of KIF1A in neuronal periphery, enhanced microtubule binding, and increased self-multimerization. Point mutagenesis, live-cell imaging in cultured neurons, microtubule-binding assay The EMBO journal High 15014437
2006 Cryo-EM structures of KIF1A–microtubule complex at ~10 Å resolution reveal that the nucleotide-binding pocket is closed in the AMP-PNP state and open in the ADP state; structural changes suggest a mechanical pathway from the nucleotide to the neck linker via motor core rotation. Cryo-electron microscopy (~10 Å resolution), two nucleotide states The EMBO journal High 16946706
2007 Alpha-tubulin polyglutamylation (generated by PGs1) is required for efficient KIF1A binding to microtubules and for proper targeting of KIF1A to neurites; ROSA22 mice lacking polyglutamylated alpha-tubulin show reduced KIF1A abundance in neurites and decreased synaptic vesicle density at hippocampal synapses, while KIF3A and KIF5 distributions are unaffected. ROSA22 knockout mice (lacking PGs1), biochemical fractionation with MT binding assay, immunofluorescence in vivo and in vitro, electrophysiology Proceedings of the National Academy of Sciences of the United States of America High 17360631
2008 DENN/MADD (Rab3-GEP) directly interacts with the stalk domain of KIF1A and KIF1Bβ, preferentially binds GTP-Rab3 (acting as a Rab3 effector), and is essential for axonal transport of both DENN/MADD and Rab3; GTP-Rab3 is transported more efficiently than GDP-Rab3, demonstrating that Rab3 nucleotide state regulates vesicle transport through preferential interaction with DENN/MADD. Co-immunoprecipitation, sequential genetic perturbations (RNAi/KO), in vivo transport assays, GTP/GDP-Rab3 binding assays Nature cell biology High 18849981
2003 C. elegans Unc104 can exist in two cryo-EM–defined conformations when microtubule-bound: a monomeric state with an intramolecular parallel coiled coil (autoinhibited) and a dimeric state with an intermolecular coiled coil; deletion of a flexible neck hinge that accommodates the intramolecular coil causes severe uncoordinated phenotype in vivo without altering motor velocity in vitro, suggesting the folded conformation regulates motility. Cryo-electron microscopy, deletion mutagenesis, in vitro motility assay, transgenic C. elegans behavioral assay The Journal of cell biology High 14638858
2009 The synaptic scaffold SYD-2 (liprin-α) clusters UNC-104/KIF1A and promotes anterograde motor activity; loss of SYD-2 reduces net anterograde movement and velocity of UNC-104, switching it toward retrograde transport characteristics; SYD-2-dependent UNC-104 clusters are dynamic (shown by FRAP) and contain synaptobrevin-1 cargo. Yeast 2-hybrid, pull-down assays, FRET/FLIM in living C. elegans, FRAP, kymograph analysis of motor motility Proceedings of the National Academy of Sciences of the United States of America High 19880746
2010 UNC-104/KIF1A is degraded at synaptic regions via the ubiquitin-proteasome pathway and is not retrogradely transported; loss of specific PI(4,5)P2 binding (PH domain mutation D1497N) reduces motor levels in vivo, and intragenic suppressors that restore PI(4,5)P2 binding also restore motor levels, demonstrating that cargo binding protects UNC-104 from degradation. Genetic analysis with PH domain point mutants and intragenic suppressors, in vitro PI(4,5)P2 binding assay, in vivo motor quantification, ubiquitin pathway inhibition PLoS genetics High 21079789
2011 KIF1A is the primary anterograde motor for dense-core vesicles (DCVs) in mammalian hippocampal neurons; two-color live imaging shows DCV markers (chromogranin A-RFP, BDNF-RFP) co-move with KIF1A-GFP; shRNA knockdown of KIF1A significantly reduces DCV organelle flux without affecting mitochondria or transferrin receptor transport. Two-color live-cell imaging, shRNA knockdown, cargo-specific flux measurements Neuroscience letters High 21256924
2012 KIF1A is upregulated by BDNF in hippocampal neurons; Kif1a+/− mice fail to show enrichment-induced synaptogenesis and learning enhancement; KIF1A overexpression promotes synaptogenesis via presynaptic bouton formation, placing KIF1A downstream of BDNF in experience-dependent neuroplasticity. Heterozygous KO mice (Kif1a+/−), Bdnf+/− mice, overexpression, hippocampal synapse counting, behavioral tests Neuron High 22365548
2016 KIF1A transports TrkA-containing vesicles via adaptor GTP-Rab3; Kif1a+/− mice show progressive loss of TrkA+ sensory neurons in DRGs, disrupted axonal transport of TrkA, hyposensitivity to NGF, and reduced TRPV1 function; PI3K signaling rescues the phenotype and increases Kif1a mRNA. Live imaging, co-immunoprecipitation (KIF1A–Rab3–TrkA), Kif1a+/− mouse model, physiological calcium imaging, pharmacological rescue Neuron High 27263974
2016 KIF1A/UNC-104 transports the integral membrane autophagy protein ATG-9 to synapses in C. elegans neurons; this delivery enables spatially localized autophagosome biogenesis near synapses, which is required for presynaptic assembly and axon outgrowth dynamics. Unbiased genetic screens, systematic genetic analysis, live imaging of autophagosome biogenesis, C. elegans loss-of-function Developmental cell High 27396362
2016 KIF1A mediates axonal transport of BACE1 in SCG neurons; two-color live imaging shows BACE1-mCherry co-moves with KIF1A-GFP; KIF1A siRNA and the dominant-negative KIF1A-T312M mutant impair BACE1 transport specifically. Two-color live-cell imaging, siRNA knockdown, dominant-negative motor mutant expression Traffic Medium 27484852
2016 KIF1A drives basal interkinetic nuclear migration (INM) in radial glial progenitors (RGPs) of the developing brain; KIF1A inhibition by RNAi reduces neurogenic divisions and independently disrupts multipolar neuronal migration in a BDNF-dependent manner. RNAi knockdown in rat RGPs in vivo (E16–P7), constitutive and conditional approaches, BDNF rescue Nature neuroscience High 26752160
2018 Calcium acting via calmodulin (CaM) enhances KIF1A binding to dense-core vesicles (DCVs) and increases DCV motility; liprin-α and TANC2 are not part of the KIF1A-cargo complex but capture DCVs at dendritic spines; TANC2 mutations associated with neuropsychiatric disorders abolish interaction with KIF1A. KIF1A interactome (proteomics/MS), co-immunoprecipitation, live-cell imaging of DCV transport, mutagenesis Cell reports High 30021165
2022 De novo KAND mutations in KIF1A dominantly inhibit motor activity through heterodimerization with wild-type KIF1A; in vitro assays show mutant KIF1A significantly impairs the motility of heterodimeric motors; C. elegans CRISPR models show both heterozygotes and homozygotes have reduced axonal transport; a suppressor mutation in the motor domain recovers mutant KIF1A motor activity. CRISPR-Cas9 C. elegans models, suppressor screen, in vitro heterodimer motility assays, axonal transport quantification Proceedings of the National Academy of Sciences of the United States of America High 35917346
2022 The E239K mutation in KIF1A's β7 strand hyper-stabilizes the motor-neck interaction at the late ATP hydrolysis stage, reducing ATPase activity and microtubule gliding velocity; X-ray crystallography shows excess positive charge on β7 creates electrostatic interaction with a negatively charged neck; quantitative mass spectrometry confirms stabilized motor-neck interaction. X-ray crystallography, quantitative mass spectrometry, ATPase assay, microtubule gliding assay, Kif1a+/− neuron complementation assay The EMBO journal High 35132656
2021 KAND mutations cause three classes of KIF1A protein dysfunction measured by TIRF microscopy: reduced microtubule binding, reduced velocity/processivity, and increased non-motile rigor MT binding; rigor phenotype correlates with most severe clinical outcomes while reduced MT binding correlates with milder phenotypes. TIRF microscopy (single-molecule), recombinant protein characterization, neurite tip accumulation assay, clinical severity scoring HGG advances High 33880452
2024 Cryo-EM structures at 2.7–3.5 Å of dimeric microtubule-bound KIF1A in multiple nucleotide states reveal one- and two-heads-bound configurations with distinct inter-head connections; the K-loop forms electrostatic interactions with C-terminal tails of both α- and β-tubulin; the P305L mutation alters loop-12 conformation, impairing strong microtubule binding without disrupting these electrostatic interactions; K-loop and head-head coordination are major determinants of KIF1A's superprocessive motility. Cryo-EM (2.7–3.5 Å resolution), structure-function analysis with P305L pathogenic variant Nature communications High 38956021
2022 The K-loop (lysine-rich loop 12) of KIF1A enhances superprocessivity by stabilizing binding in the one-head-bound (ADP) state through electrostatic interactions with the microtubule; replacing KIF1A loop-12 with kinesin-1 loop-12 decreases run length 6-fold; processivity is linearly dependent on loop-12 positive charge. In vitro microtubule pelleting, single-molecule dwell time assays, loop-swap and charge-substitution mutants, TIRF microscopy The Journal of biological chemistry High 36549649
2021 CC1 domain-mediated autoinhibition of the motor domain is a key regulatory mechanism for UNC-104/KIF1A in vivo; gain-of-function mutations in either the motor domain or the inhibitory CC1 domain cause hyperactive axonal transport and abnormal synaptic vesicle accumulation; the motor domain mutation promotes active dimeric conformation, releasing the CC1 inhibitory domain. Genetic gain-of-function allele identification, live imaging in C. elegans neurons, engineered mutations disrupting autoinhibitory interface PLoS genetics High 34843479
2013 The viral glycoproteins gE/gI of pseudorabies virus mediate efficient KIF1A-dependent anterograde axonal transport of viral particles by facilitating the interaction between the viral protein Us9 and KIF1A; in the absence of gE/gI, Us9 no longer efficiently co-purifies with KIF1A and viral particles are not sorted into axons. Affinity purification/mass spectrometry, co-purification assays, GFP-tagged viral protein live imaging, PRV mutant analysis Journal of virology Medium 23804637
2011 Tau/PTL-1 physically interacts with UNC-104/KIF1A (confirmed by co-immunoprecipitation and bimolecular fluorescence complementation in living C. elegans) and affects its motility characteristics, particularly retrograde movement parameters, without affecting anterograde displacements. Co-immunoprecipitation, BiFC in living C. elegans, confocal time-lapse imaging Neurobiology of disease Medium 21569846
2016 LIN-2 (CASK) interacts with UNC-104/KIF1A on the motor's stalk domain (overlapping with SYD-2/liprin-α binding site via L27 and GUK domains) and is a positive regulator of UNC-104 motility and run length; loss of LIN-2 reduces motor velocity and run length more profoundly than loss of SYD-2, and increases motor clustering along axons. Yeast two-hybrid, co-immunoprecipitation, BiFC in living C. elegans, kymograph analysis of motor motility Traffic Medium 27172328
2023 Huntingtin phosphorylation recruits KIF1A to increase axonal transport of synaptic vesicle precursors (SVPs) and synaptic glutamate release; constitutive HTT phosphorylation causes SV over-accumulation at synapses and impairs motor skill learning; silencing KIF1A in these mice restores SV transport and motor skill learning to wild-type levels. Microfluidic devices, in vivo mouse genetics, KIF1A silencing, synaptic vesicle quantification, behavioral testing eLife High 37431882
2024 In C. elegans, releasing UNC-104 autoinhibition (without cargo) is sufficient to trigger dimerization and processive movement at nanomolar concentrations; a coiled-coil domain (CC2) is required for efficient dimerization and processive movement, distinguishing UNC-104 activation from other kinesin-3 members. Biochemical dimerization assays, single-molecule motility assays, domain deletion/mutagenesis, C. elegans genetics eLife High 38206323
2005 Herpes simplex virus type 2 UL56 membrane protein associates with KIF1A through a yeast two-hybrid and GST pull-down interaction; co-localization of KIF1A with full-length UL56 (but not the transmembrane domain-deleted mutant) requires the UL56 C-terminal transmembrane domain in vivo, suggesting UL56 may act as a receptor for KIF1A in neurons. Yeast two-hybrid, GST pull-down, co-localization by immunofluorescence, deletion mutagenesis The Journal of general virology Medium 15722511
2020 GSK3β activity impairs KIF1A transport in hippocampal neurons treated with amyloid-β oligomers; GSK3β phosphorylates KIF1A at S402 in vitro and in AD mouse brain (confirmed by mass spectrometry on immunoprecipitated KIF1A), but phosphomimetic S402 mutations do not alter KIF1A motility, indicating GSK3β regulates KIF1A transport through a site other than S402. Live-cell imaging, pharmacological GSK3β inhibition, mass spectrometry on immunoprecipitated KIF1A, in vitro kinase assay, phosphomimetic mutagenesis, Golgi dispersion assay eNeuro Medium 33067366
2024 KIF1A is required for synaptic vesicle enrichment at ribbon synapses in zebrafish hair cells; genetic loss of kif1aa causes dramatic reduction in synaptic vesicle populations at presynapses, reduced spontaneous vesicle release, impaired evoked postsynaptic calcium responses, and defective rheotaxis behavior. Zebrafish kif1aa mutants, electron microscopy, in vivo calcium imaging, electrophysiology, behavioral testing The Journal of physiology High 39505875

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 The neuron-specific kinesin superfamily protein KIF1A is a unique monomeric motor for anterograde axonal transport of synaptic vesicle precursors. Cell 552 7539720
1991 Kinesin-related gene unc-104 is required for axonal transport of synaptic vesicles in C. elegans. Cell 509 1710172
1999 A processive single-headed motor: kinesin superfamily protein KIF1A. Science (New York, N.Y.) 295 10024239
1998 Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice. The Journal of cell biology 262 9548721
1991 The C. elegans unc-104 gene encodes a putative kinesin heavy chain-like protein. Neuron 204 1846075
2007 Loss of alpha-tubulin polyglutamylation in ROSA22 mice is associated with abnormal targeting of KIF1A and modulated synaptic function. Proceedings of the National Academy of Sciences of the United States of America 190 17360631
2008 KIF1Bbeta- and KIF1A-mediated axonal transport of presynaptic regulator Rab3 occurs in a GTP-dependent manner through DENN/MADD. Nature cell biology 180 18849981
2016 KIF1A/UNC-104 Transports ATG-9 to Regulate Neurodevelopment and Autophagy at Synapses. Developmental cell 169 27396362
2011 KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2. American journal of human genetics 165 21820098
2003 Association of the kinesin motor KIF1A with the multimodular protein liprin-alpha. The Journal of biological chemistry 164 12522103
2000 15 A resolution model of the monomeric kinesin motor, KIF1A. Cell 148 10660047
2004 KIF1A alternately uses two loops to bind microtubules. Science (New York, N.Y.) 145 15286375
2002 A balance of KIF1A-like kinesin and dynein organizes early endosomes in the fungus Ustilago maydis. The EMBO journal 130 12065408
2003 Processivity of the single-headed kinesin KIF1A through biased binding to tubulin. Nature 128 12891363
2014 De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy. Human mutation 123 25265257
2011 KIF1A is the primary anterograde motor protein required for the axonal transport of dense-core vesicles in cultured hippocampal neurons. Neuroscience letters 120 21256924
2012 KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations. European journal of human genetics : EJHG 112 22258533
2012 Motor protein KIF1A is essential for hippocampal synaptogenesis and learning enhancement in an enriched environment. Neuron 111 22365548
2004 The lipid binding pleckstrin homology domain in UNC-104 kinesin is necessary for synaptic vesicle transport in Caenorhabditis elegans. Molecular biology of the cell 109 15155810
2006 High-resolution cryo-EM maps show the nucleotide binding pocket of KIF1A in open and closed conformations. The EMBO journal 105 16946706
2004 Dense core vesicle dynamics in Caenorhabditis elegans neurons and the role of kinesin UNC-104. Traffic (Copenhagen, Denmark) 94 15180830
2015 De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy. Annals of clinical and translational neurology 93 26125038
2013 Glycoproteins gE and gI are required for efficient KIF1A-dependent anterograde axonal transport of alphaherpesvirus particles in neurons. Journal of virology 86 23804637
2009 Synaptic scaffolding protein SYD-2 clusters and activates kinesin-3 UNC-104 in C. elegans. Proceedings of the National Academy of Sciences of the United States of America 82 19880746
2001 Direct visualization of the movement of the monomeric axonal transport motor UNC-104 along neuronal processes in living Caenorhabditis elegans. The Journal of neuroscience : the official journal of the Society for Neuroscience 81 11356862
2010 KIF1A and EDNRB are differentially methylated in primary HNSCC and salivary rinses. International journal of cancer 80 20162572
2010 The Caenorhabditis elegans Kinesin-3 motor UNC-104/KIF1A is degraded upon loss of specific binding to cargo. PLoS genetics 73 21079789
2003 Distinct conformations of the kinesin Unc104 neck regulate a monomer to dimer motor transition. The Journal of cell biology 71 14638858
2019 KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia. European journal of human genetics : EJHG 69 31488895
2016 The Molecular Motor KIF1A Transports the TrkA Neurotrophin Receptor and Is Essential for Sensory Neuron Survival and Function. Neuron 68 27263974
2021 Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder. HGG advances 62 33880452
2018 Regulation of KIF1A-Driven Dense Core Vesicle Transport: Ca2+/CaM Controls DCV Binding and Liprin-α/TANC2 Recruits DCVs to Postsynaptic Sites. Cell reports 60 30021165
2006 Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3. Brain : a journal of neurology 59 16434418
2015 Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis. Journal of neurology 55 26410750
2015 De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance. Journal of human genetics 54 26354034
2004 An intramolecular interaction between the FHA domain and a coiled coil negatively regulates the kinesin motor KIF1A. The EMBO journal 54 15014437
2005 Herpes simplex virus type 2 membrane protein UL56 associates with the kinesin motor protein KIF1A. The Journal of general virology 53 15722511
2017 Autosomal dominant transmission of complicated hereditary spastic paraplegia due to a dominant negative mutation of KIF1A, SPG30 gene. Scientific reports 50 28970574
2014 KIF1A mutation in a patient with progressive neurodegeneration. Journal of human genetics 50 25253658
2016 The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory. Current biology : CB 47 26877087
2015 Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia. European journal of human genetics : EJHG 44 25585697
1999 Reconstitution of membrane transport powered by a novel dimeric kinesin motor of the Unc104/KIF1A family purified from Dictyostelium. The Journal of cell biology 44 10545495
2016 KIF1A inhibition immortalizes brain stem cells but blocks BDNF-mediated neuronal migration. Nature neuroscience 43 26752160
2015 De novo dominant variants affecting the motor domain of KIF1A are a cause of PEHO syndrome. European journal of human genetics : EJHG 41 26486474
2013 Diabetes alters KIF1A and KIF5B motor proteins in the hippocampus. PloS one 40 23776493
2022 De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors. Proceedings of the National Academy of Sciences of the United States of America 36 35917346
2020 Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders. Journal of medical genetics 35 32737135
2019 Rett and Rett-like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene. Molecular genetics & genomic medicine 33 31512412
2017 A de novo dominant mutation in KIF1A associated with axonal neuropathy, spasticity and autism spectrum disorder. Journal of the peripheral nervous system : JPNS 29 28834584
2017 Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104. eLife 29 28925357
2014 Diabetes induces changes in KIF1A, KIF5B and dynein distribution in the rat retina: implications for axonal transport. Experimental eye research 29 25064602
2011 Tau/PTL-1 associates with kinesin-3 KIF1A/UNC-104 and affects the motor's motility characteristics in C. elegans neurons. Neurobiology of disease 29 21569846
1996 mRNA expression of KIF1A, KIF1B, KIF2, KIF3A, KIF3B, KIF4, KIF5, and cytoplasmic dynein during axonal regeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 8613797
2017 Hereditary spastic paraplegia caused by compound heterozygous mutations outside the motor domain of the KIF1A gene. European journal of neurology 27 28332297
2005 Monomeric and dimeric states exhibited by the kinesin-related motor protein KIF1A. The journal of peptide research : official journal of the American Peptide Society 27 15885113
2023 KIF1A-Associated Neurological Disorder: An Overview of a Rare Mutational Disease. Pharmaceuticals (Basel, Switzerland) 25 37259299
2004 Role of Unc104/KIF1-related motor proteins in mitochondrial transport in Neurospora crassa. Molecular biology of the cell 25 15483054
2020 A Rare KIF1A Missense Mutation Enhances Synaptic Function and Increases Seizure Activity. Frontiers in genetics 24 32174959
2020 Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A). Human mutation 24 32652677
2020 Deletion of the Pseudorabies Virus gE/gI-US9p complex disrupts kinesin KIF1A and KIF5C recruitment during egress, and alters the properties of microtubule-dependent transport in vitro. PLoS pathogens 23 32511265
2000 Kinesin subfamily UNC104 contains a FHA domain: boundaries and physicochemical characterization. FEBS letters 23 11119720
2021 Monoallelic KIF1A-related disorders: a multicenter cross sectional study and systematic literature review. Journal of neurology 21 34487232
2016 The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation. Frontiers in cellular neuroscience 21 27656128
1996 Characterization of a kinesin-related gene ATSV, within the tuberous sclerosis locus (TSC1) candidate region on chromosome 9Q34. Genomics 21 8661001
2019 A Novel de novo KIF1A Mutation in a Patient with Autism, Hyperactivity, Epilepsy, Sensory Disturbance, and Spastic Paraplegia. Internal medicine (Tokyo, Japan) 20 31813911
2016 Identification and Characterization of LIN-2(CASK) as a Regulator of Kinesin-3 UNC-104(KIF1A) Motility and Clustering in Neurons. Traffic (Copenhagen, Denmark) 20 27172328
2022 A neuropathy-associated kinesin KIF1A mutation hyper-stabilizes the motor-neck interaction during the ATPase cycle. The EMBO journal 19 35132656
2022 Association of variants in the KIF1A gene with amyotrophic lateral sclerosis. Translational neurodegeneration 19 36284339
2018 PEHO syndrome: KIF1A mutation and decreased activity of mitochondrial respiratory chain complex. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 19 30385166
2016 KIF1A mediates axonal transport of BACE1 and identification of independently moving cargoes in living SCG neurons. Traffic (Copenhagen, Denmark) 19 27484852
2018 The novel de novo mutation of KIF1A gene as the cause for Spastic paraplegia 30 in a Japanese case. eNeurologicalSci 18 30582020
2013 Cooperative force generation of KIF1A Brownian motors. Physical review letters 18 23931411
2017 The KIF1A homolog Unc-104 is important for spontaneous release, postsynaptic density maturation and perisynaptic scaffold organization. Scientific reports 17 28344334
2010 Sub-cellular distribution of UNC-104(KIF1A) upon binding to adaptors as UNC-16(JIP3), DNC-1(DCTN1/Glued) and SYD-2(Liprin-α) in C. elegans neurons. Neuroscience 16 21195138
2021 The Novel KIF1A Missense Variant (R169T) Strongly Reduces Microtubule Stimulated ATPase Activity and Is Associated With NESCAV Syndrome. Frontiers in neuroscience 15 34121983
2024 Cryo-EM unveils kinesin KIF1A's processivity mechanism and the impact of its pathogenic variant P305L. Nature communications 14 38956021
2020 Pseudorabies Virus Infection Accelerates Degradation of the Kinesin-3 Motor KIF1A. Journal of virology 14 32075931
2018 Neuroprotection Exerted by Netrin-1 and Kinesin Motor KIF1A in Secondary Brain Injury following Experimental Intracerebral Hemorrhage in Rats. Frontiers in cellular neuroscience 14 29375318
2017 Multigeneration family with dominant SPG30 hereditary spastic paraplegia. Annals of clinical and translational neurology 14 29159194
2024 KIF1A promotes neuroendocrine differentiation in prostate cancer by regulating the OGT-mediated O-GlcNAcylation. Cell death & disease 13 39505875
2021 Motor domain-mediated autoinhibition dictates axonal transport by the kinesin UNC-104/KIF1A. PLoS genetics 12 34843479
2019 Mobility Characteristics of Children with Spastic Paraplegia Due to a Mutation in the KIF1A Gene. Neuropediatrics 12 31805580
2023 Huntingtin recruits KIF1A to transport synaptic vesicle precursors along the mouse axon to support synaptic transmission and motor skill learning. eLife 11 37431882
2019 Long-term follow-up until early adulthood in autosomal dominant, complex SPG30 with a novel KIF1A variant: a case report. Italian journal of pediatrics 10 31796088
2005 Stalk region of kinesin-related protein Unc104 has moderate ability to form coiled-coil dimer. Biochemical and biophysical research communications 10 16214110
2022 Positive charge in the K-loop of the kinesin-3 motor KIF1A regulates superprocessivity by enhancing microtubule affinity in the one-head-bound state. The Journal of biological chemistry 9 36549649
2020 Overexpression of Kif1A in the Developing Drosophila Heart Causes Valvar and Contractility Defects: Implications for Human Congenital Heart Disease. Journal of cardiovascular development and disease 9 32498427
2020 GSK3β Impairs KIF1A Transport in a Cellular Model of Alzheimer's Disease but Does Not Regulate Motor Motility at S402. eNeuro 9 33067366
2018 Mechanochemical Model of the Power Stroke of the Single-Headed Motor Protein KIF1A. The journal of physical chemistry. B 9 30179486
2008 Interaction forces and interface properties of KIF1A kinesin-alphabeta tubulin complex assessed by molecular dynamics. Journal of biomechanics 9 18829030
2021 A Novel Synergistic Association of Variants in PTRH2 and KIF1A Relates to a Syndrome of Hereditary Axonopathy, Outer Hair Cell Dysfunction, Intellectual Disability, Pancreatic Lipomatosis, Diabetes, Cerebellar Atrophy, and Vertebral Artery Hypoplasia. Cureus 8 33717719
2020 KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families. BMC neurology 8 32746806
2024 Comparative analysis of two Caenorhabditis elegans kinesins KLP-6 and UNC-104 reveals a common and distinct activation mechanism in kinesin-3. eLife 7 38206323
2024 Kif1a and intact microtubules maintain synaptic-vesicle populations at ribbon synapses in zebrafish hair cells. The Journal of physiology 7 39373584
2023 Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency. Frontiers in molecular neuroscience 7 37063368
2020 Generation of a human induced pluripotent stem cell line (SDUBMSi001-A) from a hereditary spastic paraplegia patient carrying kif1a c.773C>T missense mutation. Stem cell research 7 32045731
2020 PTP-3 phosphatase promotes intramolecular folding of SYD-2 to inactivate kinesin-3 UNC-104 in neurons. Molecular biology of the cell 7 33147118
2019 Physical parameters describing neuronal cargo transport by kinesin UNC-104. Biophysical reviews 7 31115864
2021 Biased Brownian Motion of KIF1A and the Role of Tubulin's C-Terminal Tail Studied by Molecular Dynamics Simulation. International journal of molecular sciences 6 33557020
2021 KLF5 promotes KIF1A expression through transcriptional repression of microRNA-338 in the development of pediatric neuroblastoma. Journal of pediatric surgery 5 35033353