Affinage

KIF1A

Kinesin-like protein KIF1A · UniProt Q12756

Length
1690 aa
Mass
191.1 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KIF1A is a neuron-specific kinesin-3 family motor that drives fast anterograde axonal transport of synaptic vesicle precursors and related cargoes along microtubules (PMID:7539720, PMID:1710172, PMID:9548721). Its loss in worms, mice, and zebrafish depletes synaptic vesicles at terminals while clear vesicles accumulate in cell bodies, causing neuronal degeneration and synaptic dysfunction, establishing it as the essential motor for this cargo class (PMID:1710172, PMID:9548721, PMID:39373584). KIF1A is unusual among kinesins in that its isolated motor domain moves processively as a monomer via biased Brownian diffusion: a positively charged K-loop (loop 12) forms an extra electrostatic microtubule-binding contact with the C-terminal tails of tubulin that stabilizes the motor in the one-head-bound state and confers superprocessivity (PMID:10024239, PMID:10660047, PMID:36549649, PMID:38956021), while nucleotide-dependent rearrangements of loops L11/L12 and the neck linker couple ATP hydrolysis to single 8 nm plus-end-directed steps (PMID:15286375, PMID:12891363, PMID:16946706). Cargo binding occurs through a PH domain that recognizes PI(4,5)P2, an interaction required for transport in vivo, and through adaptors that couple the motor to specific cargo: DENN/MADD links it to GTP-Rab3 vesicles, GTP-Rab3 also bridges TrkA vesicles, and Ca2+/calmodulin promotes dense-core vesicle loading (PMID:15155810, PMID:18849981, PMID:27263974, PMID:30021165). Motor activity is held off by intramolecular autoinhibition—an FHA–CC2 interaction and a CC1/motor-domain interface—whose release triggers CC2-dependent dimerization and processive movement, and is positively regulated by the scaffold adaptors SYD-2/liprin-α and LIN-2/CASK with upstream control by PTP-3 phosphatase (PMID:15014437, PMID:34843479, PMID:38206323, PMID:19880746, PMID:27172328, PMID:33147118). Polyglutamylated α-tubulin acts as a 'traffic sign' targeting KIF1A to neurites, and the motor is an intrinsically unstable protein degraded by the ubiquitin–proteasome pathway at synapses, with cargo binding protecting it from turnover (PMID:17360631, PMID:21079789). Through these activities KIF1A delivers dense-core vesicles, TrkA, BACE1, ATG-9, and CGRP and supports BDNF-dependent synaptogenesis, neuronal migration, and synaptic plasticity (PMID:21256924, PMID:27263974, PMID:27484852, PMID:27396362, PMID:41029476, PMID:22365548, PMID:26752160). Pathogenic de novo and inherited mutations produce graded molecular defects—reduced microtubule binding, reduced velocity/processivity, or rigor-class strong binding—that act dominantly through impaired heterodimeric motors and underlie the spectrum of KIF1A-associated neurological disorders (KAND), with rigor-class variants causing the most severe disease (PMID:33880452, PMID:35917346, PMID:35132656).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1991 High

    Established the in vivo requirement for a dedicated anterograde motor by showing the KIF1A ortholog UNC-104 is needed to deliver synaptic vesicles to axons.

    Evidence Genetic null mutants and EM of synaptic vesicle distribution in C. elegans

    PMID:1710172

    Open questions at the time
    • Did not identify the molecular cargo adaptor
    • Did not define motor mechanism or processivity
  2. 1995 High

    Identified KIF1A as a neuron-specific monomeric motor and defined its cargo specificity, answering which vesicle class it carries.

    Evidence Cloning, organelle fractionation, co-IP with synaptotagmin/synaptophysin/Rab3A, and motility assays

    PMID:7539720

    Open questions at the time
    • How a monomer achieves processivity was unexplained
    • Cargo-binding domain not yet mapped
  3. 1998 High

    Demonstrated KIF1A is the essential in vivo transporter of synaptic vesicle precursors in mammals and that its loss causes neurodegeneration.

    Evidence Kif1a knockout mice, EM, immunohistochemistry, neuronal survival assays

    PMID:9548721

    Open questions at the time
    • Did not address motor regulation or human disease relevance
  4. 2004 High

    Resolved how a single-headed motor can move processively, identifying biased Brownian diffusion and the K-loop electrostatic tubulin contact as the mechanism.

    Evidence Single-molecule motility, cryo-EM, crystallography with nucleotide analogs, optical trapping, and K-loop mutagenesis (1999–2006)

    PMID:10024239 PMID:10660047 PMID:12891363 PMID:15286375 PMID:16946706

    Open questions at the time
    • Monomer-based mechanism later refined by dimeric models
    • Relationship to cargo-bound dimeric state not yet defined
  5. 2004 High

    Defined the cargo-binding mechanism by showing the PH domain binds PI(4,5)P2 and that this lipid interaction is required for transport in vivo.

    Evidence In vitro lipid binding plus C. elegans PH-domain mutant rescue and live imaging

    PMID:15155810

    Open questions at the time
    • Did not identify protein adaptors that select specific cargoes
  6. 2004 Medium

    Established that KIF1A is autoinhibited, identifying the FHA–CC2 intramolecular interaction as a negative regulator of motor activity.

    Evidence Point mutagenesis, live imaging in neurons, MT binding and co-IP (with FHA domain folding characterization in 2005)

    PMID:11119720 PMID:15014437

    Open questions at the time
    • FHA phosphorylation partner not identified
    • Single-lab mutagenesis without reconstitution at the time
  7. 2009 High

    Identified the adaptor logic of cargo coupling and activation: liprin-α/SYD-2, DENN/MADD–Rab3, LIN-2/CASK, and CaM link KIF1A to distinct cargoes and regulate its directional movement and localization.

    Evidence Co-IP, Y2H, BiFC, FRET/FLIM in living C. elegans, interactome proteomics, and live cargo imaging (2003–2018)

    PMID:12522103 PMID:18849981 PMID:19880746 PMID:21195138 PMID:27172328 PMID:30021165

    Open questions at the time
    • Quantitative hierarchy among adaptors incompletely resolved
    • Some interactions rest on single-lab co-IP/BiFC
  8. 2007 High

    Showed microtubule post-translational modification controls KIF1A targeting, with polyglutamylated α-tubulin acting as a 'traffic sign' directing the motor to neurites.

    Evidence ROSA22 polyglutamylase-deficient mice, MT pull-down, immunofluorescence, electrophysiology

    PMID:17360631

    Open questions at the time
    • How polyglutamylation is spatially patterned in axons not addressed
  9. 2010 High

    Established that KIF1A levels are controlled by proteasomal degradation at synapses and that cargo binding stabilizes the motor.

    Evidence C. elegans alleles, PH-domain mutants, proteasome inhibition, in vivo imaging

    PMID:21079789

    Open questions at the time
    • Ubiquitin ligase responsible not identified
    • Mammalian conservation of this turnover incompletely defined
  10. 2016 High

    Broadened the KIF1A cargo and process repertoire, showing it transports dense-core vesicles, TrkA, BACE1, and ATG-9 and supports neurogenesis, neuronal migration, and BDNF-dependent synaptogenesis.

    Evidence Two-color live imaging, shRNA/siRNA knockdown, dominant-negative expression, Kif1a+/- mice, DRG physiology, genetic screens (2011–2016)

    PMID:21256924 PMID:22365548 PMID:26752160 PMID:27263974 PMID:27396362 PMID:27484852

    Open questions at the time
    • Cargo selectivity among these vesicle classes not fully resolved
    • Several cargo links rest on single-lab knockdown data
  11. 2021 High

    Resolved the autoinhibition–activation switch, showing release of the CC1/motor-domain and FHA-CC2 interfaces triggers CC2-dependent dimerization and processive movement independent of lipid microdomain enrichment.

    Evidence C. elegans gain-of-function genetics, live imaging, in vitro single-molecule motility and dimerization assays with domain mutants (2021–2024)

    PMID:34843479 PMID:38206323

    Open questions at the time
    • Physiological trigger that relieves autoinhibition on cargo not fully defined
  12. 2024 High

    Provided near-atomic structural basis for KIF1A superprocessivity, showing the K-loop contacts both α- and β-tubulin C-terminal tails and that head–head coordination governs processivity.

    Evidence Cryo-EM (2.7–3.5 Å) of dimeric MT-bound KIF1A in one- and two-heads-bound states with K-loop charge and swap mutants and TIRF (2022–2024)

    PMID:36549649 PMID:38956021

    Open questions at the time
    • How adaptor binding feeds into head coordination not structurally resolved
  13. 2022 High

    Linked specific molecular defects to disease severity, defining reduced-binding, reduced-velocity, and rigor-binding mutation classes and a dominant-negative mechanism via mutant/WT heterodimers underlying KAND.

    Evidence Recombinant variant TIRF and MT-binding assays, neurite-tip accumulation, crystallography (E239K, P305L), CRISPR knock-in worms, suppressor screens, clinical cohort scoring (2021–2022)

    PMID:33880452 PMID:35132656 PMID:35917346

    Open questions at the time
    • Mechanistic basis for variability within a mutation class incompletely defined
  14. 2024 Medium

    Extended KIF1A regulation and roles beyond classical transport, implicating it in HTT-phosphorylation-dependent SVP transport, GSK3β-regulated transport in AD models, CREB-CGRP feedback in migraine, ribbon synapse maintenance, and OGT-driven tumor differentiation.

    Evidence Mouse genetic models, kinase assays, ChIP/luciferase, co-IP, zebrafish mutants, tumor models (2020–2025)

    PMID:33067366 PMID:37431882 PMID:39373584 PMID:40000000 PMID:41029476

    Open questions at the time
    • The functional GSK3β phosphosite on KIF1A remains unidentified
    • Non-neuronal OGT/tumor role rests on single-lab data

Open questions

Synthesis pass · forward-looking unresolved questions
  • How adaptor binding, lipid signaling, and post-translational modification are integrated to switch individual KIF1A motors between autoinhibited, processive, and degradation-targeted states in vivo remains unresolved.
  • No unified model coupling cargo loading to autoinhibition release and head coordination
  • Kinase/phosphatase regulators of the human motor incompletely mapped
  • Ubiquitin ligase controlling synaptic turnover unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003774 cytoskeletal motor activity 5 GO:0008092 cytoskeletal protein binding 3 GO:0038024 cargo receptor activity 3 GO:0140657 ATP-dependent activity 3 GO:0008289 lipid binding 2
Localization
GO:0031410 cytoplasmic vesicle 3 GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1643685 Disease 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9609507 Protein localization 3 R-HSA-9612973 Autophagy 1
Partners
CASK (LIN-2)HTTMADDOGTPLEKHA-PIP2RAB3ASYD-2/PPFIA (LIPRIN-ALPHA)TANC2

Evidence

Reading pass · 44 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 acts as an anterograde axonal transporter of synaptic vesicle precursors. It was found associated with organelles containing synaptotagmin, synaptophysin, and Rab3A, but not SV2, syntaxin 1A, or SNAP-25, demonstrating cargo specificity and sorting into distinct transport organelle classes. Cloning, biochemical isolation of axonal membrane organelles, immunoprecipitation, organelle fractionation, motility assays (1.2 µm/s anterograde velocity) Cell High 7539720
1991 C. elegans UNC-104 (KIF1A ortholog) is required for anterograde axonal transport of synaptic vesicles; null mutants have few axonal synaptic vesicles but accumulate them in cell bodies, establishing UNC-104/KIF1A as a neuron-specific anterograde motor for synaptic vesicles. Genetic loss-of-function (null mutants), electron microscopy of synaptic vesicle distribution, behavioral phenotype analysis Cell High 1710172
1998 KIF1A gene disruption (knockout) in mice causes specific decrease in synaptic vesicle precursor transport, dramatic reduction in synaptic vesicle density at terminals, accumulation of clear small vesicles in cell bodies, and neuronal degeneration/death, demonstrating KIF1A is the essential transporter of synaptic vesicle precursors in vivo. Gene knockout (KIF1A-/- mice), electron microscopy, immunohistochemistry, neuronal culture survival assays The Journal of cell biology High 9548721
1999 A monomeric motor-domain construct of KIF1A moves processively along microtubules for more than 1 µm before detaching, via a biased Brownian-movement mechanism rather than a hand-over-hand walking model requiring two heads. Single-molecule motility assay, optical microscopy of motor-domain construct (C351) Science High 10024239
2000 KIF1A processivity as a monomer depends on a positively charged loop ('K-loop') that forms an extra microtubule-binding domain specific to KIF1A and binds the C-terminus of tubulin. Cryo-EM at 15 Å resolution docked with atomic models revealed the K-loop interaction; mutant analysis confirmed its importance for processivity. Cryo-electron microscopy (15 Å resolution), mutant analysis, site-specific cross-linking Cell High 10660047
2004 Crystal structures of monomeric KIF1A with transition-state analogs (AMP-PNP, ADP-vanadate, ADP-AlFx) reveal that KIF1A alternately uses loop L11 (extended in AMP-PNP state) and loop L12 (extended in ADP state) to bind microtubules during the ATP hydrolysis cycle, and ADP-vanadate shows an intermediate conformation where both loops disengage from the microtubule. X-ray crystallography with multiple nucleotide analogs Science High 15286375
2003 Single ATP hydrolysis triggers a single 8 nm stepping movement of monomeric KIF1A; the motor moves toward the microtubule plus-end by ~3 nm on binding, attributed to preferential binding to tubulin on the plus-end side (biased Brownian diffusion). Optical trapping/single-molecule force measurement, step-size analysis Nature High 12891363
2006 Cryo-EM structures of the KIF1A–microtubule complex at ~10 Å resolution reveal nucleotide-dependent conformational changes: the nucleotide-binding pocket is closed in the AMP-PNP state and open in the ADP state, differing from crystal structures; mechanical pathway runs from nucleotide to neck linker via motor core rotation. Cryo-electron microscopy of KIF1A-MT complex in two nucleotide states (~10 Å resolution) The EMBO journal High 16946706
2003 KIF1A interacts with the scaffolding protein liprin-α; the two colocalize in neurons, co-accumulate in ligated sciatic nerves, and co-immunoprecipitate along with liprin-α-associated proteins including AMPA receptors, GRIP/ABP, RIM, GIT1, and βPIX, suggesting liprin-α functions as a KIF1A receptor linking it to cargo. Co-immunoprecipitation, sciatic nerve ligation/co-accumulation assay, colocalization by immunofluorescence The Journal of biological chemistry Medium 12522103
2004 The pleckstrin homology (PH) domain of UNC-104/KIF1A binds specifically to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2); point mutations in the PH domain that abolish PI(4,5)P2 binding in vitro also abolish synaptic vesicle transport in living C. elegans, reducing both velocity and processivity of motor movement. In vitro lipid-binding assay, C. elegans rescue experiments with PH domain mutants, live imaging of UNC-104::GFP Molecular biology of the cell High 15155810
2004 An intramolecular interaction between the FHA domain and the CC2 coiled-coil domain of KIF1A negatively regulates motor activity; disrupting this interaction via point mutations in FHA or CC2, or mutations causing rigidity in the hinge, causes KIF1A to accumulate in neuronal periphery and enhances microtubule binding and self-multimerization. Point mutagenesis, live-cell imaging in cultured neurons, microtubule binding assay, co-immunoprecipitation The EMBO journal Medium 15014437
2003 UNC-104 (KIF1A) can exist in two conformations as observed by cryo-EM: a monomeric state with intramolecular parallel coiled-coil neck helices (repressed), and a dimeric state with intermolecular neck coiled-coil (active). The flexible hinge between neck helices is required for the folded monomer conformation; its deletion causes severe uncoordinated phenotype in C. elegans without altering in vitro velocity. Cryo-electron microscopy, domain deletion mutagenesis, in vitro motility assay, C. elegans transgenic rescue The Journal of cell biology High 14638858
2007 Polyglutamylation of alpha-tubulin is required for proper KIF1A targeting to neurites; ROSA22 mice lacking functional alpha-tubulin polyglutamylase (PGs1) show decreased KIF1A binding affinity to microtubules, reduced KIF1A in neurites, and decreased synaptic vesicle density at hippocampal synapses, identifying polyglutamylated alpha-tubulin as a 'traffic sign' for KIF1A. Mouse knockout model (ROSA22), microtubule pull-down assay, immunofluorescence in vitro and in vivo, 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 and acts as a Rab3 effector by preferentially binding GTP-Rab3. Sequential genetic epistasis in C. elegans showed KIF1A/KIF1Bβ are essential for DENN/MADD transport, DENN/MADD is essential for Rab3 transport, and GTP-Rab3 is more effectively transported than GDP-Rab3. Co-immunoprecipitation, yeast two-hybrid, genetic epistasis in C. elegans, live imaging Nature cell biology High 18849981
2009 The synaptic scaffolding protein SYD-2 (liprin-α) clusters UNC-104/KIF1A in axons and enhances net anterograde movement and velocity; loss of SYD-2 binding reduces anterograde transport and switches motor toward retrograde characteristics. FRET/FLIM confirmed direct SYD-2–UNC-104 binding in living C. elegans; FRAP showed clusters are dynamic. Yeast two-hybrid, pull-down, FRET/FLIM imaging in living C. elegans, FRAP, motor motility analysis Proceedings of the National Academy of Sciences of the United States of America High 19880746
2010 UNC-104/KIF1A is degraded via the ubiquitin-proteasome pathway at synaptic regions and is not retrogradely transported back to the cell body. Loss of specific PI(4,5)P2 binding through PH domain mutations reduces motor levels in vivo, showing that cargo binding protects KIF1A from ubiquitin-mediated degradation. Genetic allele analysis (C. elegans), intragenic suppressor isolation, in vitro PI(4,5)P2 binding assay, in vivo imaging, ubiquitin pathway inhibition PLoS genetics High 21079789
2011 KIF1A transports dense-core vesicles (DCVs) as the primary anterograde motor in mammalian hippocampal neurons; two-color live imaging showed KIF1A-GFP co-migrates with DCV markers (chromogranin A-RFP, BDNF-RFP), and shRNA knockdown of KIF1A significantly reduced DCV flux without affecting mitochondria or transferrin receptor transport. Two-color live-cell imaging, RNAi knockdown (shRNA), organelle flux quantification Neuroscience letters Medium 21256924
2012 KIF1A is required for BDNF-induced hippocampal synaptogenesis and learning enhancement. BDNF upregulates KIF1A levels and KIF1A-mediated cargo transport in hippocampal neurons; Kif1a+/- mice fail to show enrichment-induced synaptogenesis and learning enhancement, and KIF1A overexpression promotes presynaptic bouton formation. Mouse haploinsufficiency model, BDNF treatment in vitro, KIF1A overexpression, behavioral testing (learning), synapse morphology analysis Neuron High 22365548
2016 KIF1A transports TrkA-containing vesicles via GTP-Rab3 as adaptor; Kif1a+/- mice show progressive loss of TrkA+ sensory neurons, disrupted axonal TrkA transport, hyposensitivity to NGF, and weaker capsaicin/TRPV1 responses. PI3K signaling rescues these phenotypes and increases Kif1a mRNA. Mouse haploinsufficiency model (Kif1a+/-), live imaging, immunoprecipitation, dorsal root ganglion physiology, pharmacological rescue Neuron High 27263974
2016 KIF1A/UNC-104 transports the integral membrane autophagy protein ATG-9 to synapses in C. elegans neurons; this transport is required for spatially regulated autophagosome formation near synapses, which in turn is necessary for presynaptic assembly and axon outgrowth. Unbiased genetic screens, systematic genetic analysis, live fluorescence imaging of ATG-9 and autophagosomes in C. elegans Developmental cell High 27396362
2016 KIF1A inhibition in radial glial progenitors (RGPs) blocks basal interkinetic nuclear migration (INM) and severely reduces neurogenic divisions; KIF1A also independently regulates postmitotic neuronal migration at the multipolar stage through a BDNF-dependent mechanism. RNAi knockdown and dominant-negative KIF1A expression in rat RGPs/neurons in vivo, live imaging, BDNF rescue experiments Nature neuroscience Medium 26752160
2018 Ca2+/calmodulin (CaM) enhances KIF1A binding to dense-core vesicles (DCVs) and increases vesicle 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 the interaction with KIF1A. KIF1A interactome identification (proteomics), live imaging, co-immunoprecipitation, mutagenesis Cell reports Medium 30021165
2005 The FHA domain of UNC-104/KIF1A is an autonomously folding domain (confirmed by limited proteolysis, mass spectrometry, physicochemical analysis) that contains conserved key residues predicted to recognize phosphorylated residues, suggesting it mediates phosphorylation-regulated protein-protein interactions. Limited proteolysis, mass spectrometry, circular dichroism, sequence analysis FEBS letters Medium 11119720
2001 UNC-104 (KIF1A ortholog) moves in both directions along neuronal processes in living C. elegans at an average velocity of ~1.02 µm/s; most particles move unidirectionally but 10% reverse direction. Direct visualization establishes that UNC-104 is a bidirectionally moving motor in vivo. Live confocal fluorescence microscopy of UNC-104::GFP transgenic C. elegans, kymograph analysis The Journal of neuroscience Medium 11356862
2013 Viral glycoproteins gE/gI of pseudorabies virus (PRV) are required for efficient KIF1A-mediated anterograde axonal transport by mediating the interaction between the viral Us9 protein and KIF1A; in the absence of gE/gI, KIF1A does not efficiently co-purify with Us9. Viral mutant analysis, co-purification/co-immunoprecipitation, affinity purification with mass spectrometry (gE-GFP), live imaging of viral particles in neurons Journal of virology Medium 23804637
2011 Tau/PTL-1 physically interacts with UNC-104/KIF1A in C. elegans neurons (confirmed by BiFC and co-IP), and loss of PTL-1 specifically affects retrograde moving characteristics of UNC-104 and its synaptobrevin-1 cargo, without affecting anterograde displacement. Bimolecular fluorescence complementation (BiFC), co-immunoprecipitation, spinning disk time-lapse imaging in C. elegans Neurobiology of disease Medium 21569846
2022 KIF1A charge-inverting mutation E239K (identified in Charcot-Marie-Tooth disease and other neuropathies) hyper-stabilizes the motor-neck interaction during the ATPase cycle by excess positive charge on β7 strand electrostatically interacting with the negatively charged neck, reducing ATPase activity and microtubule gliding velocity; X-ray crystallography and quantitative mass spectrometry confirmed the mechanism. X-ray crystallography, mass spectrometry (quantitative), ATPase assay, microtubule gliding assay, expression in Kif1a+/- neurons The EMBO journal High 35132656
2021 De novo KAND mutations dominantly inhibit KIF1A motor activity by impairing heterodimeric motors composed of wild-type and mutant KIF1A; CRISPR-Cas9 C. elegans models showed both heterozygotes and homozygotes have reduced axonal transport, and a suppressor screen identified a mutation that recovers mutant KIF1A motor activity. CRISPR-Cas9 knock-in (C. elegans), in vitro heterodimer motility assay, suppressor screen Proceedings of the National Academy of Sciences of the United States of America High 35917346
2021 The CC1/motor domain interface mediates autoinhibition of UNC-104/KIF1A; gain-of-function mutations in either the motor domain or CC1 domain disrupt the autoinhibitory interface, causing hyperactive axonal transport, constitutive axonal localization, and abnormal synaptic vesicle accumulation in C. elegans. C. elegans genetic screens, engineered point mutations, live imaging of motor and synaptic vesicle distribution PLoS genetics High 34843479
2022 The positively charged K-loop (loop 12) of KIF1A enhances superprocessivity by stabilizing microtubule binding in the one-head-bound (ADP) state; replacing the K-loop with that of kinesin-1 decreases run length 6-fold, and KIF1A processivity is linearly dependent on the charge of loop-12. In vitro single-molecule TIRF microscopy, microtubule pelleting assay, K-loop swap and charge mutants The Journal of biological chemistry High 36549649
2024 Cryo-EM at 2.7–3.5 Å resolution of dimeric microtubule-bound KIF1A reveals one- and two-heads-bound configurations; K-loop (loop 12) forms electrostatic interactions with C-terminal tails of both α- and β-tubulin. The pathogenic P305L mutation alters K-loop conformation and impairs strong microtubule binding without disrupting these electrostatic contacts. Head-head coordination and K-loop are identified as major determinants of KIF1A superprocessivity. Cryo-electron microscopy (2.7-3.5 Å resolution), structure-function analysis of P305L mutant, TIRF single-molecule assay Nature communications High 38956021
2016 LIN-2 (CASK) binds to the stalk domain of UNC-104/KIF1A (overlapping with the SYD-2/liprin-α binding site) via its L27 and GUK domains; loss of LIN-2 in C. elegans neurons drastically reduces UNC-104 motility and synaptobrevin-1 cargo transport, causes increased motor clustering along axons, and LIN-2 more prominently elevates motor run lengths than SYD-2. Yeast two-hybrid, co-immunoprecipitation, BiFC, live imaging in C. elegans neurons Traffic Medium 27172328
2010 Binding of UNC-104 to adaptors UNC-16 (JIP3), DNC-1 (DCTN1), or SYD-2 (liprin-α) results in distinct sub-cellular distributions: UNC-16 binding localizes motor to soma, DNC-1 binding to axonal termini, and SYD-2 binding along axons; demonstrated by BiFC in living C. elegans. Bimolecular fluorescence complementation (BiFC) in living C. elegans neurons Neuroscience Medium 21195138
2020 PTP-3 (LAR phosphatase) promotes intramolecular folding of SYD-2 (liprin-α), keeping it in a closed/inactive conformation; in ptp-3 knockouts, SYD-2 adopts an open conformation, increasing UNC-104–SYD-2 interaction, motor clustering, velocity, and cargo transport speeds, establishing PTP-3 as upstream regulator of SYD-2-mediated UNC-104/KIF1A activation. Co-immunoprecipitation, intramolecular FRET in living C. elegans, BiFC, live imaging of motor and cargo transport Molecular biology of the cell Medium 33147118
2023 Phosphorylation of huntingtin (HTT) increases axonal transport of synaptic vesicle precursors (SVPs) and synaptic glutamate release by recruiting KIF1A; silencing KIF1A in constitutively phospho-HTT mice restored SVP transport and motor skill learning to wild-type levels, demonstrating HTT-KIF1A interaction as a regulator of SVP transport and synaptic plasticity. Mouse genetic models (constitutive HTT phosphorylation), KIF1A knockdown, microfluidic devices, live imaging, electrophysiology, behavioral assays eLife High 37431882
2016 KIF1A mediates axonal transport of BACE1 (beta-secretase 1); two-color live imaging showed BACE1-mCherry co-migrates with KIF1A-GFP, and KIF1A siRNA knockdown or dominant-negative KIF1A (T312M) impaired BACE1 transport. Two-color live imaging, siRNA knockdown, dominant-negative expression in SCG neurons Traffic Medium 27484852
2020 PRV infection induces proteasomal degradation of KIF1A specifically in axons; KIF1A is an intrinsically unstable protein prone to proteasomal degradation; the PRV US9/gE/gI complex facilitates this accelerated proteasomal degradation, and this occurs in the axonal compartment. PRV mutant virus infections, compartmented neuronal cultures, proteasome inhibitors, immunoblotting Journal of virology Medium 32075931
2024 Releasing UNC-104/KIF1A autoinhibition is sufficient to trigger dimerization at nanomolar concentrations and processive movement on microtubules, without requiring enrichment in phospholipid microdomains on cargo vesicles. The coiled-coil 2 (CC2) domain is required for efficient dimerization and processive movement. In vitro single-molecule motility assay, biochemical dimerization analysis, domain deletion mutants in C. elegans and in vitro eLife High 38206323
2021 KIF1A variants causing reduced MT binding (milder phenotype) versus rigor MT binding (most severe phenotype) produce distinct classes of molecular dysfunction; all modeled KAND variants result in defects in protein transport (neurite tip accumulation assay), and rigor-class mutations are consistently associated with the most severe clinical phenotype. Recombinant protein production, TIRF single-molecule microscopy, in vitro MT binding assay, neurite tip accumulation assay, clinical severity scoring in 117 individuals HGG advances High 33880452
2020 GSK3β impairs KIF1A-mediated transport in an Alzheimer's disease model (amyloid-β oligomers), and pharmacological inhibition of GSK3β prevents these transport defects. GSK3β phosphorylates KIF1A at S402 in vitro, but a phosphomimic at S402 does not alter KIF1A motility, indicating GSK3β regulates KIF1A transport through a site other than S402. Live cell imaging (hippocampal neurons), GSK3β inhibitors, mass spectrometry on KIF1A from transgenic AD mouse brain, in vitro kinase assay, Golgi dispersion assay eNeuro Medium 33067366
2024 KIF1A binds OGT (O-linked N-acetylglucosamine transferase) and regulates its protein expression and activity; KIF1A overexpression induces nuclear accumulation of OGT, promoting O-GlcNAcylation of β-catenin and OCT4, thereby driving neuroendocrine differentiation in prostate cancer cells. Co-immunoprecipitation (KIF1A-OGT), OGT activity assays, KIF1A knockdown/overexpression, in vitro and in vivo tumor models Cell death & disease Medium 39505875
2025 CREB directly binds the Kif1a promoter and transcriptionally upregulates KIF1A; KIF1A physically associates with CGRP and transports it in synaptic vesicles; KIF1A knockdown reduces synaptosomal CGRP, establishing a CREB-KIF1A-CGRP positive feedback loop driving central sensitization in chronic migraine. Chromatin immunoprecipitation, dual-luciferase reporter assay, co-immunoprecipitation, synaptosome CGRP analysis after Kif1a knockdown, behavioral assays The journal of headache and pain Medium 41029476
2024 Kif1a is essential for maintaining synaptic vesicle populations at ribbon synapses in zebrafish hair cells; Kif1aa mutants show dramatic reductions in spontaneous vesicle release, impaired evoked postsynaptic calcium responses, and behavioral deficits (impaired rheotaxis), demonstrating KIF1A-mediated microtubule transport is critical for ribbon synapse function. Zebrafish kif1aa mutant genetics, electron microscopy, in vivo calcium imaging, electrophysiology, behavioral assay (rheotaxis) The Journal of physiology High 39373584
2022 ALS-associated KIF1A variants in the C-terminal cargo-binding region preferentially enhance binding to synaptic vesicle precursors (SVPs) containing RAB3A, VAMP2, and synaptophysin, and expression of these mutants in cultured mouse cortical neurons leads to enhanced colocalization of RAB3A or VAMP2 with the KIF1A motor. Whole-exome sequencing analysis, co-localization in cultured mouse neurons, cargo-binding assay Translational neurodegeneration Medium 36284339

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 556 7539720
1991 Kinesin-related gene unc-104 is required for axonal transport of synaptic vesicles in C. elegans. Cell 512 1710172
1999 A processive single-headed motor: kinesin superfamily protein KIF1A. Science (New York, N.Y.) 296 10024239
1998 Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice. The Journal of cell biology 266 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 191 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 170 27396362
2011 KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2. American journal of human genetics 166 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 149 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 121 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 113 22258533
2012 Motor protein KIF1A is essential for hippocampal synaptogenesis and learning enhancement in an enriched environment. Neuron 112 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
2015 De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy. Annals of clinical and translational neurology 95 26125038
2004 Dense core vesicle dynamics in Caenorhabditis elegans neurons and the role of kinesin UNC-104. Traffic (Copenhagen, Denmark) 95 15180830
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 83 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 74 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 63 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 61 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 48 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 37 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 34 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
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 28 15885113
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
2023 KIF1A-Associated Neurological Disorder: An Overview of a Rare Mutational Disease. Pharmaceuticals (Basel, Switzerland) 26 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
2022 Association of variants in the KIF1A gene with amyotrophic lateral sclerosis. Translational neurodegeneration 20 36284339
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
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
2017 The KIF1A homolog Unc-104 is important for spontaneous release, postsynaptic density maturation and perisynaptic scaffold organization. Scientific reports 18 28344334
2013 Cooperative force generation of KIF1A Brownian motors. Physical review letters 18 23931411
2021 The Novel KIF1A Missense Variant (R169T) Strongly Reduces Microtubule Stimulated ATPase Activity and Is Associated With NESCAV Syndrome. Frontiers in neuroscience 16 34121983
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
2024 Cryo-EM unveils kinesin KIF1A's processivity mechanism and the impact of its pathogenic variant P305L. Nature communications 15 38956021
2024 KIF1A promotes neuroendocrine differentiation in prostate cancer by regulating the OGT-mediated O-GlcNAcylation. Cell death & disease 15 39505875
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
2023 Huntingtin recruits KIF1A to transport synaptic vesicle precursors along the mouse axon to support synaptic transmission and motor skill learning. eLife 13 37431882
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
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 11 36549649
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
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
2024 Comparative analysis of two Caenorhabditis elegans kinesins KLP-6 and UNC-104 reveals a common and distinct activation mechanism in kinesin-3. eLife 8 38206323
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 8 37063368
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
2025 CREB-KIF1A-CGRP-positive feedback loop drives central sensitization in chronic migraine. The journal of headache and pain 7 41029476
2024 Kif1a and intact microtubules maintain synaptic-vesicle populations at ribbon synapses in zebrafish hair cells. The Journal of physiology 7 39373584
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
2024 KIF1A, R1457Q, and P1688L Mutations Induce Protein Abnormal Aggregation and Autophagy Impairment in iPSC-Derived Motor Neurons. Biomedicines 6 39200158

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