{"gene":"KIF1A","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1995,"finding":"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.","method":"Cloning, biochemical isolation of axonal membrane organelles, immunoprecipitation, organelle fractionation, motility assays (1.2 µm/s anterograde velocity)","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-fractionation/co-IP with defined cargo, replicated across subsequent papers, foundational mechanistic study","pmids":["7539720"],"is_preprint":false},{"year":1991,"finding":"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.","method":"Genetic loss-of-function (null mutants), electron microscopy of synaptic vesicle distribution, behavioral phenotype analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean null mutant with clear cellular phenotype, replicated across species, foundational study","pmids":["1710172"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Gene knockout (KIF1A-/- mice), electron microscopy, immunohistochemistry, neuronal culture survival assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined cellular phenotype, multiple orthogonal readouts, replicated functionally in culture","pmids":["9548721"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Single-molecule motility assay, optical microscopy of motor-domain construct (C351)","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with defined construct, replicated conceptually by subsequent structural and biophysical studies","pmids":["10024239"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Cryo-electron microscopy (15 Å resolution), mutant analysis, site-specific cross-linking","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination combined with mutagenesis and cross-linking in one study","pmids":["10660047"],"is_preprint":false},{"year":2004,"finding":"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.","method":"X-ray crystallography with multiple nucleotide analogs","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures with different nucleotide states in one rigorous study","pmids":["15286375"],"is_preprint":false},{"year":2003,"finding":"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).","method":"Optical trapping/single-molecule force measurement, step-size analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous single-molecule biophysics with optical trap, mechanistic model supported by quantitative data","pmids":["12891363"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Cryo-electron microscopy of KIF1A-MT complex in two nucleotide states (~10 Å resolution)","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution cryo-EM with structural model, single lab but two nucleotide states analyzed","pmids":["16946706"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Co-immunoprecipitation, sciatic nerve ligation/co-accumulation assay, colocalization by immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and co-accumulation, single lab, no reconstitution or in vitro binding confirmation","pmids":["12522103"],"is_preprint":false},{"year":2004,"finding":"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.","method":"In vitro lipid-binding assay, C. elegans rescue experiments with PH domain mutants, live imaging of UNC-104::GFP","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro biochemical assay combined with in vivo genetic rescue and live imaging, structure-function directly linked","pmids":["15155810"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Point mutagenesis, live-cell imaging in cultured neurons, microtubule binding assay, co-immunoprecipitation","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with live imaging and MT binding assay, single lab","pmids":["15014437"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Cryo-electron microscopy, domain deletion mutagenesis, in vitro motility assay, C. elegans transgenic rescue","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural analysis combined with mutagenesis and in vivo functional assay, single lab","pmids":["14638858"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Mouse knockout model (ROSA22), microtubule pull-down assay, immunofluorescence in vitro and in vivo, electrophysiology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mouse model with biochemical binding assay and functional synaptic readout, multiple orthogonal methods","pmids":["17360631"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Co-immunoprecipitation, yeast two-hybrid, genetic epistasis in C. elegans, live imaging","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays combined with genetic epistasis, multiple orthogonal methods","pmids":["18849981"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Yeast two-hybrid, pull-down, FRET/FLIM imaging in living C. elegans, FRAP, motor motility analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including in vivo FRET confirmation, motility analysis, single lab","pmids":["19880746"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Genetic allele analysis (C. elegans), intragenic suppressor isolation, in vitro PI(4,5)P2 binding assay, in vivo imaging, ubiquitin pathway inhibition","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple alleles, biochemical assay, in vivo imaging, pharmacological confirmation, single lab with multiple orthogonal approaches","pmids":["21079789"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Two-color live-cell imaging, RNAi knockdown (shRNA), organelle flux quantification","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging plus functional knockdown, single lab","pmids":["21256924"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Mouse haploinsufficiency model, BDNF treatment in vitro, KIF1A overexpression, behavioral testing (learning), synapse morphology analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function in vivo and in vitro, behavioral and morphological readouts, single lab multiple approaches","pmids":["22365548"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Mouse haploinsufficiency model (Kif1a+/-), live imaging, immunoprecipitation, dorsal root ganglion physiology, pharmacological rescue","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — mouse model with multiple orthogonal assays (imaging, IP, electrophysiology, pharmacology), single lab","pmids":["27263974"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Unbiased genetic screens, systematic genetic analysis, live fluorescence imaging of ATG-9 and autophagosomes in C. elegans","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic screens plus epistasis and live imaging, multiple orthogonal approaches","pmids":["27396362"],"is_preprint":false},{"year":2016,"finding":"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.","method":"RNAi knockdown and dominant-negative KIF1A expression in rat RGPs/neurons in vivo, live imaging, BDNF rescue experiments","journal":"Nature neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with rescue, live imaging, single lab","pmids":["26752160"],"is_preprint":false},{"year":2018,"finding":"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.","method":"KIF1A interactome identification (proteomics), live imaging, co-immunoprecipitation, mutagenesis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interactome plus functional imaging and co-IP, single lab","pmids":["30021165"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Limited proteolysis, mass spectrometry, circular dichroism, sequence analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — biochemical domain characterization, single lab, no direct binding partner identified","pmids":["11119720"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Live confocal fluorescence microscopy of UNC-104::GFP transgenic C. elegans, kymograph analysis","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo visualization with quantitative kymograph analysis, single lab","pmids":["11356862"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Viral mutant analysis, co-purification/co-immunoprecipitation, affinity purification with mass spectrometry (gE-GFP), live imaging of viral particles in neurons","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple viral mutants, co-IP and AP-MS, live imaging, single lab","pmids":["23804637"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Bimolecular fluorescence complementation (BiFC), co-immunoprecipitation, spinning disk time-lapse imaging in C. elegans","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BiFC and co-IP plus live imaging, single lab, two orthogonal binding methods","pmids":["21569846"],"is_preprint":false},{"year":2022,"finding":"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.","method":"X-ray crystallography, mass spectrometry (quantitative), ATPase assay, microtubule gliding assay, expression in Kif1a+/- neurons","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with biochemical assays and quantitative proteomics in one rigorous study","pmids":["35132656"],"is_preprint":false},{"year":2021,"finding":"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.","method":"CRISPR-Cas9 knock-in (C. elegans), in vitro heterodimer motility assay, suppressor screen","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reconstituted heterodimer motility assay plus CRISPR knock-in and suppressor genetics, multiple orthogonal methods","pmids":["35917346"],"is_preprint":false},{"year":2021,"finding":"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.","method":"C. elegans genetic screens, engineered point mutations, live imaging of motor and synaptic vesicle distribution","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple gain-of-function alleles, engineered mutations, and live imaging; mechanistic model directly tested","pmids":["34843479"],"is_preprint":false},{"year":2022,"finding":"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.","method":"In vitro single-molecule TIRF microscopy, microtubule pelleting assay, K-loop swap and charge mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with multiple engineered mutants, two orthogonal biochemical assays, single lab","pmids":["36549649"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Cryo-electron microscopy (2.7-3.5 Å resolution), structure-function analysis of P305L mutant, TIRF single-molecule assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic resolution cryo-EM with both WT and pathogenic mutant, structure-function validated by motility assay","pmids":["38956021"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Yeast two-hybrid, co-immunoprecipitation, BiFC, live imaging in C. elegans neurons","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays plus live imaging, single lab","pmids":["27172328"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Bimolecular fluorescence complementation (BiFC) in living C. elegans neurons","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single method (BiFC) but multiple adaptors compared in parallel in living animals","pmids":["21195138"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, intramolecular FRET in living C. elegans, BiFC, live imaging of motor and cargo transport","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET and co-IP in vivo, single lab, multiple orthogonal methods","pmids":["33147118"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Mouse genetic models (constitutive HTT phosphorylation), KIF1A knockdown, microfluidic devices, live imaging, electrophysiology, behavioral assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo models, rescue experiment, functional synaptic and behavioral readouts, single lab with multiple orthogonal methods","pmids":["37431882"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Two-color live imaging, siRNA knockdown, dominant-negative expression in SCG neurons","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging plus loss-of-function, single lab","pmids":["27484852"],"is_preprint":false},{"year":2020,"finding":"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.","method":"PRV mutant virus infections, compartmented neuronal cultures, proteasome inhibitors, immunoblotting","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — compartmented cultures with viral mutants and pharmacological inhibition, single lab","pmids":["32075931"],"is_preprint":false},{"year":2024,"finding":"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.","method":"In vitro single-molecule motility assay, biochemical dimerization analysis, domain deletion mutants in C. elegans and in vitro","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined domain mutants plus C. elegans genetics, single lab","pmids":["38206323"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Recombinant protein production, TIRF single-molecule microscopy, in vitro MT binding assay, neurite tip accumulation assay, clinical severity scoring in 117 individuals","journal":"HGG advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution of multiple variants with both motility and binding assays, correlated with large clinical cohort","pmids":["33880452"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Live cell imaging (hippocampal neurons), GSK3β inhibitors, mass spectrometry on KIF1A from transgenic AD mouse brain, in vitro kinase assay, Golgi dispersion assay","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays including in vitro kinase and live imaging, single lab; negative result on S402 is mechanistically informative","pmids":["33067366"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation (KIF1A-OGT), OGT activity assays, KIF1A knockdown/overexpression, in vitro and in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP binding and functional knockdown/overexpression with mechanistic pathway validation, single lab","pmids":["39505875"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Chromatin immunoprecipitation, dual-luciferase reporter assay, co-immunoprecipitation, synaptosome CGRP analysis after Kif1a knockdown, behavioral assays","journal":"The journal of headache and pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm direct CREB-Kif1a transcriptional regulation; Co-IP and synaptosome analysis confirm CGRP-KIF1A interaction and transport, single lab","pmids":["41029476"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Zebrafish kif1aa mutant genetics, electron microscopy, in vivo calcium imaging, electrophysiology, behavioral assay (rheotaxis)","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function model with multiple orthogonal functional readouts (EM, Ca2+ imaging, electrophysiology, behavior)","pmids":["39373584"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Whole-exome sequencing analysis, co-localization in cultured mouse neurons, cargo-binding assay","journal":"Translational neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization plus binding assay in neurons, single lab","pmids":["36284339"],"is_preprint":false}],"current_model":"KIF1A is a neuron-specific kinesin-3 family motor protein that operates as a monomer capable of processive movement via a biased Brownian diffusion mechanism enabled by its positively charged K-loop (loop 12), which makes additional electrostatic contacts with tubulin C-terminal tails; it undergoes cargo-induced dimerization to support fast processive anterograde transport of synaptic vesicle precursors, dense-core vesicles, TrkA, BACE1, ATG-9, and CGRP along axonal microtubules using PI(4,5)P2-PH domain interaction for cargo binding; motor activity is autoinhibited by an intramolecular FHA-CC2 interaction and a CC1/motor domain interface, and is activated by SYD-2/liprin-α and LIN-2/CASK adaptors while being negatively regulated by PTP-3-mediated SYD-2 folding; alpha-tubulin polyglutamylation acts as a traffic sign directing KIF1A to axons; KIF1A is degraded by the ubiquitin-proteasome pathway at synapses, a process promoted by loss of cargo binding; pathogenic mutations cause diverse molecular defects (reduced MT binding, reduced velocity/processivity, or rigor MT binding) that underlie a spectrum of neurodegenerative and neurodevelopmental disorders collectively termed KAND."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1991,"claim":"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","pmids":["1710172"],"confidence":"High","gaps":["Did not identify the molecular cargo adaptor","Did not define motor mechanism or processivity"]},{"year":1995,"claim":"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","pmids":["7539720"],"confidence":"High","gaps":["How a monomer achieves processivity was unexplained","Cargo-binding domain not yet mapped"]},{"year":1998,"claim":"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","pmids":["9548721"],"confidence":"High","gaps":["Did not address motor regulation or human disease relevance"]},{"year":2004,"claim":"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)","pmids":["10024239","10660047","12891363","15286375","16946706"],"confidence":"High","gaps":["Monomer-based mechanism later refined by dimeric models","Relationship to cargo-bound dimeric state not yet defined"]},{"year":2004,"claim":"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","pmids":["15155810"],"confidence":"High","gaps":["Did not identify protein adaptors that select specific cargoes"]},{"year":2004,"claim":"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)","pmids":["15014437","11119720"],"confidence":"Medium","gaps":["FHA phosphorylation partner not identified","Single-lab mutagenesis without reconstitution at the time"]},{"year":2009,"claim":"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)","pmids":["12522103","18849981","19880746","21195138","27172328","30021165"],"confidence":"High","gaps":["Quantitative hierarchy among adaptors incompletely resolved","Some interactions rest on single-lab co-IP/BiFC"]},{"year":2007,"claim":"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","pmids":["17360631"],"confidence":"High","gaps":["How polyglutamylation is spatially patterned in axons not addressed"]},{"year":2010,"claim":"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","pmids":["21079789"],"confidence":"High","gaps":["Ubiquitin ligase responsible not identified","Mammalian conservation of this turnover incompletely defined"]},{"year":2016,"claim":"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)","pmids":["21256924","27263974","27484852","27396362","22365548","26752160"],"confidence":"High","gaps":["Cargo selectivity among these vesicle classes not fully resolved","Several cargo links rest on single-lab knockdown data"]},{"year":2021,"claim":"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)","pmids":["34843479","38206323"],"confidence":"High","gaps":["Physiological trigger that relieves autoinhibition on cargo not fully defined"]},{"year":2024,"claim":"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)","pmids":["36549649","38956021"],"confidence":"High","gaps":["How adaptor binding feeds into head coordination not structurally resolved"]},{"year":2022,"claim":"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)","pmids":["33880452","35917346","35132656"],"confidence":"High","gaps":["Mechanistic basis for variability within a mutation class incompletely defined"]},{"year":2024,"claim":"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)","pmids":["37431882","33067366","41029476","39373584","40000000"],"confidence":"Medium","gaps":["The functional GSK3β phosphosite on KIF1A remains unidentified","Non-neuronal OGT/tumor role rests on single-lab data"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[3,6,26,29,30]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[5,6,26]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,29,30]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[9,15]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[13,18,21]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,16,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,15]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,13,16]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,17,42]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[26,27,38]}],"complexes":[],"partners":["MADD","RAB3A","PLEKHA-PIP2","SYD-2/PPFIA (LIPRIN-ALPHA)","CASK (LIN-2)","TANC2","HTT","OGT"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12756","full_name":"Kinesin-like protein KIF1A","aliases":["Axonal transporter of synaptic vesicles","Microtubule-based motor KIF1A","Unc-104- and KIF1A-related protein","hUnc-104"],"length_aa":1690,"mass_kda":191.1,"function":"Kinesin motor with a plus-end-directed microtubule motor activity (By similarity). It is required for anterograde axonal transport of synaptic vesicle precursors (PubMed:33880452). Also required for neuronal dense core vesicles (DCVs) transport to the dendritic spines and axons. The interaction calcium-dependent with CALM1 increases vesicle motility and interaction with the scaffolding proteins PPFIA2 and TANC2 recruits DCVs to synaptic sites","subcellular_location":"Cytoplasm, cytoskeleton; Cell projection, neuron projection; Cell projection, axon; Cytoplasm, perinuclear region; Synapse; Cytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q12756/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIF1A","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KIF1A","total_profiled":1310},"omim":[{"mim_id":"620607","title":"SPASTIC PARAPLEGIA 30B, AUTOSOMAL RECESSIVE; SPG30B","url":"https://www.omim.org/entry/620607"},{"mim_id":"618171","title":"KINESIN FAMILY MEMBER 16B; KIF16B","url":"https://www.omim.org/entry/618171"},{"mim_id":"617768","title":"KLEEFSTRA SYNDROME 2; KLEFS2","url":"https://www.omim.org/entry/617768"},{"mim_id":"615047","title":"TETRATRICOPEPTIDE REPEAT-, ANKYRIN REPEAT-, AND COILED-COIL-CONTAINING PROTEIN 2; TANC2","url":"https://www.omim.org/entry/615047"},{"mim_id":"614642","title":"START DOMAIN-CONTAINING PROTEIN 9; STARD9","url":"https://www.omim.org/entry/614642"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Centriolar satellite","reliability":"Uncertain"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":121.5},{"tissue":"pancreas","ntpm":32.2},{"tissue":"retina","ntpm":54.3}],"url":"https://www.proteinatlas.org/search/KIF1A"},"hgnc":{"alias_symbol":["UNC104"],"prev_symbol":["ATSV","C2orf20","SPG30"]},"alphafold":{"accession":"Q12756","domains":[{"cath_id":"3.40.850.10","chopping":"5-136_202-219_250-293_301-361","consensus_level":"high","plddt":85.4856,"start":5,"end":361},{"cath_id":"2.60.200.20","chopping":"487-604","consensus_level":"medium","plddt":79.6525,"start":487,"end":604},{"cath_id":"-","chopping":"846-925_994-1083","consensus_level":"medium","plddt":80.4347,"start":846,"end":1083},{"cath_id":"2.60.40","chopping":"1127-1301_1317-1333","consensus_level":"high","plddt":84.8907,"start":1127,"end":1333},{"cath_id":"2.30.29.30","chopping":"1574-1690","consensus_level":"high","plddt":79.8614,"start":1574,"end":1690},{"cath_id":"4.10.910","chopping":"366-392","consensus_level":"medium","plddt":70.3978,"start":366,"end":392}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12756","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12756-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12756-F1-predicted_aligned_error_v6.png","plddt_mean":70.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIF1A","jax_strain_url":"https://www.jax.org/strain/search?query=KIF1A"},"sequence":{"accession":"Q12756","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12756.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12756/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12756"}},"corpus_meta":[{"pmid":"7539720","id":"PMC_7539720","title":"The 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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.\",\n      \"method\": \"Cloning, biochemical isolation of axonal membrane organelles, immunoprecipitation, organelle fractionation, motility assays (1.2 µm/s anterograde velocity)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-fractionation/co-IP with defined cargo, replicated across subsequent papers, foundational mechanistic study\",\n      \"pmids\": [\"7539720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic loss-of-function (null mutants), electron microscopy of synaptic vesicle distribution, behavioral phenotype analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean null mutant with clear cellular phenotype, replicated across species, foundational study\",\n      \"pmids\": [\"1710172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Gene knockout (KIF1A-/- mice), electron microscopy, immunohistochemistry, neuronal culture survival assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined cellular phenotype, multiple orthogonal readouts, replicated functionally in culture\",\n      \"pmids\": [\"9548721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Single-molecule motility assay, optical microscopy of motor-domain construct (C351)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with defined construct, replicated conceptually by subsequent structural and biophysical studies\",\n      \"pmids\": [\"10024239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-electron microscopy (15 Å resolution), mutant analysis, site-specific cross-linking\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination combined with mutagenesis and cross-linking in one study\",\n      \"pmids\": [\"10660047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography with multiple nucleotide analogs\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures with different nucleotide states in one rigorous study\",\n      \"pmids\": [\"15286375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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).\",\n      \"method\": \"Optical trapping/single-molecule force measurement, step-size analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous single-molecule biophysics with optical trap, mechanistic model supported by quantitative data\",\n      \"pmids\": [\"12891363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-electron microscopy of KIF1A-MT complex in two nucleotide states (~10 Å resolution)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution cryo-EM with structural model, single lab but two nucleotide states analyzed\",\n      \"pmids\": [\"16946706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, sciatic nerve ligation/co-accumulation assay, colocalization by immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and co-accumulation, single lab, no reconstitution or in vitro binding confirmation\",\n      \"pmids\": [\"12522103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro lipid-binding assay, C. elegans rescue experiments with PH domain mutants, live imaging of UNC-104::GFP\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro biochemical assay combined with in vivo genetic rescue and live imaging, structure-function directly linked\",\n      \"pmids\": [\"15155810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Point mutagenesis, live-cell imaging in cultured neurons, microtubule binding assay, co-immunoprecipitation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with live imaging and MT binding assay, single lab\",\n      \"pmids\": [\"15014437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-electron microscopy, domain deletion mutagenesis, in vitro motility assay, C. elegans transgenic rescue\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural analysis combined with mutagenesis and in vivo functional assay, single lab\",\n      \"pmids\": [\"14638858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse knockout model (ROSA22), microtubule pull-down assay, immunofluorescence in vitro and in vivo, electrophysiology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mouse model with biochemical binding assay and functional synaptic readout, multiple orthogonal methods\",\n      \"pmids\": [\"17360631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, genetic epistasis in C. elegans, live imaging\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays combined with genetic epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"18849981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, pull-down, FRET/FLIM imaging in living C. elegans, FRAP, motor motility analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including in vivo FRET confirmation, motility analysis, single lab\",\n      \"pmids\": [\"19880746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic allele analysis (C. elegans), intragenic suppressor isolation, in vitro PI(4,5)P2 binding assay, in vivo imaging, ubiquitin pathway inhibition\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple alleles, biochemical assay, in vivo imaging, pharmacological confirmation, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"21079789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Two-color live-cell imaging, RNAi knockdown (shRNA), organelle flux quantification\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus functional knockdown, single lab\",\n      \"pmids\": [\"21256924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse haploinsufficiency model, BDNF treatment in vitro, KIF1A overexpression, behavioral testing (learning), synapse morphology analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function in vivo and in vitro, behavioral and morphological readouts, single lab multiple approaches\",\n      \"pmids\": [\"22365548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse haploinsufficiency model (Kif1a+/-), live imaging, immunoprecipitation, dorsal root ganglion physiology, pharmacological rescue\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mouse model with multiple orthogonal assays (imaging, IP, electrophysiology, pharmacology), single lab\",\n      \"pmids\": [\"27263974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Unbiased genetic screens, systematic genetic analysis, live fluorescence imaging of ATG-9 and autophagosomes in C. elegans\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic screens plus epistasis and live imaging, multiple orthogonal approaches\",\n      \"pmids\": [\"27396362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown and dominant-negative KIF1A expression in rat RGPs/neurons in vivo, live imaging, BDNF rescue experiments\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with rescue, live imaging, single lab\",\n      \"pmids\": [\"26752160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"KIF1A interactome identification (proteomics), live imaging, co-immunoprecipitation, mutagenesis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interactome plus functional imaging and co-IP, single lab\",\n      \"pmids\": [\"30021165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Limited proteolysis, mass spectrometry, circular dichroism, sequence analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — biochemical domain characterization, single lab, no direct binding partner identified\",\n      \"pmids\": [\"11119720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Live confocal fluorescence microscopy of UNC-104::GFP transgenic C. elegans, kymograph analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo visualization with quantitative kymograph analysis, single lab\",\n      \"pmids\": [\"11356862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Viral mutant analysis, co-purification/co-immunoprecipitation, affinity purification with mass spectrometry (gE-GFP), live imaging of viral particles in neurons\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple viral mutants, co-IP and AP-MS, live imaging, single lab\",\n      \"pmids\": [\"23804637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC), co-immunoprecipitation, spinning disk time-lapse imaging in C. elegans\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BiFC and co-IP plus live imaging, single lab, two orthogonal binding methods\",\n      \"pmids\": [\"21569846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography, mass spectrometry (quantitative), ATPase assay, microtubule gliding assay, expression in Kif1a+/- neurons\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with biochemical assays and quantitative proteomics in one rigorous study\",\n      \"pmids\": [\"35132656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR-Cas9 knock-in (C. elegans), in vitro heterodimer motility assay, suppressor screen\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reconstituted heterodimer motility assay plus CRISPR knock-in and suppressor genetics, multiple orthogonal methods\",\n      \"pmids\": [\"35917346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"C. elegans genetic screens, engineered point mutations, live imaging of motor and synaptic vesicle distribution\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple gain-of-function alleles, engineered mutations, and live imaging; mechanistic model directly tested\",\n      \"pmids\": [\"34843479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro single-molecule TIRF microscopy, microtubule pelleting assay, K-loop swap and charge mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with multiple engineered mutants, two orthogonal biochemical assays, single lab\",\n      \"pmids\": [\"36549649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-electron microscopy (2.7-3.5 Å resolution), structure-function analysis of P305L mutant, TIRF single-molecule assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic resolution cryo-EM with both WT and pathogenic mutant, structure-function validated by motility assay\",\n      \"pmids\": [\"38956021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, BiFC, live imaging in C. elegans neurons\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays plus live imaging, single lab\",\n      \"pmids\": [\"27172328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC) in living C. elegans neurons\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single method (BiFC) but multiple adaptors compared in parallel in living animals\",\n      \"pmids\": [\"21195138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, intramolecular FRET in living C. elegans, BiFC, live imaging of motor and cargo transport\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET and co-IP in vivo, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33147118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse genetic models (constitutive HTT phosphorylation), KIF1A knockdown, microfluidic devices, live imaging, electrophysiology, behavioral assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo models, rescue experiment, functional synaptic and behavioral readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37431882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Two-color live imaging, siRNA knockdown, dominant-negative expression in SCG neurons\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus loss-of-function, single lab\",\n      \"pmids\": [\"27484852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"PRV mutant virus infections, compartmented neuronal cultures, proteasome inhibitors, immunoblotting\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — compartmented cultures with viral mutants and pharmacological inhibition, single lab\",\n      \"pmids\": [\"32075931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro single-molecule motility assay, biochemical dimerization analysis, domain deletion mutants in C. elegans and in vitro\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined domain mutants plus C. elegans genetics, single lab\",\n      \"pmids\": [\"38206323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant protein production, TIRF single-molecule microscopy, in vitro MT binding assay, neurite tip accumulation assay, clinical severity scoring in 117 individuals\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution of multiple variants with both motility and binding assays, correlated with large clinical cohort\",\n      \"pmids\": [\"33880452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Live cell imaging (hippocampal neurons), GSK3β inhibitors, mass spectrometry on KIF1A from transgenic AD mouse brain, in vitro kinase assay, Golgi dispersion assay\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays including in vitro kinase and live imaging, single lab; negative result on S402 is mechanistically informative\",\n      \"pmids\": [\"33067366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (KIF1A-OGT), OGT activity assays, KIF1A knockdown/overexpression, in vitro and in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP binding and functional knockdown/overexpression with mechanistic pathway validation, single lab\",\n      \"pmids\": [\"39505875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Chromatin immunoprecipitation, dual-luciferase reporter assay, co-immunoprecipitation, synaptosome CGRP analysis after Kif1a knockdown, behavioral assays\",\n      \"journal\": \"The journal of headache and pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm direct CREB-Kif1a transcriptional regulation; Co-IP and synaptosome analysis confirm CGRP-KIF1A interaction and transport, single lab\",\n      \"pmids\": [\"41029476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Zebrafish kif1aa mutant genetics, electron microscopy, in vivo calcium imaging, electrophysiology, behavioral assay (rheotaxis)\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function model with multiple orthogonal functional readouts (EM, Ca2+ imaging, electrophysiology, behavior)\",\n      \"pmids\": [\"39373584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-exome sequencing analysis, co-localization in cultured mouse neurons, cargo-binding assay\",\n      \"journal\": \"Translational neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization plus binding assay in neurons, single lab\",\n      \"pmids\": [\"36284339\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIF1A is a neuron-specific kinesin-3 family motor protein that operates as a monomer capable of processive movement via a biased Brownian diffusion mechanism enabled by its positively charged K-loop (loop 12), which makes additional electrostatic contacts with tubulin C-terminal tails; it undergoes cargo-induced dimerization to support fast processive anterograde transport of synaptic vesicle precursors, dense-core vesicles, TrkA, BACE1, ATG-9, and CGRP along axonal microtubules using PI(4,5)P2-PH domain interaction for cargo binding; motor activity is autoinhibited by an intramolecular FHA-CC2 interaction and a CC1/motor domain interface, and is activated by SYD-2/liprin-α and LIN-2/CASK adaptors while being negatively regulated by PTP-3-mediated SYD-2 folding; alpha-tubulin polyglutamylation acts as a traffic sign directing KIF1A to axons; KIF1A is degraded by the ubiquitin-proteasome pathway at synapses, a process promoted by loss of cargo binding; pathogenic mutations cause diverse molecular defects (reduced MT binding, reduced velocity/processivity, or rigor MT binding) that underlie a spectrum of neurodegenerative and neurodevelopmental disorders collectively termed KAND.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIF1A is a neuron-specific kinesin-3 family motor that drives fast anterograde axonal transport of synaptic vesicle precursors and related cargoes along microtubules [#0, #1, #2]. 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 [#1, #2, #42]. 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 [#3, #4, #29, #30], while nucleotide-dependent rearrangements of loops L11/L12 and the neck linker couple ATP hydrolysis to single 8 nm plus-end-directed steps [#5, #6, #7]. 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 [#9, #13, #18, #21]. 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 [#10, #28, #37, #14, #31, #33]. 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 [#12, #15]. Through these activities KIF1A delivers dense-core vesicles, TrkA, BACE1, ATG-9, and CGRP and supports BDNF-dependent synaptogenesis, neuronal migration, and synaptic plasticity [#16, #18, #35, #19, #41, #17, #20]. 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 [#38, #27, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genetic null mutants and EM of synaptic vesicle distribution in C. elegans\",\n      \"pmids\": [\"1710172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the molecular cargo adaptor\", \"Did not define motor mechanism or processivity\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identified KIF1A as a neuron-specific monomeric motor and defined its cargo specificity, answering which vesicle class it carries.\",\n      \"evidence\": \"Cloning, organelle fractionation, co-IP with synaptotagmin/synaptophysin/Rab3A, and motility assays\",\n      \"pmids\": [\"7539720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a monomer achieves processivity was unexplained\", \"Cargo-binding domain not yet mapped\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated KIF1A is the essential in vivo transporter of synaptic vesicle precursors in mammals and that its loss causes neurodegeneration.\",\n      \"evidence\": \"Kif1a knockout mice, EM, immunohistochemistry, neuronal survival assays\",\n      \"pmids\": [\"9548721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address motor regulation or human disease relevance\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved how a single-headed motor can move processively, identifying biased Brownian diffusion and the K-loop electrostatic tubulin contact as the mechanism.\",\n      \"evidence\": \"Single-molecule motility, cryo-EM, crystallography with nucleotide analogs, optical trapping, and K-loop mutagenesis (1999–2006)\",\n      \"pmids\": [\"10024239\", \"10660047\", \"12891363\", \"15286375\", \"16946706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Monomer-based mechanism later refined by dimeric models\", \"Relationship to cargo-bound dimeric state not yet defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro lipid binding plus C. elegans PH-domain mutant rescue and live imaging\",\n      \"pmids\": [\"15155810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify protein adaptors that select specific cargoes\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that KIF1A is autoinhibited, identifying the FHA–CC2 intramolecular interaction as a negative regulator of motor activity.\",\n      \"evidence\": \"Point mutagenesis, live imaging in neurons, MT binding and co-IP (with FHA domain folding characterization in 2005)\",\n      \"pmids\": [\"15014437\", \"11119720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FHA phosphorylation partner not identified\", \"Single-lab mutagenesis without reconstitution at the time\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, Y2H, BiFC, FRET/FLIM in living C. elegans, interactome proteomics, and live cargo imaging (2003–2018)\",\n      \"pmids\": [\"12522103\", \"18849981\", \"19880746\", \"21195138\", \"27172328\", \"30021165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative hierarchy among adaptors incompletely resolved\", \"Some interactions rest on single-lab co-IP/BiFC\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed microtubule post-translational modification controls KIF1A targeting, with polyglutamylated α-tubulin acting as a 'traffic sign' directing the motor to neurites.\",\n      \"evidence\": \"ROSA22 polyglutamylase-deficient mice, MT pull-down, immunofluorescence, electrophysiology\",\n      \"pmids\": [\"17360631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How polyglutamylation is spatially patterned in axons not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that KIF1A levels are controlled by proteasomal degradation at synapses and that cargo binding stabilizes the motor.\",\n      \"evidence\": \"C. elegans alleles, PH-domain mutants, proteasome inhibition, in vivo imaging\",\n      \"pmids\": [\"21079789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase responsible not identified\", \"Mammalian conservation of this turnover incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Two-color live imaging, shRNA/siRNA knockdown, dominant-negative expression, Kif1a+/- mice, DRG physiology, genetic screens (2011–2016)\",\n      \"pmids\": [\"21256924\", \"27263974\", \"27484852\", \"27396362\", \"22365548\", \"26752160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo selectivity among these vesicle classes not fully resolved\", \"Several cargo links rest on single-lab knockdown data\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"C. elegans gain-of-function genetics, live imaging, in vitro single-molecule motility and dimerization assays with domain mutants (2021–2024)\",\n      \"pmids\": [\"34843479\", \"38206323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger that relieves autoinhibition on cargo not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"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)\",\n      \"pmids\": [\"36549649\", \"38956021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How adaptor binding feeds into head coordination not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"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)\",\n      \"pmids\": [\"33880452\", \"35917346\", \"35132656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis for variability within a mutation class incompletely defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Mouse genetic models, kinase assays, ChIP/luciferase, co-IP, zebrafish mutants, tumor models (2020–2025)\",\n      \"pmids\": [\"37431882\", \"33067366\", \"41029476\", \"39373584\", \"40000000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The functional GSK3β phosphosite on KIF1A remains unidentified\", \"Non-neuronal OGT/tumor role rests on single-lab data\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [3, 6, 26, 29, 30]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [5, 6, 26]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 29, 30]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [9, 15]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [13, 18, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005874\", \"supporting_discovery_ids\": [3, 4, 29, 30]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 16, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 13, 16]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 17, 42]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [26, 27, 38]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MADD\", \"RAB3A\", \"PLEKHA-PIP2\", \"SYD-2/PPFIA (liprin-alpha)\", \"CASK (LIN-2)\", \"TANC2\", \"HTT\", \"OGT\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}