{"gene":"KIF5C","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2000,"finding":"KIF5C is a neuronal kinesin heavy chain enriched in lower motor neurons; KIF5C knockout mice show relative loss of motor neurons, and KIF5C can form heterodimers with other KIF5 family members and rescue KIF5B mutant cells, demonstrating functional redundancy among KIF5 isoforms.","method":"Gene knockout in mice, antibody staining, heterodimer formation assays, complementation rescue","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mouse phenotype, rescue assay, co-localization), replicated across isoforms in a single focused study","pmids":["10964943"],"is_preprint":false},{"year":2001,"finding":"KIF5C (and KIF5B, but not KIF5A) directly docks to a novel domain of RanBP2 located between RBD2 and RBD3; the kinesin light chain and RanGTPase are also part of this macroassembly complex, positioning RanBP2 as a selective docking scaffold for these two kinesin isoforms.","method":"In vitro direct binding assay, co-immunoprecipitation (in vitro and in vivo), domain mapping of RanBP2","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP in vitro and in vivo, domain-mapping, direct binding shown, single lab with multiple orthogonal methods","pmids":["11553612"],"is_preprint":false},{"year":2007,"finding":"A ~100-residue segment spanning the coiled-coil and globular tail cargo-binding domains of KIF5C mediates selective interaction with the kinesin-binding domain (KBD) of RanBP2; a single residue conserved in KIF5B and KIF5C but not KIF5A confers isoform-specific binding. Selective inhibition of this interaction causes perinuclear clustering of mitochondria, deficits in mitochondrial membrane potential, and cell shrinkage, establishing KIF5C as a motor for mitochondrial transport via RanBP2.","method":"Domain truncation mapping, site-directed mutagenesis, co-immunoprecipitation, selective peptide inhibition, mitochondrial localization assay, membrane potential measurement","journal":"Traffic","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, Co-IP, functional inhibition, organelle localization), clear mechanistic phenotype, single lab but comprehensive","pmids":["17887960"],"is_preprint":false},{"year":2006,"finding":"GRIF-1 (a proposed kinesin adaptor) directly and specifically binds to the C-terminal cargo-binding region of the KIF5C non-motor domain; this interaction is confirmed by FRET, yeast two-hybrid, and Co-IP, and GRIF-1 can also associate with the tetrameric kinesin light-chain/KIF5C complex, supporting a role for GRIF-1 as an adaptor for KIF5C-mediated anterograde delivery of mitochondria and GABAA receptor-containing vesicles.","method":"Yeast two-hybrid, co-immunoprecipitation, FRET (fluorescence resonance energy transfer), confocal co-localization, truncation mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction confirmed by FRET (Tier 1 proximity assay) plus reciprocal Co-IP and yeast two-hybrid; multiple orthogonal methods, precise domain mapped","pmids":["16835241"],"is_preprint":false},{"year":2008,"finding":"KIF5C is a substrate for protein kinase CK2; phosphorylation occurs at amino acid Ser338 in the non-motor domain and is carried out by CK2α/CK2β and CK2α'/CK2β holoenzymes as well as by CK2α' alone, but not by CK2α alone.","method":"In vitro kinase assay, deletion mutants, peptide library screening, site-directed mutagenesis (phosphorylation site mapping), in vivo phosphorylation","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and site mapping, in vivo confirmation, single lab but multiple methods","pmids":["18682247"],"is_preprint":false},{"year":2009,"finding":"KIF5C preferentially binds to the CK2α' catalytic subunit over CK2α; the direct interaction was confirmed by pull-down and surface plasmon resonance; co-localization in neuroblastoma cells and primary neurons is consistent with biochemical data.","method":"Yeast two-hybrid, co-sedimentation, co-immunoprecipitation, pull-down, surface plasmon resonance, co-localization immunofluorescence","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — surface plasmon resonance (direct binding, quantitative) plus pull-down and Co-IP, single lab with multiple orthogonal methods","pmids":["19011756"],"is_preprint":false},{"year":2010,"finding":"KIF5C functions as a kinesin motor for apical trafficking in MDCK epithelial cells; it was identified by mass spectrometry on immunoisolated post-Golgi vesicles carrying apical cargo (both raft-associated sucrase isomaltase and raft-independent neurotrophin receptor), and vesicle-associated KIF5C was highest immediately after trans-Golgi network release.","method":"Mass spectrometry of vesicle fractions, immunoisolation of post-Golgi vesicles, subcellular fractionation","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry on immunoisolated vesicles with temporal fractionation; single lab, no direct functional KD rescue shown in abstract","pmids":["20094756"],"is_preprint":false},{"year":2013,"finding":"A germline mosaic KIF5C mutation found in MCD patients was shown to affect ATP hydrolysis activity of the KIF5C motor domain, establishing impaired ATPase function as a pathogenic mechanism.","method":"ATP hydrolysis assay (in vitro biochemical assay on patient-mutation protein)","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro ATPase assay on mutant protein, published in high-impact journal, subsequently replicated by multiple independent clinical studies","pmids":["23603762"],"is_preprint":false},{"year":2016,"finding":"KIF5C mediates polarized vesicular transport of syntaxin 6 and VAMP4 to the nascent axon; silencing KIF5C prevents polarized insertion of IGF-1R into the neuronal plasma membrane and blocks neuronal polarization, linking stable microtubule accumulation to KIF5C-dependent vesicular trafficking as a mechanistic step in axon specification.","method":"siRNA knockdown of KIF5C in cultured neurons, immunofluorescence co-localization of syntaxin 6/VAMP4 with KIF5C vesicles, membrane IGF-1R insertion assay","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotype (loss of polarized IGF-1R insertion, loss of neuronal polarization), cargo co-localization; single lab, single study","pmids":["27699600"],"is_preprint":false},{"year":2019,"finding":"HAP1a and GRIP1 form a protein complex in the brain and cooperate to activate kinesin-1 subunit KIF5C in vitro; their cooperative action is proposed to stabilize the central hinge region that is critical for kinesin-1 autoinhibition relief.","method":"Co-immunoprecipitation (brain tissue), in vitro kinesin activation assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP from brain and in vitro activation assay; single lab, two complementary methods but mechanism of hinge stabilization inferred, not directly demonstrated","pmids":["31757889"],"is_preprint":false},{"year":2020,"finding":"KIF5C associates with Pseudorabies virus (PRV) particles in differentiated neurons (but not undifferentiated cells) and is recruited to viral particles via the gE/gI-US9p complex; loss of gE/gI-US9p abolishes KIF5C recruitment to PRV particles without affecting dynein binding, implicating KIF5C in plus-end-directed anterograde axonal transport of PRV.","method":"Motor co-sedimentation with purified viral particles, quantitative transport assay in differentiated neuronal cells, genetic deletion of viral gE/gI-US9p","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct motor recruitment assay with viral particle pulldown and genetic deletion; single lab, differentiation-dependent finding adds mechanistic depth","pmids":["32511265"],"is_preprint":false},{"year":2021,"finding":"KIF5C loss of function in dorsal hippocampal CA1 neurons impairs both spatial and contextual fear memory, while gain of function specifically enhances spatial memory and extinction of contextual fear; KIF5C is associated with ~650 dendritic RNAs including EIF3G (a translation initiation regulator) and is a rate-determining component of local translation underlying structural plasticity.","method":"Conditional loss-of-function and gain-of-function (viral vector), behavioral memory assays, RNA immunoprecipitation (RIP-seq, identifying 650 associated RNAs), dendritic arborization and spine density measurement","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — LOF and GOF with defined behavioral and structural phenotypes, RIP-seq for cargo identification, multiple orthogonal readouts in single study","pmids":["34260917"],"is_preprint":false},{"year":2021,"finding":"KIF5C knockout does not alter PrPSc spread, distribution, or survival times in prion-inoculated mice, indicating that KIF5C is dispensable for prion disease propagation in vivo despite its known role in PrPC vesicle transport.","method":"Kif5c knockout mouse model, stereotactic prion inoculation, immunohistochemistry for PrP, survival analysis","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined negative phenotype; single lab, well-controlled negative result","pmids":["34372599"],"is_preprint":false},{"year":2021,"finding":"Kif5c deficiency in mice causes disturbed cortical neuronal migration, reduced dendritic branching, and decreased dendritic spine density, as demonstrated by in utero electroporation knockdown both in vitro and in vivo.","method":"In utero electroporation knockdown, in vitro neuron knockdown, cortical migration assay, dendritic morphology analysis, RNA sequencing of knockdown neurons","journal":"Pediatric research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro KD with defined structural/migration phenotype; single lab, multiple readouts","pmids":["34966180"],"is_preprint":false},{"year":2024,"finding":"A pathogenic in-frame deletion removing Ser90 from the KIF5C ATP-binding domain significantly reduces ATP hydrolysis activity in vitro, causes mutant KIF5C to co-localize with microtubules (unlike wild-type which is distributed throughout cytoplasm), and abolishes peroxisome transport in live-cell cargo-trafficking assays.","method":"In vitro ATP hydrolysis assay, immunofluorescence co-localization, live-cell cargo-trafficking (peroxisome transport) assay, Drosophila nervous system model","journal":"MedComm","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ATPase assay plus live-cell cargo transport assay with mutagenesis-equivalent variant; multiple orthogonal methods, single lab","pmids":["38525108"],"is_preprint":false},{"year":2024,"finding":"Pathogenic de novo KIF5C variants (including Glu237Val, Thr93Ile, Thr93Asn, Ser90del, Lys92Arg, Glu237Lys) display significantly reduced motor domain activity compared to wild-type KIF5C when expressed in hippocampal neurons, establishing loss of motor function as the molecular basis of disease.","method":"Fluorescently-tagged KIF5C variant expression in isolated hippocampal neurons, motor function assay (motility measurement)","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional motor assay in neurons for multiple variants; single lab, no in vitro reconstitution, but direct functional measurement","pmids":["39503049"],"is_preprint":false},{"year":2025,"finding":"A conditional knock-in mouse model of a pathogenic KIF5C variant reveals that KIF5C dysfunction decreases mature dendritic spine density, impairs axonal mitochondrial transport, reduces miniature EPSC frequency, impairs long-term potentiation, and alters presynaptic vesicle release probability; overexpression of KIF5C in hippocampal CA1 rescues memory and excitatory synaptic transmission deficits.","method":"Conditional knock-in mouse, electrophysiology (mEPSC, LTP), dendritic spine morphology, live axonal mitochondria transport imaging, KIF5C overexpression rescue","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse with electrophysiology, organelle transport imaging, and rescue experiment; multiple orthogonal methods establishing mechanistic pathway","pmids":["41260309"],"is_preprint":false},{"year":2025,"finding":"Tau weakly inhibits KIF5C motility in vitro but does not strongly block it; hyperphosphorylation of tau further reduces KIF5C inhibition (decreases processivity inhibition), in contrast to strong inhibition of KIF1A by hyperphosphorylated tau, indicating KIF5C is differentially regulated by tau phosphorylation state on the microtubule lattice.","method":"In vitro single-molecule motility assay with tau phosphomutants, live neuron axonal transport assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with phosphomutants is rigorous, but preprint not yet peer-reviewed; single lab","pmids":["bio_10.1101_2025.07.31.667882"],"is_preprint":true}],"current_model":"KIF5C is a neuronal kinesin-1 heavy chain that drives anterograde microtubule-based transport of diverse cargoes—including mitochondria (via RanBP2 adaptor), GABAA receptor vesicles (via GRIF-1 adaptor), IGF-1R vesicles (via syntaxin 6/VAMP4), dendritic RNAs/local translation machinery, and apical trafficking vesicles in epithelial cells—using ATP hydrolysis in its motor domain; it is activated cooperatively by HAP1a and GRIP1 adaptors that relieve autoinhibition, phosphorylated by CK2 (preferentially CK2α') at Ser338 in its non-motor domain, and is required for cortical neuronal migration, dendritic spine maturation, axonal mitochondrial transport, and synaptic plasticity underlying spatial memory."},"narrative":{"mechanistic_narrative":"KIF5C is a neuronal kinesin-1 heavy chain that powers anterograde, microtubule-based transport of diverse cargoes through ATP hydrolysis in its motor domain, and is required for cortical neuronal migration, dendritic branching, spine maturation, and synaptic plasticity underlying spatial and contextual memory [PMID:10964943, PMID:34966180, PMID:34260917, PMID:41260309]. Cargo selection is achieved through its non-motor coiled-coil and globular tail, which engages cargo-specific adaptors: a unique domain of RanBP2 docks KIF5C (and KIF5B but not KIF5A) for mitochondrial transport, with a single isoform-discriminating residue conferring this selectivity and its disruption causing perinuclear mitochondrial clustering and loss of membrane potential [PMID:11553612, PMID:17887960]; GRIF-1 binds the C-terminal cargo-binding region as an adaptor for mitochondria and GABAA-receptor vesicles [PMID:16835241]; and KIF5C delivers syntaxin 6/VAMP4 vesicles to drive polarized IGF-1R insertion during axon specification [PMID:27699600]. KIF5C also transports apical post-Golgi vesicles in epithelial cells [PMID:20094756] and associates with ~650 dendritic RNAs including the translation regulator EIF3G, acting as a rate-determining component of local translation that supports structural plasticity [PMID:34260917]. Its activity is regulated by CK2, which phosphorylates Ser338 in the non-motor domain preferentially through the CK2α' subunit [PMID:18682247, PMID:19011756], and by cooperative HAP1a/GRIP1-mediated relief of kinesin-1 autoinhibition [PMID:31757889]. Pathogenic germline and de novo KIF5C variants clustering in the ATP-binding and motor domain reduce ATP hydrolysis and motility, abolish cargo transport, and cause malformations of cortical development; knock-in mouse models recapitulate impaired axonal mitochondrial transport, reduced spine density, and deficient LTP, with overexpression rescuing memory and synaptic deficits [PMID:23603762, PMID:38525108, PMID:39503049, PMID:41260309].","teleology":[{"year":2000,"claim":"Established KIF5C as a neuronal kinesin heavy chain with isoform redundancy, answering whether this KIF5 paralog has a distinct neuronal role.","evidence":"Knockout mice, antibody staining, heterodimer and complementation rescue assays","pmids":["10964943"],"confidence":"High","gaps":["Specific cargoes not identified","Mechanism of motor neuron loss unresolved"]},{"year":2001,"claim":"Identified RanBP2 as a selective docking scaffold for KIF5C and KIF5B, beginning to explain how this kinesin is targeted to specific cargo.","evidence":"In vitro direct binding, reciprocal Co-IP, RanBP2 domain mapping","pmids":["11553612"],"confidence":"High","gaps":["Cargo identity at the time unclear","Structural basis of isoform selectivity not defined"]},{"year":2006,"claim":"Defined GRIF-1 as a direct adaptor binding the KIF5C non-motor cargo-binding domain, linking KIF5C to mitochondrial and GABAA-receptor vesicle delivery.","evidence":"Yeast two-hybrid, FRET, Co-IP, truncation mapping","pmids":["16835241"],"confidence":"High","gaps":["In vivo cargo delivery not directly demonstrated","Regulation of adaptor binding unknown"]},{"year":2007,"claim":"Mapped the RanBP2-binding segment and a single isoform-determining residue, and showed disruption causes mitochondrial mislocalization, establishing KIF5C as a mitochondrial motor.","evidence":"Domain truncation, site-directed mutagenesis, peptide inhibition, organelle localization and membrane potential assays","pmids":["17887960"],"confidence":"High","gaps":["Activation/regulation of this transport not addressed","Relationship to GRIF-1 pathway unclear"]},{"year":2009,"claim":"Showed CK2 phosphorylates KIF5C at Ser338 with preferential engagement of the CK2α' subunit, identifying a post-translational regulatory input on the non-motor domain.","evidence":"In vitro kinase assays, site mapping, pull-down, surface plasmon resonance, co-localization","pmids":["18682247","19011756"],"confidence":"High","gaps":["Functional consequence of Ser338 phosphorylation on transport not defined","Physiological trigger of CK2 phosphorylation unknown"]},{"year":2010,"claim":"Extended KIF5C's role beyond neurons by identifying it on apical post-Golgi carriers in epithelial cells, indicating broad cargo versatility.","evidence":"Mass spectrometry of immunoisolated post-Golgi vesicles, temporal subcellular fractionation","pmids":["20094756"],"confidence":"Medium","gaps":["No knockdown/rescue demonstrating functional requirement","Adaptor mediating apical recruitment unidentified"]},{"year":2013,"claim":"Demonstrated that a disease mutation impairs motor-domain ATP hydrolysis, establishing reduced ATPase activity as a pathogenic mechanism in cortical malformation.","evidence":"In vitro ATP hydrolysis assay on patient-mutation protein","pmids":["23603762"],"confidence":"High","gaps":["Link from ATPase deficit to cellular phenotype not yet shown","In vivo modeling absent at this stage"]},{"year":2016,"claim":"Connected KIF5C to axon specification by showing it transports syntaxin 6/VAMP4 vesicles required for polarized IGF-1R membrane insertion.","evidence":"siRNA knockdown in neurons, cargo co-localization, membrane IGF-1R insertion assay","pmids":["27699600"],"confidence":"Medium","gaps":["Direct adaptor for these vesicles not mapped","Single study, single system"]},{"year":2019,"claim":"Identified HAP1a and GRIP1 as cooperating activators of KIF5C, addressing how the autoinhibited motor is switched on.","evidence":"Co-IP from brain tissue, in vitro kinesin activation assay","pmids":["31757889"],"confidence":"Medium","gaps":["Hinge-stabilization mechanism inferred, not directly shown","Cargo specificity of this activation unknown"]},{"year":2020,"claim":"Showed KIF5C is recruited to pseudorabies virus particles via the gE/gI-US9p complex in differentiated neurons, implicating it in anterograde axonal viral transport.","evidence":"Motor co-sedimentation with viral particles, transport assay, viral gene deletion","pmids":["32511265"],"confidence":"Medium","gaps":["Direct vs indirect motor-particle binding not resolved","Relevance to other viruses untested"]},{"year":2021,"claim":"Established KIF5C as a rate-determining carrier of dendritic RNAs and local translation machinery linking transport to memory and structural plasticity.","evidence":"Conditional LOF/GOF, behavioral memory assays, RIP-seq (650 RNAs incl. EIF3G), spine/dendrite morphology","pmids":["34260917"],"confidence":"High","gaps":["Mechanism of RNA cargo selection unknown","How transport rate controls translation not defined"]},{"year":2021,"claim":"Defined KIF5C's requirement for cortical neuronal migration and dendritic maturation, and showed it is dispensable for prion propagation, delimiting its in vivo roles.","evidence":"In utero electroporation knockdown, migration and morphology assays, RNA-seq; separate prion-inoculated KO survival study","pmids":["34966180","34372599"],"confidence":"Medium","gaps":["Cargo driving migration phenotype unidentified","Redundancy with other KIF5 isoforms in vivo not dissected"]},{"year":2024,"claim":"Showed disease variants in the ATP-binding/motor domain reduce ATPase activity and motility and abolish cargo (peroxisome) transport, unifying patient genetics with motor mechanism.","evidence":"In vitro ATP hydrolysis, live-cell peroxisome transport, motility in neurons, Drosophila model (idx14); variant motility in hippocampal neurons (idx15)","pmids":["38525108","39503049"],"confidence":"High","gaps":["Quantitative link between residual motor activity and clinical severity unclear","Effect on adaptor binding not assessed"]},{"year":2025,"claim":"A pathogenic knock-in mouse causally linked KIF5C dysfunction to impaired axonal mitochondrial transport, reduced spine density, and deficient synaptic transmission/LTP, with overexpression rescuing memory deficits.","evidence":"Conditional knock-in mouse, electrophysiology (mEPSC, LTP), spine morphology, live mitochondrial transport imaging, overexpression rescue","pmids":["41260309"],"confidence":"High","gaps":["Which cargo deficit is primary driver of synaptic phenotype unresolved","Cell-type contributions not fully separated"]},{"year":null,"claim":"How CK2 phosphorylation, adaptor-mediated activation (HAP1a/GRIP1), and microtubule lattice regulators (e.g., tau phosphorylation state) are integrated to control KIF5C cargo specificity and processivity in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling activation, phosphorylation, and lattice cues","Tau modulation shown only in vitro/preprint","Cargo-specific regulation in living neurons unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,14,15]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[2,7,14]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[11]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[14,17]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[14,17]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[6,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,6,8]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,8,10]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[11,13,16]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[13]}],"complexes":["kinesin-1 (KIF5C/kinesin light chain)"],"partners":["RANBP2","GRIF-1","HAP1","GRIP1","CSNK2A2","STX6","VAMP4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60282","full_name":"Kinesin heavy chain isoform 5C","aliases":["Kinesin heavy chain neuron-specific 2","Kinesin-1"],"length_aa":957,"mass_kda":109.5,"function":"Microtubule-associated force-producing protein that may play a role in organelle transport. Has ATPase activity (By similarity). Involved in synaptic transmission (PubMed:24812067). Mediates dendritic trafficking of mRNAs (By similarity). Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/O60282/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIF5C","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":77,"dependency_fraction":0.012987012987012988},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"KLC4","stoichiometry":4.0},{"gene":"KLC2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KIF5C","total_profiled":1310},"omim":[{"mim_id":"615412","title":"CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 4; CDCBM4","url":"https://www.omim.org/entry/615412"},{"mim_id":"615411","title":"CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 3; CDCBM3","url":"https://www.omim.org/entry/615411"},{"mim_id":"615282","title":"CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 2; CDCBM2","url":"https://www.omim.org/entry/615282"},{"mim_id":"614563","title":"CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 13; CDCBM13","url":"https://www.omim.org/entry/614563"},{"mim_id":"614039","title":"CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 1; CDCBM1","url":"https://www.omim.org/entry/614039"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cytosol","reliability":"Uncertain"},{"location":"Equatorial segment","reliability":"Uncertain"},{"location":"Connecting piece","reliability":"Uncertain"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":51.8}],"url":"https://www.proteinatlas.org/search/KIF5C"},"hgnc":{"alias_symbol":["NKHC2"],"prev_symbol":[]},"alphafold":{"accession":"O60282","domains":[{"cath_id":"3.40.850.10","chopping":"7-126_184-206_231-333","consensus_level":"high","plddt":89.3154,"start":7,"end":333},{"cath_id":"-","chopping":"338-385","consensus_level":"medium","plddt":79.5529,"start":338,"end":385}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60282","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60282-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60282-F1-predicted_aligned_error_v6.png","plddt_mean":78.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIF5C","jax_strain_url":"https://www.jax.org/strain/search?query=KIF5C"},"sequence":{"accession":"O60282","fasta_url":"https://rest.uniprot.org/uniprotkb/O60282.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60282/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60282"}},"corpus_meta":[{"pmid":"23603762","id":"PMC_23603762","title":"Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23603762","citation_count":367,"is_preprint":false},{"pmid":"10964943","id":"PMC_10964943","title":"KIF5C, a novel neuronal kinesin enriched in motor neurons.","date":"2000","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/10964943","citation_count":256,"is_preprint":false},{"pmid":"17887960","id":"PMC_17887960","title":"Association of the kinesin-binding domain of RanBP2 to KIF5B and KIF5C determines mitochondria localization and function.","date":"2007","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/17887960","citation_count":107,"is_preprint":false},{"pmid":"11553612","id":"PMC_11553612","title":"The docking of kinesins, KIF5B and KIF5C, to Ran-binding protein 2 (RanBP2) is mediated via a novel RanBP2 domain.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11553612","citation_count":87,"is_preprint":false},{"pmid":"24812067","id":"PMC_24812067","title":"Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic function.","date":"2014","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24812067","citation_count":84,"is_preprint":false},{"pmid":"16835241","id":"PMC_16835241","title":"Mapping the GRIF-1 binding domain of the kinesin, KIF5C, substantiates a role for GRIF-1 as an adaptor protein in the anterograde trafficking of cargoes.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16835241","citation_count":69,"is_preprint":false},{"pmid":"31757889","id":"PMC_31757889","title":"The adaptor proteins HAP1a and GRIP1 collaborate to activate the kinesin-1 isoform KIF5C.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/31757889","citation_count":39,"is_preprint":false},{"pmid":"29048727","id":"PMC_29048727","title":"Mutations of KIF5C cause a neurodevelopmental disorder of infantile-onset epilepsy, absent language, and distinctive malformations of cortical development.","date":"2017","source":"American journal of medical genetics. 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Selective inhibition of this interaction causes perinuclear clustering of mitochondria, deficits in mitochondrial membrane potential, and cell shrinkage, establishing KIF5C as a motor for mitochondrial transport via RanBP2.\",\n      \"method\": \"Domain truncation mapping, site-directed mutagenesis, co-immunoprecipitation, selective peptide inhibition, mitochondrial localization assay, membrane potential measurement\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, Co-IP, functional inhibition, organelle localization), clear mechanistic phenotype, single lab but comprehensive\",\n      \"pmids\": [\"17887960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GRIF-1 (a proposed kinesin adaptor) directly and specifically binds to the C-terminal cargo-binding region of the KIF5C non-motor domain; this interaction is confirmed by FRET, yeast two-hybrid, and Co-IP, and GRIF-1 can also associate with the tetrameric kinesin light-chain/KIF5C complex, supporting a role for GRIF-1 as an adaptor for KIF5C-mediated anterograde delivery of mitochondria and GABAA receptor-containing vesicles.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, FRET (fluorescence resonance energy transfer), confocal co-localization, truncation mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction confirmed by FRET (Tier 1 proximity assay) plus reciprocal Co-IP and yeast two-hybrid; multiple orthogonal methods, precise domain mapped\",\n      \"pmids\": [\"16835241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIF5C is a substrate for protein kinase CK2; phosphorylation occurs at amino acid Ser338 in the non-motor domain and is carried out by CK2α/CK2β and CK2α'/CK2β holoenzymes as well as by CK2α' alone, but not by CK2α alone.\",\n      \"method\": \"In vitro kinase assay, deletion mutants, peptide library screening, site-directed mutagenesis (phosphorylation site mapping), in vivo phosphorylation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and site mapping, in vivo confirmation, single lab but multiple methods\",\n      \"pmids\": [\"18682247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KIF5C preferentially binds to the CK2α' catalytic subunit over CK2α; the direct interaction was confirmed by pull-down and surface plasmon resonance; co-localization in neuroblastoma cells and primary neurons is consistent with biochemical data.\",\n      \"method\": \"Yeast two-hybrid, co-sedimentation, co-immunoprecipitation, pull-down, surface plasmon resonance, co-localization immunofluorescence\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — surface plasmon resonance (direct binding, quantitative) plus pull-down and Co-IP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19011756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KIF5C functions as a kinesin motor for apical trafficking in MDCK epithelial cells; it was identified by mass spectrometry on immunoisolated post-Golgi vesicles carrying apical cargo (both raft-associated sucrase isomaltase and raft-independent neurotrophin receptor), and vesicle-associated KIF5C was highest immediately after trans-Golgi network release.\",\n      \"method\": \"Mass spectrometry of vesicle fractions, immunoisolation of post-Golgi vesicles, subcellular fractionation\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry on immunoisolated vesicles with temporal fractionation; single lab, no direct functional KD rescue shown in abstract\",\n      \"pmids\": [\"20094756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A germline mosaic KIF5C mutation found in MCD patients was shown to affect ATP hydrolysis activity of the KIF5C motor domain, establishing impaired ATPase function as a pathogenic mechanism.\",\n      \"method\": \"ATP hydrolysis assay (in vitro biochemical assay on patient-mutation protein)\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro ATPase assay on mutant protein, published in high-impact journal, subsequently replicated by multiple independent clinical studies\",\n      \"pmids\": [\"23603762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KIF5C mediates polarized vesicular transport of syntaxin 6 and VAMP4 to the nascent axon; silencing KIF5C prevents polarized insertion of IGF-1R into the neuronal plasma membrane and blocks neuronal polarization, linking stable microtubule accumulation to KIF5C-dependent vesicular trafficking as a mechanistic step in axon specification.\",\n      \"method\": \"siRNA knockdown of KIF5C in cultured neurons, immunofluorescence co-localization of syntaxin 6/VAMP4 with KIF5C vesicles, membrane IGF-1R insertion assay\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotype (loss of polarized IGF-1R insertion, loss of neuronal polarization), cargo co-localization; single lab, single study\",\n      \"pmids\": [\"27699600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HAP1a and GRIP1 form a protein complex in the brain and cooperate to activate kinesin-1 subunit KIF5C in vitro; their cooperative action is proposed to stabilize the central hinge region that is critical for kinesin-1 autoinhibition relief.\",\n      \"method\": \"Co-immunoprecipitation (brain tissue), in vitro kinesin activation assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP from brain and in vitro activation assay; single lab, two complementary methods but mechanism of hinge stabilization inferred, not directly demonstrated\",\n      \"pmids\": [\"31757889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KIF5C associates with Pseudorabies virus (PRV) particles in differentiated neurons (but not undifferentiated cells) and is recruited to viral particles via the gE/gI-US9p complex; loss of gE/gI-US9p abolishes KIF5C recruitment to PRV particles without affecting dynein binding, implicating KIF5C in plus-end-directed anterograde axonal transport of PRV.\",\n      \"method\": \"Motor co-sedimentation with purified viral particles, quantitative transport assay in differentiated neuronal cells, genetic deletion of viral gE/gI-US9p\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct motor recruitment assay with viral particle pulldown and genetic deletion; single lab, differentiation-dependent finding adds mechanistic depth\",\n      \"pmids\": [\"32511265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIF5C loss of function in dorsal hippocampal CA1 neurons impairs both spatial and contextual fear memory, while gain of function specifically enhances spatial memory and extinction of contextual fear; KIF5C is associated with ~650 dendritic RNAs including EIF3G (a translation initiation regulator) and is a rate-determining component of local translation underlying structural plasticity.\",\n      \"method\": \"Conditional loss-of-function and gain-of-function (viral vector), behavioral memory assays, RNA immunoprecipitation (RIP-seq, identifying 650 associated RNAs), dendritic arborization and spine density measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — LOF and GOF with defined behavioral and structural phenotypes, RIP-seq for cargo identification, multiple orthogonal readouts in single study\",\n      \"pmids\": [\"34260917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIF5C knockout does not alter PrPSc spread, distribution, or survival times in prion-inoculated mice, indicating that KIF5C is dispensable for prion disease propagation in vivo despite its known role in PrPC vesicle transport.\",\n      \"method\": \"Kif5c knockout mouse model, stereotactic prion inoculation, immunohistochemistry for PrP, survival analysis\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined negative phenotype; single lab, well-controlled negative result\",\n      \"pmids\": [\"34372599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Kif5c deficiency in mice causes disturbed cortical neuronal migration, reduced dendritic branching, and decreased dendritic spine density, as demonstrated by in utero electroporation knockdown both in vitro and in vivo.\",\n      \"method\": \"In utero electroporation knockdown, in vitro neuron knockdown, cortical migration assay, dendritic morphology analysis, RNA sequencing of knockdown neurons\",\n      \"journal\": \"Pediatric research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro KD with defined structural/migration phenotype; single lab, multiple readouts\",\n      \"pmids\": [\"34966180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A pathogenic in-frame deletion removing Ser90 from the KIF5C ATP-binding domain significantly reduces ATP hydrolysis activity in vitro, causes mutant KIF5C to co-localize with microtubules (unlike wild-type which is distributed throughout cytoplasm), and abolishes peroxisome transport in live-cell cargo-trafficking assays.\",\n      \"method\": \"In vitro ATP hydrolysis assay, immunofluorescence co-localization, live-cell cargo-trafficking (peroxisome transport) assay, Drosophila nervous system model\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ATPase assay plus live-cell cargo transport assay with mutagenesis-equivalent variant; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38525108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Pathogenic de novo KIF5C variants (including Glu237Val, Thr93Ile, Thr93Asn, Ser90del, Lys92Arg, Glu237Lys) display significantly reduced motor domain activity compared to wild-type KIF5C when expressed in hippocampal neurons, establishing loss of motor function as the molecular basis of disease.\",\n      \"method\": \"Fluorescently-tagged KIF5C variant expression in isolated hippocampal neurons, motor function assay (motility measurement)\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional motor assay in neurons for multiple variants; single lab, no in vitro reconstitution, but direct functional measurement\",\n      \"pmids\": [\"39503049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A conditional knock-in mouse model of a pathogenic KIF5C variant reveals that KIF5C dysfunction decreases mature dendritic spine density, impairs axonal mitochondrial transport, reduces miniature EPSC frequency, impairs long-term potentiation, and alters presynaptic vesicle release probability; overexpression of KIF5C in hippocampal CA1 rescues memory and excitatory synaptic transmission deficits.\",\n      \"method\": \"Conditional knock-in mouse, electrophysiology (mEPSC, LTP), dendritic spine morphology, live axonal mitochondria transport imaging, KIF5C overexpression rescue\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse with electrophysiology, organelle transport imaging, and rescue experiment; multiple orthogonal methods establishing mechanistic pathway\",\n      \"pmids\": [\"41260309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Tau weakly inhibits KIF5C motility in vitro but does not strongly block it; hyperphosphorylation of tau further reduces KIF5C inhibition (decreases processivity inhibition), in contrast to strong inhibition of KIF1A by hyperphosphorylated tau, indicating KIF5C is differentially regulated by tau phosphorylation state on the microtubule lattice.\",\n      \"method\": \"In vitro single-molecule motility assay with tau phosphomutants, live neuron axonal transport assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with phosphomutants is rigorous, but preprint not yet peer-reviewed; single lab\",\n      \"pmids\": [\"bio_10.1101_2025.07.31.667882\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KIF5C is a neuronal kinesin-1 heavy chain that drives anterograde microtubule-based transport of diverse cargoes—including mitochondria (via RanBP2 adaptor), GABAA receptor vesicles (via GRIF-1 adaptor), IGF-1R vesicles (via syntaxin 6/VAMP4), dendritic RNAs/local translation machinery, and apical trafficking vesicles in epithelial cells—using ATP hydrolysis in its motor domain; it is activated cooperatively by HAP1a and GRIP1 adaptors that relieve autoinhibition, phosphorylated by CK2 (preferentially CK2α') at Ser338 in its non-motor domain, and is required for cortical neuronal migration, dendritic spine maturation, axonal mitochondrial transport, and synaptic plasticity underlying spatial memory.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIF5C is a neuronal kinesin-1 heavy chain that powers anterograde, microtubule-based transport of diverse cargoes through ATP hydrolysis in its motor domain, and is required for cortical neuronal migration, dendritic branching, spine maturation, and synaptic plasticity underlying spatial and contextual memory [#0, #13, #11, #16]. Cargo selection is achieved through its non-motor coiled-coil and globular tail, which engages cargo-specific adaptors: a unique domain of RanBP2 docks KIF5C (and KIF5B but not KIF5A) for mitochondrial transport, with a single isoform-discriminating residue conferring this selectivity and its disruption causing perinuclear mitochondrial clustering and loss of membrane potential [#1, #2]; GRIF-1 binds the C-terminal cargo-binding region as an adaptor for mitochondria and GABAA-receptor vesicles [#3]; and KIF5C delivers syntaxin 6/VAMP4 vesicles to drive polarized IGF-1R insertion during axon specification [#8]. KIF5C also transports apical post-Golgi vesicles in epithelial cells [#6] and associates with ~650 dendritic RNAs including the translation regulator EIF3G, acting as a rate-determining component of local translation that supports structural plasticity [#11]. Its activity is regulated by CK2, which phosphorylates Ser338 in the non-motor domain preferentially through the CK2\\u03b1' subunit [#4, #5], and by cooperative HAP1a/GRIP1-mediated relief of kinesin-1 autoinhibition [#9]. Pathogenic germline and de novo KIF5C variants clustering in the ATP-binding and motor domain reduce ATP hydrolysis and motility, abolish cargo transport, and cause malformations of cortical development; knock-in mouse models recapitulate impaired axonal mitochondrial transport, reduced spine density, and deficient LTP, with overexpression rescuing memory and synaptic deficits [#7, #14, #15, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established KIF5C as a neuronal kinesin heavy chain with isoform redundancy, answering whether this KIF5 paralog has a distinct neuronal role.\",\n      \"evidence\": \"Knockout mice, antibody staining, heterodimer and complementation rescue assays\",\n      \"pmids\": [\"10964943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific cargoes not identified\", \"Mechanism of motor neuron loss unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified RanBP2 as a selective docking scaffold for KIF5C and KIF5B, beginning to explain how this kinesin is targeted to specific cargo.\",\n      \"evidence\": \"In vitro direct binding, reciprocal Co-IP, RanBP2 domain mapping\",\n      \"pmids\": [\"11553612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo identity at the time unclear\", \"Structural basis of isoform selectivity not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined GRIF-1 as a direct adaptor binding the KIF5C non-motor cargo-binding domain, linking KIF5C to mitochondrial and GABAA-receptor vesicle delivery.\",\n      \"evidence\": \"Yeast two-hybrid, FRET, Co-IP, truncation mapping\",\n      \"pmids\": [\"16835241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo cargo delivery not directly demonstrated\", \"Regulation of adaptor binding unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped the RanBP2-binding segment and a single isoform-determining residue, and showed disruption causes mitochondrial mislocalization, establishing KIF5C as a mitochondrial motor.\",\n      \"evidence\": \"Domain truncation, site-directed mutagenesis, peptide inhibition, organelle localization and membrane potential assays\",\n      \"pmids\": [\"17887960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activation/regulation of this transport not addressed\", \"Relationship to GRIF-1 pathway unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed CK2 phosphorylates KIF5C at Ser338 with preferential engagement of the CK2\\u03b1' subunit, identifying a post-translational regulatory input on the non-motor domain.\",\n      \"evidence\": \"In vitro kinase assays, site mapping, pull-down, surface plasmon resonance, co-localization\",\n      \"pmids\": [\"18682247\", \"19011756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Ser338 phosphorylation on transport not defined\", \"Physiological trigger of CK2 phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended KIF5C's role beyond neurons by identifying it on apical post-Golgi carriers in epithelial cells, indicating broad cargo versatility.\",\n      \"evidence\": \"Mass spectrometry of immunoisolated post-Golgi vesicles, temporal subcellular fractionation\",\n      \"pmids\": [\"20094756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No knockdown/rescue demonstrating functional requirement\", \"Adaptor mediating apical recruitment unidentified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that a disease mutation impairs motor-domain ATP hydrolysis, establishing reduced ATPase activity as a pathogenic mechanism in cortical malformation.\",\n      \"evidence\": \"In vitro ATP hydrolysis assay on patient-mutation protein\",\n      \"pmids\": [\"23603762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link from ATPase deficit to cellular phenotype not yet shown\", \"In vivo modeling absent at this stage\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected KIF5C to axon specification by showing it transports syntaxin 6/VAMP4 vesicles required for polarized IGF-1R membrane insertion.\",\n      \"evidence\": \"siRNA knockdown in neurons, cargo co-localization, membrane IGF-1R insertion assay\",\n      \"pmids\": [\"27699600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct adaptor for these vesicles not mapped\", \"Single study, single system\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified HAP1a and GRIP1 as cooperating activators of KIF5C, addressing how the autoinhibited motor is switched on.\",\n      \"evidence\": \"Co-IP from brain tissue, in vitro kinesin activation assay\",\n      \"pmids\": [\"31757889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hinge-stabilization mechanism inferred, not directly shown\", \"Cargo specificity of this activation unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed KIF5C is recruited to pseudorabies virus particles via the gE/gI-US9p complex in differentiated neurons, implicating it in anterograde axonal viral transport.\",\n      \"evidence\": \"Motor co-sedimentation with viral particles, transport assay, viral gene deletion\",\n      \"pmids\": [\"32511265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect motor-particle binding not resolved\", \"Relevance to other viruses untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established KIF5C as a rate-determining carrier of dendritic RNAs and local translation machinery linking transport to memory and structural plasticity.\",\n      \"evidence\": \"Conditional LOF/GOF, behavioral memory assays, RIP-seq (650 RNAs incl. EIF3G), spine/dendrite morphology\",\n      \"pmids\": [\"34260917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of RNA cargo selection unknown\", \"How transport rate controls translation not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined KIF5C's requirement for cortical neuronal migration and dendritic maturation, and showed it is dispensable for prion propagation, delimiting its in vivo roles.\",\n      \"evidence\": \"In utero electroporation knockdown, migration and morphology assays, RNA-seq; separate prion-inoculated KO survival study\",\n      \"pmids\": [\"34966180\", \"34372599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cargo driving migration phenotype unidentified\", \"Redundancy with other KIF5 isoforms in vivo not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed disease variants in the ATP-binding/motor domain reduce ATPase activity and motility and abolish cargo (peroxisome) transport, unifying patient genetics with motor mechanism.\",\n      \"evidence\": \"In vitro ATP hydrolysis, live-cell peroxisome transport, motility in neurons, Drosophila model (idx14); variant motility in hippocampal neurons (idx15)\",\n      \"pmids\": [\"38525108\", \"39503049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative link between residual motor activity and clinical severity unclear\", \"Effect on adaptor binding not assessed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A pathogenic knock-in mouse causally linked KIF5C dysfunction to impaired axonal mitochondrial transport, reduced spine density, and deficient synaptic transmission/LTP, with overexpression rescuing memory deficits.\",\n      \"evidence\": \"Conditional knock-in mouse, electrophysiology (mEPSC, LTP), spine morphology, live mitochondrial transport imaging, overexpression rescue\",\n      \"pmids\": [\"41260309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which cargo deficit is primary driver of synaptic phenotype unresolved\", \"Cell-type contributions not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CK2 phosphorylation, adaptor-mediated activation (HAP1a/GRIP1), and microtubule lattice regulators (e.g., tau phosphorylation state) are integrated to control KIF5C cargo specificity and processivity in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling activation, phosphorylation, and lattice cues\", \"Tau modulation shown only in vitro/preprint\", \"Cargo-specific regulation in living neurons unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 14, 15]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [2, 7, 14]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [14, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [14, 17]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 6, 8]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 8, 10]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [11, 13, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\"kinesin-1 (KIF5C/kinesin light chain)\"],\n    \"partners\": [\"RanBP2\", \"GRIF-1\", \"HAP1\", \"GRIP1\", \"CSNK2A2\", \"STX6\", \"VAMP4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}