Affinage

KIF5C

Kinesin heavy chain isoform 5C · UniProt O60282

Length
957 aa
Mass
109.5 kDa
Annotated
2026-06-10
25 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    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

    PMID:10964943

    Open questions at the time
    • Specific cargoes not identified
    • Mechanism of motor neuron loss unresolved
  2. 2001 High

    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

    PMID:11553612

    Open questions at the time
    • Cargo identity at the time unclear
    • Structural basis of isoform selectivity not defined
  3. 2006 High

    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

    PMID:16835241

    Open questions at the time
    • In vivo cargo delivery not directly demonstrated
    • Regulation of adaptor binding unknown
  4. 2007 High

    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

    PMID:17887960

    Open questions at the time
    • Activation/regulation of this transport not addressed
    • Relationship to GRIF-1 pathway unclear
  5. 2009 High

    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

    PMID:18682247 PMID:19011756

    Open questions at the time
    • Functional consequence of Ser338 phosphorylation on transport not defined
    • Physiological trigger of CK2 phosphorylation unknown
  6. 2010 Medium

    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

    PMID:20094756

    Open questions at the time
    • No knockdown/rescue demonstrating functional requirement
    • Adaptor mediating apical recruitment unidentified
  7. 2013 High

    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

    PMID:23603762

    Open questions at the time
    • Link from ATPase deficit to cellular phenotype not yet shown
    • In vivo modeling absent at this stage
  8. 2016 Medium

    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

    PMID:27699600

    Open questions at the time
    • Direct adaptor for these vesicles not mapped
    • Single study, single system
  9. 2019 Medium

    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

    PMID:31757889

    Open questions at the time
    • Hinge-stabilization mechanism inferred, not directly shown
    • Cargo specificity of this activation unknown
  10. 2020 Medium

    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

    PMID:32511265

    Open questions at the time
    • Direct vs indirect motor-particle binding not resolved
    • Relevance to other viruses untested
  11. 2021 High

    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

    PMID:34260917

    Open questions at the time
    • Mechanism of RNA cargo selection unknown
    • How transport rate controls translation not defined
  12. 2021 Medium

    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

    PMID:34372599 PMID:34966180

    Open questions at the time
    • Cargo driving migration phenotype unidentified
    • Redundancy with other KIF5 isoforms in vivo not dissected
  13. 2024 High

    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)

    PMID:38525108 PMID:39503049

    Open questions at the time
    • Quantitative link between residual motor activity and clinical severity unclear
    • Effect on adaptor binding not assessed
  14. 2025 High

    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

    PMID:41260309

    Open questions at the time
    • Which cargo deficit is primary driver of synaptic phenotype unresolved
    • Cell-type contributions not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003774 cytoskeletal motor activity 3 GO:0140657 ATP-dependent activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0003723 RNA binding 1
Localization
GO:0005856 cytoskeleton 2 GO:0031410 cytoplasmic vesicle 2 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9609507 Protein localization 3 R-HSA-1266738 Developmental Biology 1
Partners
CSNK2A2GRIF-1GRIP1HAP1RANBP2STX6VAMP4
Complex memberships
kinesin-1 (KIF5C/kinesin light chain)

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 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. Gene knockout in mice, antibody staining, heterodimer formation assays, complementation rescue The Journal of neuroscience High 10964943
2001 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. In vitro direct binding assay, co-immunoprecipitation (in vitro and in vivo), domain mapping of RanBP2 The Journal of biological chemistry High 11553612
2007 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. Domain truncation mapping, site-directed mutagenesis, co-immunoprecipitation, selective peptide inhibition, mitochondrial localization assay, membrane potential measurement Traffic High 17887960
2006 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. Yeast two-hybrid, co-immunoprecipitation, FRET (fluorescence resonance energy transfer), confocal co-localization, truncation mapping The Journal of biological chemistry High 16835241
2008 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. In vitro kinase assay, deletion mutants, peptide library screening, site-directed mutagenesis (phosphorylation site mapping), in vivo phosphorylation Biochemical and biophysical research communications High 18682247
2009 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. Yeast two-hybrid, co-sedimentation, co-immunoprecipitation, pull-down, surface plasmon resonance, co-localization immunofluorescence Cellular and molecular life sciences High 19011756
2010 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. Mass spectrometry of vesicle fractions, immunoisolation of post-Golgi vesicles, subcellular fractionation Cellular and molecular life sciences Medium 20094756
2013 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. ATP hydrolysis assay (in vitro biochemical assay on patient-mutation protein) Nature genetics High 23603762
2016 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. siRNA knockdown of KIF5C in cultured neurons, immunofluorescence co-localization of syntaxin 6/VAMP4 with KIF5C vesicles, membrane IGF-1R insertion assay Molecular neurobiology Medium 27699600
2019 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. Co-immunoprecipitation (brain tissue), in vitro kinesin activation assay Journal of cell science Medium 31757889
2020 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. Motor co-sedimentation with purified viral particles, quantitative transport assay in differentiated neuronal cells, genetic deletion of viral gE/gI-US9p PLoS pathogens Medium 32511265
2021 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. 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 Cell reports High 34260917
2021 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. Kif5c knockout mouse model, stereotactic prion inoculation, immunohistochemistry for PrP, survival analysis Viruses Medium 34372599
2021 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. In utero electroporation knockdown, in vitro neuron knockdown, cortical migration assay, dendritic morphology analysis, RNA sequencing of knockdown neurons Pediatric research Medium 34966180
2024 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. In vitro ATP hydrolysis assay, immunofluorescence co-localization, live-cell cargo-trafficking (peroxisome transport) assay, Drosophila nervous system model MedComm High 38525108
2024 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. Fluorescently-tagged KIF5C variant expression in isolated hippocampal neurons, motor function assay (motility measurement) American journal of medical genetics. Part A Medium 39503049
2025 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. Conditional knock-in mouse, electrophysiology (mEPSC, LTP), dendritic spine morphology, live axonal mitochondria transport imaging, KIF5C overexpression rescue Neurobiology of disease High 41260309
2025 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. In vitro single-molecule motility assay with tau phosphomutants, live neuron axonal transport assay bioRxivpreprint Medium bio_10.1101_2025.07.31.667882

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nature genetics 367 23603762
2000 KIF5C, a novel neuronal kinesin enriched in motor neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 256 10964943
2007 Association of the kinesin-binding domain of RanBP2 to KIF5B and KIF5C determines mitochondria localization and function. Traffic (Copenhagen, Denmark) 107 17887960
2001 The docking of kinesins, KIF5B and KIF5C, to Ran-binding protein 2 (RanBP2) is mediated via a novel RanBP2 domain. The Journal of biological chemistry 87 11553612
2014 Involvement of the kinesin family members KIF4A and KIF5C in intellectual disability and synaptic function. Journal of medical genetics 84 24812067
2006 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. The Journal of biological chemistry 69 16835241
2019 The adaptor proteins HAP1a and GRIP1 collaborate to activate the kinesin-1 isoform KIF5C. Journal of cell science 39 31757889
2017 Mutations of KIF5C cause a neurodevelopmental disorder of infantile-onset epilepsy, absent language, and distinctive malformations of cortical development. American journal of medical genetics. Part A 34 29048727
2021 Molecular motor protein KIF5C mediates structural plasticity and long-term memory by constraining local translation. Cell reports 28 34260917
2020 Deletion of the Pseudorabies Virus gE/gI-US9p complex disrupts kinesin KIF1A and KIF5C recruitment during egress, and alters the properties of microtubule-dependent transport in vitro. PLoS pathogens 23 32511265
2010 KIF5C, a kinesin motor involved in apical trafficking of MDCK cells. Cellular and molecular life sciences : CMLS 22 20094756
2009 KIF5C: a new binding partner for protein kinase CK2 with a preference for the CK2alpha' subunit. Cellular and molecular life sciences : CMLS 16 19011756
2008 The kinesin I family member KIF5C is a novel substrate for protein kinase CK2. Biochemical and biophysical research communications 15 18682247
2004 Expression of kinesin kif5c during chick development. Anatomy and embryology 14 14758548
2020 Phenotype description in KIF5C gene hot-spot mutations responsible for malformations of cortical development (MCD). European journal of medical genetics 13 32562872
2021 KIF5C deficiency causes abnormal cortical neuronal migration, dendritic branching, and spine morphology in mice. Pediatric research 8 34966180
2016 The Motor KIF5C Links the Requirements of Stable Microtubules and IGF-1 Receptor Membrane Insertion for Neuronal Polarization. Molecular neurobiology 8 27699600
2024 A novel in-frame deletion in KIF5C gene causes infantile onset epilepsy and psychomotor retardation. MedComm 6 38525108
2022 Abnormal course of the corticospinal tracts in KIF5C-related encephalopathy. European journal of medical genetics 5 36122673
2023 LncRNA ZNF667-AS1 Targets miR-523-3p/KIF5C Axis to Hinder Colon Cancer Progression. Molecular biotechnology 3 37322260
2021 Deletion of Kif5c Does Not Alter Prion Disease Tempo or Spread in Mouse Brain. Viruses 2 34372599
2024 Expanding the Molecular and Clinical Phenotype of Patients With De Novo Variants in KIF5C: A Six Patient Case Series. American journal of medical genetics. Part A 1 39503049
2026 KIF5C-Related Neurodevelopmental Disorder: Three New Cases and Additional Neuroradiologic Insights. Neurology. Genetics 0 42146894
2025 Pathogenic KIF5C mutation disrupts dendritic spine maturation and mitochondrial trafficking in neurodevelopmental disorders. Neurobiology of disease 0 41260309
2024 Role of hsa-miR-543-KIF5C/CALM3 pathway in neuron differentiation of embryonic mesenchymal stem cells. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 0 39444227

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