Affinage

KIF21B

Kinesin-like protein KIF21B · UniProt O75037

Length
1637 aa
Mass
182.7 kDa
Annotated
2026-06-10
22 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KIF21B is a processive plus end-directed kinesin-4 motor enriched in neuronal dendrites that couples microtubule-based cargo transport with autonomous control of cytoskeletal dynamics to shape neuronal architecture and synaptic function (PMID:10225949, PMID:27117409, PMID:28290984). Beyond translocating along microtubules, KIF21B accumulates at growing plus ends and induces pausing and catastrophe through non-motor microtubule-binding domains in its stalk and a C-terminal WD40 domain that preferentially engages the GTP-type lattice; its autoinhibitory domain enhances pause induction by preventing detachment from microtubule tips rather than blocking lattice binding (PMID:28290984). This length-restricting activity has consequences across cell types: in neurons it controls microtubule growth, dendritic arborization, spine density and synaptic transmission (PMID:27117409), and in T cells it limits microtubule overgrowth to permit dynein-driven centrosome translocation to the immunological synapse (PMID:33346730). As a transporter and scaffold, KIF21B delivers and regulates synaptic receptors and signaling complexes, mediating dendritic delivery of GABAA receptor γ2-subunit vesicles (PMID:25172774), regulating endocytic recycling of GluN2B-NMDARs within an NBEA–recycling endosome complex (PMID:29847800), and sequestering the Rac1-GEF ELMO1 out of spines in an NMDAR-LTD-dependent manner to terminate Rac1 signaling and drive long-term depression (PMID:29949770). KIF21B additionally binds and regulates the actin cytoskeleton independently of its motor activity, controlling branching and nucleokinesis during neuronal migration (PMID:37418324) and, via interactions with GKAP and myosin Va, driving spine actin turnover and GKAP/GluA2-AMPAR removal during homeostatic synaptic downscaling (PMID:37418322). Its motility is positively regulated by the E3 ligase TRIM3 through an RBCC-domain interaction without degradation (PMID:24086586), and neurodevelopmental-disorder-associated missense variants impair neuronal migration by attenuating autoinhibition and producing aberrant excess motor activity (PMID:32415109).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 Medium

    Established that a plus end-directed kinesin could be selectively enriched in dendrites, raising the question of how directional motors achieve compartment-specific localization.

    Evidence Immunolocalization in neurons and motor/WD-40 domain analysis

    PMID:10225949

    Open questions at the time
    • Cargo bound by the WD-40 domain not identified
    • Mechanism of dendritic sorting unresolved
  2. 2013 Medium

    Identified a non-degradative regulator of KIF21B motility, showing motor activity is positively tuned by a binding partner rather than solely intrinsic.

    Evidence Co-IP, co-localization at Golgi-derived vesicles, Trim3 knockout mice and motility assays

    PMID:24086586

    Open questions at the time
    • Molecular mechanism by which TRIM3 enhances motility unknown
    • Single lab
  3. 2014 Medium

    Assigned a defined transport cargo to KIF21B, demonstrating it delivers inhibitory receptor vesicles to dendrites and the surface.

    Evidence Co-IP, co-localization, shRNA knockdown and surface receptor quantification in neurons

    PMID:25172774

    Open questions at the time
    • Direct vs adaptor-mediated binding to GABAAR γ2 not resolved
    • Single lab, two methods
  4. 2016 High

    Revealed that KIF21B is not only a transporter but a regulator of microtubule dynamics whose loss alters dendrite and spine architecture and impairs learning in vivo.

    Evidence Kif21b knockout mice, live microtubule imaging, morphology, electrophysiology, behavior

    PMID:27117409

    Open questions at the time
    • Whether dynamics effects are direct or via cargo not separated in vivo
    • Molecular basis of microtubule regulation not defined here
  5. 2017 High

    Defined the biophysical mechanism of KIF21B's microtubule regulation, localizing pause-induction to stalk non-motor and WD40 domains and redefining the autoinhibitory domain's role.

    Evidence In vitro reconstitution with purified KIF21B, TIRF microscopy, domain mutagenesis, lattice-binding assays

    PMID:28290984

    Open questions at the time
    • How autoinhibition is relieved physiologically not established
    • Structural basis of GTP-lattice preference unresolved
  6. 2018 High

    Connected KIF21B to activity-dependent synaptic depression by showing it sequesters the Rac1-GEF ELMO1 to terminate Rac1 signaling and drive LTD.

    Evidence Kif21b knockout mice, Co-IP, live ELMO1 imaging, fear extinction behavior, CPYPP rescue

    PMID:29949770

    Open questions at the time
    • Stimulus-dependence of KIF21B-ELMO1 binding mechanism unclear
    • Link between transport and signaling termination not fully separated
  7. 2018 High

    Placed KIF21B in an NBEA–recycling endosome complex controlling GluN2B-NMDAR surface recycling, linking it to social behavior.

    Evidence Kif21b knockout mice, Co-IP, live NBEA imaging, surface receptor and social behavior assays

    PMID:29847800

    Open questions at the time
    • Direct binding partner within complex not pinpointed
    • Mechanism of recycling control vs transport not separated
  8. 2018 Medium

    Showed KIF21B acts as an inhibitory constraint on excitatory transmission, distinct from other kinesins.

    Evidence RNAi knockdown and whole-cell patch-clamp in hippocampal neurons

    PMID:30479371

    Open questions at the time
    • Molecular basis of the constraint not defined
    • Single method, single lab
  9. 2020 High

    Generalized the length-restricting function beyond neurons, showing KIF21B-induced catastrophe enables centrosome polarization to the immunological synapse in T cells.

    Evidence KIF21B knockout T cells, live imaging, vinblastine rescue, biophysical simulations

    PMID:33346730

    Open questions at the time
    • Whether the same domains operate in T cells not tested directly
    • Cargo functions in T cells not addressed
  10. 2020 High

    Linked disease variants to a defined mechanism, showing attenuated autoinhibition produces excess motility that impairs neuronal migration.

    Evidence In utero electroporation of patient variants in mouse, migration and axon assays, motor activity measurement

    PMID:32415109

    Open questions at the time
    • Named Mendelian disorder not formally defined in timeline
    • Genotype-phenotype range across variants not fully mapped
  11. 2023 High

    Established a motor-independent function for KIF21B in directly binding and regulating actin during neuronal migration.

    Evidence In utero electroporation, slice live imaging, in vitro actin binding, in vivo actin dynamics

    PMID:37418324

    Open questions at the time
    • Actin-binding domain not mapped
    • Coordination between actin and microtubule activities unclear
  12. 2023 High

    Defined a KIF21B–GKAP–myosin Va axis controlling spine actin turnover and AMPAR removal during homeostatic downscaling.

    Evidence Co-IP, live actin imaging, Kif21b knockout neurons, overexpression, surface receptor assays, chronic activity protocols

    PMID:37418322

    Open questions at the time
    • Direct vs indirect binding to GKAP/myosin Va not fully resolved
    • How activity gates spine localization not mechanistically defined
  13. 2023 Medium

    Positioned KIF21B downstream of estradiol/BDNF/TrkB signaling in neuritogenesis.

    Evidence siRNA knockdown, morphological analysis, TrkB inhibition, Ngn3 expression assays

    PMID:37078090

    Open questions at the time
    • Mechanism connecting KIF21B to Ngn3 expression unknown
    • Single lab, correlative pathway placement

Open questions

Synthesis pass · forward-looking unresolved questions
  • How KIF21B's microtubule-regulating, actin-binding, and cargo-transport activities are physiologically coordinated and switched within a single cell remains unresolved.
  • No integrated structural model of full-length regulation
  • Triggers that relieve autoinhibition in vivo unknown
  • Relationship between actin and microtubule functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003774 cytoskeletal motor activity 3 GO:0008092 cytoskeletal protein binding 3 GO:0140096 catalytic activity, acting on a protein 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005856 cytoskeleton 3 GO:0031410 cytoplasmic vesicle 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-1266738 Developmental Biology 2 R-HSA-9609507 Protein localization 2 R-HSA-168256 Immune System 1
Partners
ELMO1GABRG2GKAPMYO5ANBEATRIM3
Complex memberships
NBEA–recycling endosome–GluN2B-NMDAR complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 KIF21B is a plus end-directed kinesin motor protein highly enriched in dendrites (not axons) of neurons, and contains a WD-40 repeat domain potentially involved in cargo binding. Its dendritic enrichment despite plus-end directionality indicated a novel kinesin sorting mechanism beyond minus-end-directed motor activity. Immunolocalization in neurons, motor domain analysis, identification of WD-40 domain The Journal of cell biology Medium 10225949
2013 The ubiquitin E3 ligase TRIM3 interacts with KIF21B via its RBCC domain, co-localizes with KIF21B at intracellular and Golgi-derived vesicles in neurons, and positively regulates KIF21B motor motility (TRIM3 depletion reduces KIF21B motility) without targeting KIF21B for degradation. Co-immunoprecipitation, co-localization in neurons, Trim3 knockout mice, TRIM3 overexpression in cultured neurons, motility assays PloS one Medium 24086586
2014 KIF21B interacts with (co-precipitates and co-localizes with) the GABAA receptor γ2 subunit in hippocampal neurons, and KIF21B knockdown reduces γ2-subunit-containing GABAAR clusters in neurites and at the cell surface, indicating KIF21B mediates dendritic delivery of GABAAR transport vesicles. Co-immunoprecipitation, co-localization, shRNA knockdown, surface receptor quantification in cultured neurons European journal of cell biology Medium 25172774
2016 KIF21B is a processive motor protein that also regulates microtubule dynamics: in Kif21b knockout neurons, microtubules grow more slowly and persistently, leading to tighter packing in dendrites, decreased dendritic arbor complexity, reduced spine density, and deficits in synaptic transmission. Kif21b-null mice show learning and memory deficits. Kif21b knockout mice, live cell microtubule dynamics imaging, dendritic morphology quantification, electrophysiology, behavioral assays Cell reports High 27117409
2017 KIF21B is a processive kinesin-4 motor that accumulates at microtubule plus ends and induces pausing. Even a few KIF21B molecules are sufficient to strongly inhibit microtubule plus-end growth in vitro. The pause-inducing activity depends on non-motor microtubule-binding domains in the stalk region and the C-terminal WD40 domain. The WD40 tail preferentially binds GTP-type over GDP-type microtubule lattice, contributing to plus-end association. KIF21B also contains a motor-inhibiting (autoinhibitory) domain that, rather than blocking microtubule interaction, enhances pause induction by preventing KIF21B detachment from microtubule tips. In vitro reconstitution with purified KIF21B, TIRF microscopy, domain deletion/mutation analysis, microtubule lattice-binding assays eLife High 28290984
2018 KIF21B interacts with the Rac1GEF subunit ELMO1 in an NMDAR-LTD stimulus-dependent manner, leading to ELMO1 translocation out of dendritic spines into endosomes. This KIF21B-mediated sequestration terminates Rac1 activation, causes spine shrinkage, facilitates AMPAR endocytosis, and reduces postsynaptic strength, constituting a mechanism for NMDAR-dependent LTD underlying fear extinction. Kif21b knockout mice, co-immunoprecipitation, live imaging of ELMO1 in spines, fear extinction behavioral assays, pharmacological rescue with CPYPP Cell reports High 29949770
2018 KIF21B constrains the dynamics of neurobeachin (NBEA) and is present in the NBEA–recycling endosome–GluN2B-NMDAR complex. Kif21b knockout decreases GluN2B-NMDAR surface expression and alters social behavior in mice, indicating KIF21B regulates endocytic recycling and local re-insertion of GluN2B-NMDARs at synapses. Kif21b knockout mice, co-immunoprecipitation, live imaging of NBEA in spines, surface receptor quantification, social behavior assays Cell reports High 29847800
2018 KIF21B knockdown in hippocampal neurons increases excitatory post-synaptic current frequency and amplitude, indicating KIF21B functions as an inhibitory constraint on excitatory synaptic transmission through a mechanism distinct from pre-synaptic NMDAR activity (unlike Kif11). RNAi knockdown, whole-cell patch-clamp electrophysiology in primary hippocampal neurons Scientific reports Medium 30479371
2020 KIF21B restricts microtubule length in T cells by inducing microtubule pausing followed by catastrophe. KIF21B knockout causes microtubule overgrowth that perturbs dynein-driven centrosome translocation to the immunological synapse. Catastrophe induction with vinblastine rescues centrosome polarization in KIF21B-knockout T cells. KIF21B knockout T cells, live microtubule imaging, vinblastine pharmacological rescue, biophysical simulations of dynein-mediated pulling forces eLife High 33346730
2020 Missense variants in KIF21B associated with neurodevelopmental disorders impede neuronal migration by attenuating kinesin autoinhibition, leading to aberrant (excess) KIF21B motility activity. An ACC-associated variant independently disrupts axonal growth and ipsilateral axon branching via deregulation of canonical kinesin motor activity. Kif21b haploinsufficiency impairs neuronal positioning in vivo. In vivo expression of KIF21B variants via in utero electroporation in mouse, neuronal migration assays, axonal growth quantification, motor activity measurements Nature communications High 32415109
2023 Kif21b directly binds and regulates the actin cytoskeleton (both in vitro and in vivo), influencing branching and nucleokinesis during radial glia-guided locomotion of cortical projection neurons, independently of its microtubule motor activity. This constitutes a non-canonical function of Kif21b on actin cytoskeleton during neuronal migration. In utero electroporation in mouse, live imaging on cultured cortical slices, in vitro actin binding assays, in vivo actin dynamics analysis in migratory neurons Cell reports High 37418324
2023 Kif21b binds GKAP (guanylate kinase-associated protein) and myosin Va, localizes in dendritic spines in a myosin Va- and neuronal activity-dependent manner, and regulates actin dynamics in spines. Kif21b depletion impairs actin turnover adaptation following chronic activity. Kif21b overexpression promotes actin polymerization. Kif21b controls GKAP removal from spines and reduction of surface GluA2-AMPARs, mediating homeostatic synaptic downscaling. Co-immunoprecipitation, live actin imaging in spines, Kif21b knockout neurons, overexpression assays, surface receptor quantification, chronic activity protocols Cell reports High 37418322
2023 KIF21B is required for estradiol- and BDNF-mediated neuronal morphology changes in hippocampal neurons. Kif21b silencing abolishes estradiol and BDNF effects on both axon and dendrite morphology, and also decreases Ngn3 expression. This places KIF21B in an Estradiol/BDNF/TrkB/KIF21B/Ngn3 signaling pathway regulating neuritogenesis. siRNA knockdown of Kif21b in cultured hippocampal neurons, morphological analysis, pharmacological TrkB inhibition, Ngn3 expression assays Frontiers in molecular neuroscience Medium 37078090

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Novel dendritic kinesin sorting identified by different process targeting of two related kinesins: KIF21A and KIF21B. The Journal of cell biology 142 10225949
2016 The Kinesin KIF21B Regulates Microtubule Dynamics and Is Essential for Neuronal Morphology, Synapse Function, and Learning and Memory. Cell reports 74 27117409
2017 Kinesin-4 KIF21B is a potent microtubule pausing factor. eLife 47 28290984
2018 Neurobeachin and the Kinesin KIF21B Are Critical for Endocytic Recycling of NMDA Receptors and Regulate Social Behavior. Cell reports 43 29847800
2018 The Molecular Motor KIF21B Mediates Synaptic Plasticity and Fear Extinction by Terminating Rac1 Activation. Cell reports 42 29949770
2020 Kinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells. eLife 37 33346730
2020 Mutations in the KIF21B kinesin gene cause neurodevelopmental disorders through imbalanced canonical motor activity. Nature communications 36 32415109
2013 TRIM3 regulates the motility of the kinesin motor protein KIF21B. PloS one 34 24086586
2010 Replication of KIF21B as a susceptibility locus for multiple sclerosis. Journal of medical genetics 30 20587413
2018 Kinesin Family of Proteins Kif11 and Kif21B Act as Inhibitory Constraints of Excitatory Synaptic Transmission Through Distinct Mechanisms. Scientific reports 27 30479371
2014 The kinesin KIF21B participates in the cell surface delivery of γ2 subunit-containing GABAA receptors. European journal of cell biology 26 25172774
2014 Abundant kif21b is associated with accelerated progression in neurodegenerative diseases. Acta neuropathologica communications 25 25274010
2021 KIF21B Expression in Osteosarcoma and Its Regulatory Effect on Osteosarcoma Cell Proliferation and Apoptosis Through the PI3K/AKT Pathway. Frontiers in oncology 12 33585227
2016 Different Contributions of CDKAL1, KIF21B, and LRRK2/MUC19 Polymorphisms to SAPHO Syndrome, Rheumatoid Arthritis, Ankylosing Spondylitis, and Seronegative Spondyloarthropathy. Genetic testing and molecular biomarkers 12 27936930
2014 Association of KIF21B genetic polymorphisms with ankylosing spondylitis in a Chinese Han population of Shandong Province. Clinical rheumatology 8 25149646
2022 SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis. Open medicine (Warsaw, Poland) 6 35233463
2023 The kinesin Kif21b regulates radial migration of cortical projection neurons through a non-canonical function on actin cytoskeleton. Cell reports 5 37418324
2022 Further delineation of KIF21B-related neurodevelopmental disorders. Journal of human genetics 5 36198761
2023 Kif21B mediates the effect of estradiol on the morphological plasticity of mouse hippocampal neurons. Frontiers in molecular neuroscience 4 37078090
2023 The kinesin Kif21b binds myosin Va and mediates changes in actin dynamics underlying homeostatic synaptic downscaling. Cell reports 4 37418322
2024 Mitochondrial ATP Synthesis and Proton Transport Synergistically Mitigate Oligodendrocyte Progenitor Cell Dysfunction Following Transient Middle Cerebral Artery Occlusion via the Pbx3/Dguok/Kif21b Signaling Pathway. International journal of medical sciences 1 39239553
2026 KIF21B, Ubiquitinated by TRIM3, Exerts Oncogenic Role in T-Cell Acute Lymphoblastic Leukemia by Activating Wnt/β-Catenin Pathway. Cancers 0 42122124

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