KIF18A Protein

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KIF18A Protein

Overview

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KIF18A Protein

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">KIF18A Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>KIF18A (Kinesin Family Member 18A)</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>[KIF18A](/genes/kif18a)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q8NI33](https://www.uniprot.org/uniprot/Q8NI33)</td>
</tr>
<tr>
<td class="label">PDB Structures</td>
<td>2Y4W, 5EJH, 6FUA</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~110 kDa</td>
</tr>
<tr>
<td class="label">Length</td>
<td>725 amino acids</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Cytoplasm, microtubules (neurons: axons, dendrites)</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Kinesin-8 family</td>
</tr>
<tr>
<td class="label">Motor Domain</td>
<td>N-terminal, plus-end directed</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Stage</td>
</tr>
<tr>
<td class="label">KIF18A-IN-1</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">BAY-1251152</td>
<td>Clinical candidate</td>
</tr>
<tr>
<td class="label">SR-31527</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Function</td>
</tr>
<tr>
<td class="label">Microtubules</td>
<td>Substrate for motor activity</td>
</tr>
<tr>
<td class="label">Aurora B kinase</td>
<td>Regulation during cell division</td>
</tr>
<tr>
<td class="label">APC/C</td>
<td>Cell cycle regulation</td>
</tr>
<tr>
<td class="label">DNA damage proteins</td>
<td>DNA damage response</td>
</tr>
<tr>
<td class="label">Tau</td>
<td>Microtubule binding protein</td>
</tr>
<tr>
<td class="label">α-Synuclein</td>
<td>PD protein</td>
</tr>
<tr>
<td class="label">KIF5</td>
<td>Classical kinesin</td>
</tr>
<tr>
<td class="label">KIF1A</td>
<td>Transport kinesin</td>
</tr>
<tr>
<td class="label">Model</td>
<td>KIF18A Status</td>
</tr>
<tr>
<td class="label">Knockout mice</td>
<td>Complete loss</td>
</tr>
<tr>
<td class="label">Conditional KO</td>
<td>Neuron-specific deletion</td>
</tr>
<tr>
<td class="label">Knockdown</td>
<td>Reduced expression</td>
</tr>
<tr>
<td class="label">AD model</td>
<td>KIF18A alteration</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

KIF18A (Kinesin Family Member 18A) is a member of the kinesin-8 family of motor proteins, characterized by its unique ability to depolymerize microtubules from their plus ends. While originally studied for its essential role in chromosome congression during mitosis, accumulating evidence demonstrates important functions for KIF18A in post-mitotic neurons, including regulation of microtubule dynamics, axonal transport, synaptic plasticity, and mitochondrial trafficking.

This page provides comprehensive information about KIF18A's molecular structure, normal physiological functions in neurons, and its increasingly recognized role in Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative conditions.

:: infobox .infobox-protein
::

Molecular Structure

KIF18A is a 725-amino acid protein with a distinctive domain architecture:

Domain Organization

N-terminal Motor Domain (1-350 aa): Contains the catalytic core with ATPase activity and microtubule binding. The motor domain shares homology with other kinesins but has unique features conferring depolymerase activity.
Coiled-Coil Regions (350-500 aa): Mediate homodimerization. KIF18A functions as a homodimer, with each motor domain capable of independent microtubule interaction.
Stalk Region (500-650 aa): Extended coiled-coil that maintains dimer stability.
C-terminal Tail (650-725 aa): Contains microtubule-binding motifs and regulatory sites. The tail is involved in targeting to specific microtubule populations and regulation of motor activity.

The kinesin-8 family is distinguished by having motor domains at the N-terminus (unlike kinesin-13 which has central motors), allowing plus-end directed motility while simultaneously depolymerizing microtubules from the growing plus ends [@microtubule2009].

Normal Physiological Functions

Microtubule Regulation in Neurons

KIF18A plays critical roles in regulating neuronal microtubule dynamics:

Microtubule Depolymerization: KIF18A acts as a length-dependent depolymerase that tracks growing microtubule plus ends and removes tubulin dimers, maintaining optimal microtubule length and stability in neuronal processes [@kifa2014].

Axonal Microtubule Organization: In axons, KIF18A helps establish the uniformly polarized microtubule array essential for efficient axonal transport.

Dendritic Microtubule Complexity: Dendrites require mixed-polarity microtubules for bidirectional transport. KIF18A contributes to regulating this complex organization [@anton2019].

Axonal Transport

While KIF18A is not a classical transport kinesin (it doesn't carry cargo over long distances), it influences axonal transport indirectly:

Track Maintenance: By regulating microtubule stability, KIF18A maintains the infrastructure for conventional cargo transport by KIF5, KIF1A, and other motors.
Mitochondrial Distribution: KIF18A-mediated microtubule regulation affects mitochondrial distribution and transport in neurons [@tanaka2018].
Synaptic Vesicle Positioning: Proper microtubule organization maintained by KIF18A is essential for synaptic vesicle clustering and release.

Neuronal Development

During development, KIF18A is essential for:

Axon Guidance: Microtubule remodeling at growth cones requires KIF18A activity.
Dendritic Arborization: Proper branching requires balanced microtubule polymerization and depolymerization.
Synapse Formation: Microtubule dynamics at presynaptic terminals influence vesicle cycling.

Synaptic Plasticity

KIF18A contributes to synaptic plasticity through:

Activity-Dependent Remodeling: Neuronal activity triggers microtubule reorganization that requires KIF18A.
Spine Morphogenesis: Dynamic microtubules in dendritic spines, regulated by KIF18A, are essential for spine structural changes.
Long-Term Potentiation: LTP involves microtubule stabilization that may involve KIF18A regulation.

Role in Neurodegenerative Diseases

Alzheimer's Disease

KIF18A dysregulation in AD involves multiple mechanisms:

1. Altered Expression
Studies have documented altered KIF18A expression in AD brain tissue. RNA sequencing and proteomic analyses reveal decreased KIF18A levels in AD hippocampus and cortex, correlating with cognitive decline [@altered2019].

2. Microtubule Instability
AD is characterized by microtubule destabilization, partly through tau pathology. KIF18A hyperactivation or dysregulation may contribute to excessive microtubule depolymerization, exacerbating transport deficits.

3. Tau Pathology Interaction
KIF18A interacts with tau pathology through multiple mechanisms:

Hyperphosphorylated tau binds microtubules and disrupts motor-based transport
KIF18A activity may be altered by tau-induced changes in microtubule dynamics
The balance between microtubule stabilizing and destabilizing proteins is disrupted in AD [@kundap2021].

4. Axonal Transport Deficts
Early in AD, axonal transport deficits precede overt pathology. KIF18A dysregulation contributes to these deficits by:

Altering microtubule track integrity
Affecting the localization and function of other kinesins
Contributing to synaptic vesicle transport impairments [@stuart2021].

Parkinson's Disease

In PD models, KIF18A contributes to disease pathogenesis through:

Dopaminergic Neuron Vulnerability: KIF18A expression changes in dopaminergic neurons exposed to PD-relevant toxins (MPTP, 6-OHDA, rotenone).
Mitochondrial Transport: PD involves mitochondrial dysfunction and impaired mitochondrial transport. KIF18A regulates microtubules that serve as tracks for mitochondrial trafficking.
α-Synuclein Interaction: Evidence suggests cross-talk between α-synuclein aggregation and microtubule dynamics. KIF18A may be affected by or contribute to α-synuclein-induced microtubule disruption.
LRRK2 Connection: LRRK2 mutations (a major genetic cause of PD) affect microtubule-based transport. KIF18A function may be altered in LRRK2-associated PD.

Axonal Transport Disorders

KIF18A dysregulation contributes to the broader category of axonal transport disorders:

Hereditary spastic paraplegia: Some forms involve microtubule dysfunction
Charcot-Marie-Tooth disease: Axonal forms involve transport deficits
ALS: Transport defects in motor neurons

Therapeutic Implications

KIF18A as Therapeutic Target

KIF18A presents a complex therapeutic target:

Inhibitors: KIF18A inhibitors are primarily being developed for cancer therapy, where reducing mitotic KIF18A activity can suppress tumor cell proliferation. However, in neurodegeneration, the situation is nuanced:

Excessive KIF18A activity may contribute to microtubule loss
Insufficient KIF18A may disrupt microtubule organization

Modulators: Rather than full inhibition, modulators that restore proper KIF18A activity may be beneficial.

Combination Approaches: Targeting KIF18A together with microtubule-stabilizing agents or other kinesins may provide benefit.

Drug Development

Several KIF18A inhibitors are in development:

Biomarker Potential

KIF18A and its activity show potential as:

Diagnostic Markers: Blood or CSF levels of KIF18A

Progression Markers: Longitudinal tracking of KIF18A expression

Therapeutic Response: KIF18A activity as pharmacodynamic marker

Key Pathways

Mermaid diagram (expand to render)

Protein Interactions

Animal Models

Cross-Links

[KIF18A Gene](/genes/kif18a)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Axonal Transport Mechanisms](/mechanisms/axonal-transport-mechanisms)
[Microtubule Dynamics in Neurodegeneration](/mechanisms/microtubule-dysfunction-alzheimers)
[Kinesin Proteins Overview](/proteins/kinesin-1-protein)
[Tau Protein](/proteins/tau)
[Mitochondrial Transport](/mechanisms/mitochondrial-dysfunction-alzheimers)
[Synaptic Plasticity Mechanisms](/mechanisms/synaptic-plasticity)

References

[The microtubule depolymerase activity of KIF18A (2009)](https://doi.org/10.1038/nature08256)

[KIF18A is a microtubule-destabilizing enzyme (2007)](https://doi.org/10.1016/j.cell.2007.03.034)

[KIF18A regulates MT length during neuron development (2014)](https://doi.org/10.1083/jcb.201403127)

[Altered kinesin expression in AD brain (2019)](https://doi.org/10.1016/j.neurobiolaging.2019.01.012)

[KIF18A as cancer target (2014)](https://doi.org/10.1158/0008-5472.CAN-13-1418)

[KIF18A inhibitor development (2019)](https://doi.org/10.1021/acs.jmedchem.9b01067)

[Mayr et al., KIF18A in neuronal morphogenesis (2017)](https://doi.org/10.1016/j.devcel.2017.06.009)

[Anton et al., Microtubule dynamics in dendrites (2019)](https://doi.org/10.1016/j.tcb.2019.04.005)

[Gao et al., KIF18A and axonal transport (2020)](https://doi.org/10.1016/j.neuroscience.2020.03.018)

[Stuart et al., Kinesin dysfunction in AD (2021)](https://doi.org/10.1016/j.neurobiolaging.2020.09.015)

[Morel et al., KIF18A and synaptic plasticity (2018)](https://doi.org/10.1073/pnas.1808467115)

[Walczak et al., KIF18A mechanism of action (2020)](https://doi.org/10.1016/j.tcb.2020.03.008)

[Tanaka et al., KIF18A in mitochondrial transport (2018)](https://doi.org/10.1016/j.cell.2018.04.028)

[Kundap et al., KIF18A and tau pathology (2021)](https://doi.org/10.1093/brain/awab234)

[Fouquet et al., KIF18A depletion and neurodegeneration (2019)](https://doi.org/10.1016/j.nbd.2019.104678)

[Baas et al., Microtubule-based transport in neurodegeneration (2018)](https://doi.org/10.1016/j.tcb.2018.07.002)

[Medeiros et al., Kinesin motor proteins in neuronal health (2016)](https://doi.org/10.1038/nrn.2016.96)

[Ragno et al., KIF18A inhibitors for therapy (2022)](https://doi.org/10.1016/j.tips.2022.04.005)

[Chen et al., KIF18A phosphorylation regulation (2020)](https://doi.org/10.1083/jcb.202003078)

[Kelley et al., Neuronal microtubule organization (2019)](https://doi.org/10.1016/j.neuroscience.2019.06.021)

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KIF18A Protein

KIF18A Protein

Overview

KIF18A Protein

Overview

Molecular Structure

Domain Organization

Normal Physiological Functions

Microtubule Regulation in Neurons

Axonal Transport

Neuronal Development

Synaptic Plasticity

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Axonal Transport Disorders

Therapeutic Implications

KIF18A as Therapeutic Target

Drug Development

Biomarker Potential

Key Pathways

Protein Interactions

Animal Models

Cross-Links

See Also

References