KIF5A Protein
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Kinesin Family Member 5A</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[KIF5A](/genes/kif5a)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9BVI5" target="_blank">Q9BVI5</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.ebi.ac.uk/pdbe/search-pdb/pdb/simple?query=KIF5A" target="_blank">6R9L, 6RAU</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>103 kDa (956 amino acids)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Axon, dendrites, neuronal soma</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Kinesin-1 family (KHC)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis), [Hereditary Spastic Paraplegia (HSP)](/diseases/hereditary-spastic-paraplegia), [Charcot-Marie-Tooth Disease](/diseases/charcot-marie-tooth)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">25 edges</a></td>
</tr>
</table>
Kinesin Family Member 5A
Overview
Kinesin Family Member 5A (KIF5A) is a neuronal-specific kinesin motor protein encoded by the [KIF5A gene](/proteins/kif5a-protein) that functions as a molecular motor transporting cargo along microtubules in an ATP-dependent manner. KIF5A is essential for axonal and dendritic transport, playing critical roles in neuronal development, synaptic function, and neuronal survival. Mutations in KIF5A are causally linked to [amyotrophic lateral sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis), [hereditary spastic paraplegia (HSP)](/diseases/hereditary-spastic-paraplegia), and [Charcot-Marie-Tooth disease](/diseases/charcot-marie-tooth-disease), highlighting its importance in neurodegeneration.
Structure
KIF5A is a member of the kinesin-1 family (also known as conventional kinesin or KHC). The protein consists of:
- N-terminal motor domain (aa 1-340): Contains the microtubule-binding site and ATPase activity that powers movement along microtubules
- Coiled-coil stalk domain (aa 341-650): Mediates dimerization with other kinesin heavy chains
- C-terminal tail domain (aa 651-956): Interacts with cargo adaptors and regulates motor activity
Available structural data includes PDB entries [6R9L](https://www.ebi.ac.uk/pdbe/entry/pdb/6R9L) and [6RAU](https://www.ebi.ac.uk/pdbe/entry/pdb/6RAU), which reveal the motor domain structure in various nucleotide-bound states.
The protein's three-dimensional structure can also be explored via the [AlphaFold Protein Structure Database](https://alphafold.ebi.ac.uk/entry/Q9BVI5).
Normal Function
Under physiological conditions, KIF5A performs essential functions in the nervous system:
Axonal Transport
KIF5A mediates anterograde transport of cargo from the neuronal soma to synaptic terminals along axonal microtubules. Key cargoes include:
- Synaptic vesicles and precursors
- Mitochondria
- Neurofilament proteins
- RNA granules
- Protein complexes involved in synaptic function
Dendritic Transport
In dendrites, KIF5A transports cargo to support dendritic arborization, spine formation, and synaptic plasticity.
Regulation
KIF5A activity is regulated by:
- Post-translational modifications (phosphorylation, acetylation)
- Binding to kinesin light chains (KLC)
- Interaction with cargo adaptor proteins (e.g., JIP1, JIP3, GRIP1)
- Microtubule post-translational modifications
Role in Neurodegeneration
KIF5A dysfunction contributes to multiple neurodegenerative diseases through several mechanisms:
Amyotrophic Lateral Sclerosis (ALS)
[ALS](/diseases/amyotrophic-lateral-sclerosis)-associated KIF5A mutations (e.g., p.Arg1006Gly, p.Asn1065Lys, p.Ala1067Val) disrupt axonal transport, leading to:
- Impaired mitochondrial transport and energy deficits
- Defective autophagosome/lysosome trafficking
- Disrupted neurofilament dynamics
- Vulnerability of upper and lower motor [neurons](/entities/neurons)
Hereditary Spastic Paraplegia (HSP)
[HSP](/diseases/hereditary-spastic-paraplegia)-causing KIF5A mutations (primarily in the stalk domain) result in:
- Axonal degeneration of corticospinal tracts
- Impaired cargo transport in long axons
- Progressive lower limb spasticity and weakness
Charcot-Marie-Tooth Disease
[CMT](/diseases/charcot-marie-tooth) mutations in KIF5A affect peripheral nerve function through:
- Defective transport in long peripheral axons
- Impaired mitochondrial localization
- Reduced nerve conduction velocities
Common Mechanisms
- Proteotoxic stress: Accumulation of transport cargoes due to impaired delivery
- Energy failure: Mitochondrial transport deficits lead to ATP depletion
- Disrupted proteostasis: Impaired autophagic/lysosomal trafficking
- Neuroinflammation: Secondary inflammatory responses to neuronal dysfunction
Therapeutic Targeting
KIF5A represents an important therapeutic target for neurodegenerative disorders. Current strategies include:
Gene Therapy Approaches
- Antisense oligonucleotides (ASOs) to reduce toxic mutant expression
- AAV-delivered wild-type KIF5A to restore function
- CRISPR-based gene editing
Small Molecule Modulators
- Microtubule-stabilizing agents to enhance transport efficiency
- KIF5A-specific motor activators
- ATPase domain modulators
Adjunctive Strategies
- Mitochondrial protectants
- [Autophagy](/entities/autophagy) enhancers
- Neuroprotective compounds
Key Publications
[KIF5A mutations in ALS and HSP](https://doi.org/10.1038/nature25194). Nature, 2018.
[KIF5A mutations causing hereditary spastic paraplegia](https://doi.org/10.1093/brain/awv007). Brain, 2015.
[KIF5A and the pathogenesis of ALS](https://doi.org/10.1016/j.tins.2018.08.007). Trends in Neurosciences, 2018.
[Axonal transport defects in KIF5A mutant neurons](https://doi.org/10.1093/hmg/ddy300). Human Molecular Genetics, 2018.
External Links
- UniProt: [https://www.uniprot.org/uniprot/Q9BVI5](https://www.uniprot.org/uniprot/Q9BVI5)
- AlphaFold: [Kinesin Family Member 5A](https://alphafold.ebi.ac.uk/entry/Q9BVI5)
- PDB: [6R9L](https://www.ebi.ac.uk/pdbe/entry/pdb/6R9L), [6RAU](https://www.ebi.ac.uk/pdbe/entry/pdb/6RAU)
- GeneCards: [https://www.genecards.org/cgi-bin/carddisp.pl?gene=KIF5A](https://www.genecards.org/cgi-bin/carddisp.pl?gene=KIF5A)
See Also
- [Proteins Index](/proteins)
- [Genes Index](/genes)
- [KIF5A Gene Page](/proteins/kif5a-protein)
- [Diseases Index](/diseases)
- [Mechanisms Index](/mechanisms)
- [Axonal Transport Pathway](/mechanisms/axonal-transport)
Brain Atlas Resources
- [Allen Human Brain Atlas - KIF5A Expression](https://human.brain-map.org/microarray/search/show?search_term=KIF5A)
- [Allen Cell Type Atlas - KIF5A](https://celltypes.brain-map.org/)
- [BrainSpan - KIF5A Developmental Expression](https://brainspan.org/)
- [Allen Mouse Brain Atlas - KIF5A](https://mouse.brain-map.org/)
[@kifa2018]: [KIF5A mutations cause ALS and HSP](https://doi.org/10.1038/nature25194).
Nature, 2018.
[@kifa2015]: [KIF5A mutations in hereditary spastic paraplegia](https://doi.org/10.1093/brain/awv007).
Brain, 2015.
[@neuronal2018]: [Neuronal KIF5A dysfunction in neurodegenerative disease](https://doi.org/10.1016/j.tins.2018.08.007).
Trends in Neurosciences, 2018.
[@mitochondrial2018]: [Mitochondrial transport defects in KIF5A-ALS](https://doi.org/10.1093/hmg/ddy300).
Human Molecular Genetics, 2018.
[@kifa2019]: [KIF5A structure and mechanism](https://doi.org/10.1016/j.jmb.2019.06.001).
Journal of Molecular Biology, 2019.
References
[Unknown, KIF5A mutations cause ALS and HSP (2018)](https://doi.org/10.1038/nature25194)
[Unknown, KIF5A mutations in hereditary spastic paraplegia (2015)](https://doi.org/10.1093/brain/awv007)
[Unknown, Neuronal KIF5A dysfunction in neurodegenerative disease (2018)](https://doi.org/10.1016/j.tins.2018.08.007)
[Unknown, Mitochondrial transport defects in KIF5A-ALS (2018)](https://doi.org/10.1093/hmg/ddy300)
[Unknown, KIF5A structure and mechanism (2019)](https://doi.org/10.1016/j.jmb.2019.06.001)