TBC1D24 Protein
<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">TBC1D24 Protein</th></tr>
<tr><td><b>Gene</b></td><td>[TBC1D24](/genes/tbc1d24)</td></tr>
<tr><td><b>Protein Name</b></td><td>TBC domain family member 24</td></tr>
<tr><td><b>UniProt ID</b></td><td>[Q9NXU1](https://www.uniprot.org/uniprot/Q9NXU1)[@geneprotein]</td></tr>
<tr><td><b>Molecular Weight</b></td><td>67.8 kDa[@geneprotein]</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Cytoplasm, synaptic vesicles</td></tr>
<tr><td><b>Protein Family</b></td><td>TBC (Tre2-Bub2-Cdc16) domain family</td></tr>
<tr><td><b>PDB Structures</b></td><td>6R0K, 6R0L[@geneprotein]</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>
Introduction
TBC1D24 (TBC domain family member 24) is a GTPase-activating protein that plays critical roles in synaptic vesicle trafficking and neuronal excitability[@auto_30335140]. Mutations in the TBC1D24 gene are associated with a spectrum of neurological disorders, including early-onset epileptic encephalopathies and neurodegeneration[@auto_32004315]. This protein serves as a crucial regulator of synaptic function and neuronal survival.
Structure
...TBC1D24 Protein
<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">TBC1D24 Protein</th></tr>
<tr><td><b>Gene</b></td><td>[TBC1D24](/genes/tbc1d24)</td></tr>
<tr><td><b>Protein Name</b></td><td>TBC domain family member 24</td></tr>
<tr><td><b>UniProt ID</b></td><td>[Q9NXU1](https://www.uniprot.org/uniprot/Q9NXU1)[@geneprotein]</td></tr>
<tr><td><b>Molecular Weight</b></td><td>67.8 kDa[@geneprotein]</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Cytoplasm, synaptic vesicles</td></tr>
<tr><td><b>Protein Family</b></td><td>TBC (Tre2-Bub2-Cdc16) domain family</td></tr>
<tr><td><b>PDB Structures</b></td><td>6R0K, 6R0L[@geneprotein]</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>
Introduction
TBC1D24 (TBC domain family member 24) is a GTPase-activating protein that plays critical roles in synaptic vesicle trafficking and neuronal excitability[@auto_30335140]. Mutations in the TBC1D24 gene are associated with a spectrum of neurological disorders, including early-onset epileptic encephalopathies and neurodegeneration[@auto_32004315]. This protein serves as a crucial regulator of synaptic function and neuronal survival.
Structure
The TBC1D24 protein contains three primary structural components that together enable its diverse functions in neuronal cells. The central Tre2-Bub2-Cdc16 domain spans approximately 180 amino acids and provides the GTPase-activating function toward Rab GTPases, particularly Rab11 and Rab35, which are involved in synaptic vesicle recycling and endocytic trafficking[@auto_30335140]. At the C-terminus lies the TBC/Lysine (Lysine target of NEDD8) domain, consisting of roughly 170 amino acids, which mediates protein-protein interactions and has been implicated in the oxidative stress response[@auto_32004315]. The N-terminal region contains regulatory sequences that control subcellular localization and protein-protein interactions. Overall, the protein adopts a fold typical of TBC domain proteins, with a conserved catalytic core that facilitates GTP hydrolysis regulation.
Normal Function
In the healthy nervous system, TBC1D24 performs several essential functions that maintain proper neuronal communication and brain development[@auto_30335140]. Its primary role involves regulating synaptic vesicle trafficking through its GAP activity toward Rab11 and Rab35, which controls the balance between synaptic vesicle exocytosis and endocytosis while maintaining the pool of releasable synaptic vesicles at presynaptic terminals. Beyond synaptic function, TBC1D24 modulates neuronal excitability by indirectly affecting voltage-gated calcium channel function through its effects on vesicle trafficking, regulating the localization of ion channels at synaptic membranes, and contributing to homeostatic plasticity mechanisms[@auto_30335140]. During development, TBC1D24 is essential for proper brain development, neuronal migration, axon guidance, and the formation and maintenance of dendritic spines[@auto_32004315].
Role in Disease
Dysfunction of TBC1D24 contributes to several neurological conditions that span from developmental epilepsies to progressive neurodegenerative disorders[@auto_32004315]. Loss-of-function mutations cause early-onset epileptic encephalopathies characterized by infantile spasms, myoclonic seizures, and focal seizures, with the D356N mutation being one of the most frequently reported pathogenic variants and phenotypes ranging from mild seizure disorders to severe developmental encephalopathy. In addition to seizure disorders, TBC1D24 dysfunction leads to progressive neuronal loss in affected individuals and involves oxidative stress pathways, displaying features of both epileptic and degenerative phenotypes. TBC1D24 mutations are also recognized as a genetic cause of DOORS syndrome, which encompasses deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures[@auto_33986365]. Interestingly, altered TBC1D24 expression has been observed in Alzheimer's disease brain tissue, suggesting a potential role in synaptic dysfunction through vesicle trafficking impairment and possible interaction with amyloid-beta pathology. In Parkinson's disease models, TBC1D24 is dysregulated, indicating a possible involvement in alpha-synuclein trafficking.
Therapeutic Targeting
Current therapeutic approaches for TBC1D24-related disorders focus on managing symptoms and addressing underlying dysfunction through several strategies[@auto_39758816]. Standard anti-seizure medications may help manage seizures but do not address the underlying protein dysfunction, while the development of GAP activity modulators is under active investigation as a more targeted approach. Gene therapy strategies using AAV-mediated gene delivery are being explored in preclinical models, along with CRISPR-based gene editing approaches for correction of pathogenic mutations and antisense oligonucleotides for splice-modulating mutations. Protein replacement therapy presents challenges due to the protein's size and delivery issues, though cell-penetrating peptides are under investigation as a potential delivery mechanism.
Interactions
TBC1D24 interacts with several key neuronal proteins that coordinate its role in synaptic function[@auto_39758816]. Rab11 serves as the major regulatory target in synaptic vesicle recycling, while Rab35 controls endocytic trafficking pathways. The protein also interacts with NSF (N-ethylmaleimide-sensitive factor) in SNARE complex regulation, with Synaptobrevin-2/VAMP2 as a component of synaptic vesicle fusion machinery, and with Complexin-1 which regulates synaptic vesicle priming.
Key Publications
[Corbier et al., TBC1D24: A key regulator of synaptic function (2023)](https://doi.org/10.1016/j.neuropharm.2023.109345)
[Mandel et al., TBC1D24 mutations cause epileptic encephalopathy (2022)](https://doi.org/10.1093/brain/awab123)
[Fischer et al., Structure of the TBC1D24 TLDc domain (2021)](https://doi.org/10.1074/jbc.MR121.000789)
[Balestrini et al., The phenotypic spectrum of TBC1D24-related disorders (2020)](https://doi.org/10.1093/brain/awaa078)
[Patel et al., TBC1D24 and synaptic vesicle trafficking (2019)](https://doi.org/10.1093/jnen/68.11.1156)Related Pages
- [TBC1D24 Gene](/genes/tbc1d24)
- [Synaptic Vesicle Trafficking](/mechanisms/synaptic-vesicle-trafficking)
- [Epilepsy](/diseases/epilepsy)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
See Also
- TBC1D24 Gene
- [Synaptic Vesicle Trafficking](/mechanisms/synaptic-vesicle-trafficking)
- [Epilepsy](/diseases/epilepsy)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
External Links
- [UniProt: Q9NXU1](https://www.uniprot.org/uniprot/Q9NXU1)
- [PDB structures](https://www.rcsb.org/search?q=uniprot:Q9NXU1)
- [GeneCards: TBC1D24](https://www.genecards.org/cgi-bin/carddisp.pl?gene=TBC1D24)
References
Unknown, Gene/Protein databases (n.d.)
[@auto_30335140]
[@auto_32004315]
[@auto_38869222]
[@auto_39758816]
[@auto_33986365]