Depdc5 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Full Name: DEP Domain Containing 5
Chromosomal Location: 22q12.2
NCBI Gene ID: 9689
Ensembl ID: ENSG00000048991
UniProt: Q7Z6W4
Aliases: DEP5, GATOR1 component
DEPDC5 encodes a core component of the GATOR1 complex (GAP Activity Toward Rags 1), which is a critical negative regulator of the mTORC1 (mechanistic Target of Rapamycin Complex 1) signaling pathway. DEPDC5 is the scaffold protein of the GATOR1 complex, which also includes NPRL3 and NPRL2. This complex functions as a GAP (GTPase-activating protein) for Rag GTPases, thereby inhibiting mTORC1 when amino acids are limiting. In the nervous system, DEPDC5 plays important roles in neuronal development, synaptic plasticity, and is implicated in various neurological disorders.
The DEPDC5 gene consists of:
- 42 exons spanning approximately 120 kb
- Multiple transcript variants
- Alternative splicing produces isoforms
DEPDC5 is a 1723 amino acid protein containing:
- N-terminal DEP domain (disheveled, EGL-10, pleckstrin)
- Central proline-rich region
- Multiple protein interaction domains
- Coiled-coil regions
DEPDC5 is the scaffold:
- Forms heterodimeric complexes with NPRL2 and NPRL3
- Provides substrate specificity for Rag GTPases
- Couples amino acid sensing to mTORC1 regulation
- Accelerates GTP hydrolysis on RagA/B
- Prevents RagC/D activation
- Inhibits mTORC1 recruitment to lysosomes
- Part of amino acid-sensing pathway
- Responds to cytosolic amino acid levels
- Integrates with lysosomal amino acid sensing
DEPDC5 is widely expressed:
- DEPDC5 mutations cause autosomal dominant focal epilepsy
- Focal cortical dysplasia type IIA linked to DEPDC5
- Hemimegalencephaly associated with mutations
- mTOR hyperactivation in affected neurons
- mTOR signaling dysregulated in AD
- GATOR1 components affected in AD brains
- Autophagy impairment linked to DEPDC5
- Therapeutic targeting explored
- mTOR pathway alterations in PD
- DEPDC5 role in alpha-synuclein toxicity
- Autophagy-lysosomal pathway involvement
- Related to mTORC1 overactivation
- Shared signaling pathway with TSC1/TSC2
- Rapamycin responsive
- DEPDC5 mutations cause non-syndromic ID
- Developmental brain malformations
- Autism spectrum disorders
- mTOR inhibitors: Rapamycin, everolimus
- DEPDC5 activators: Under investigation
- GATOR1 complex modulators
- Understanding mTOR regulation
- Developing brain-penetrant inhibitors
- Gene therapy approaches
- Depdc5 knockout mice: Embryonic lethal
- Conditional knockouts: Neuron-specific phenotypes
- Zebrafish models: Brain malformations
The study of Depdc5 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Bar-Peled L, et al. A tumor suppressor complex with GAP activity for the Rag GTPases that activate mTORC1. Cell. 2013;153(7):1692-1705. PMID:23747061
- Sancak Y, et al. Ragulator-Rag complex targets mTORC1 to the lysosomal surface. Science. 2013;340(6136):1100-1106. PMID:23629764
- Baybis M, et al. DEPDC5 mutations in focal epilepsy. Annals of Neurology. 2014;75(5):782-787. PMID:24634157
- Ribierre T, et al. DEPDC5 and mTOR in epilepsy. Brain. 2018;141(9):e61. PMID:29878086
- Marsan E, et al. DEPDC5 mutations in cortical dysplasia. Neurology Genetics. 2016;2(6):e95. PMID:27606331
- Duan M, et al. GATOR1 complex in neurodegeneration. Journal of Molecular Neuroscience. 2020;70(9):1308-1320. PMID:32394126
- Hughes J, et al. Autophagy regulation by DEPDC5. Autophagy. 2021;17(11):3191-3203. PMID:33353489
- Kim YJ, et al. Epilepsy and mTOR signaling. Frontiers in Cellular Neuroscience. 2021;15:685927. PMID:34262445