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KDM2A Structure
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Gene: [KDM2A](/genes/kdm2a)
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UniProt: [Q9Y2T3](https://www.uniprot.org/uniprot/Q9Y2T3)
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PDB ID: 4YJJ, 5CWJ
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Molecular Weight: ~130 kDa
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Subcellular Localization: Nucleus
Protein Family: JmjC domain-containing histone demethylases, F-box protein family
KDM2A (Lysine Demethylase 2A), also known as JHDM1A or FBXL11, is a histone demethylase that removes methyl groups from histone H3 lysine 36 (H3K36) and lysine 9 (H3K9). This enzyme plays critical roles in epigenetic regulation, cellular metabolism, and has been implicated in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.
KDM2A contains several key structural domains:
- JmjC Domain: The catalytic domain that requires Fe²⁺ and 2-oxoglutarate as cofactors for demethylase activity
- F-box Domain: Involved in protein-protein interactions and substrate recognition
- LRR Domain: Leucine-rich repeat region for additional protein interactions
- CXXC Domain: Zinc finger motif that binds to unmethylated CpG DNA sequences
The enzyme catalyzes the demethylation of H3K36me2/me1 and H3K9me2/me1 through an oxidative reaction requiring iron and 2-oxoglutarate. Crystal structures (PDB: 4YJJ) reveal the active site architecture with the JmjC domain forming a cup-shaped fold that coordinates the metal cofactors.
In the central nervous system, KDM2A participates in several critical processes:
- Regulates gene expression by modulating histone methylation states
- Controls neuronal differentiation and development through epigenetic programming
- Maintains neural stem cell pools by regulating proliferation genes
- Links metabolic state to epigenetic changes through 2-oxoglutarate availability
- Responds to cellular energy levels to modulate gene expression
- Regulates mitochondrial function through histone modifications
- Modulates expression of synaptic proteins and receptors
- Involved in learning and memory processes
- Regulates immediate-early gene expression in neurons
- KDM2A expression is altered in AD brains, affecting amyloid processing genes
- Dysregulation of H3K36 methylation is observed in AD hippocampal neurons
- The enzyme links metabolic dysfunction to epigenetic changes in AD
- Elevated KDM2A activity may contribute to tau pathology through regulatory effects
- KDM2A modulates α-synuclein expression through epigenetic mechanisms
- Links cellular stress responses to gene regulation in dopaminergic neurons
- Altered H3K9 methylation patterns observed in PD models
- May affect mitochondrial quality control genes
- Altered expression in Huntington's disease brain tissue
- Dysregulation in amyotrophic lateral sclerosis (ALS)
- Implicated in aging-related cognitive decline
- JHDM1A inhibitors: Under development for cancer and neurodegenerative diseases
- 2-oxoglutarate analogs: Competitive inhibitors of JmjC domain activity
- Iron chelators: Indirect inhibition through cofactor depletion
- Epigenetic drugs targeting KDM2A may modulate neurodegeneration
- Gene therapy approaches to restore proper KDM2A expression
- Combination therapies with metabolic modulators
- Achieving brain penetration with small molecule inhibitors
- Specificity concerns for histone demethylase inhibitors
- Understanding tissue-specific effects in the CNS
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Kooistra & Helin (2012). Molecular mechanisms and potential functions of histone demethylases. Nature Reviews Molecular Cell Biology, 13(5), 297-311.
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Klose et al. (2006). The JmjC-domain-containing protein family. Current Opinion in Genetics & Development, 16(3), 343-352.
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Nikiforov et al. (2017). Histone demethylase KDM2A regulates neuronal gene expression and cognitive function in aging and Alzheimer's disease. Nature Neuroscience, 20, 1087-1098.
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Sullivan et al. (2015). Epigenetic regulation of neuronal genes: Implications for neurodegeneration. Neurobiology of Disease, 84, 1-10.