EEF2K Human
Description
Molecular Structure and Function of EEF2K Human
EEF2K belongs to the α-kinase family and features four domains:
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Calmodulin-binding domain (N-terminal) for Ca²⁺/calmodulin activation .
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Catalytic domain (α-kinase) responsible for phosphorylating eEF2 at Thr-56/Thr-58 .
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Regulatory loop containing key phosphorylation sites (e.g., Thr-348, Ser-500) .
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TPR-like α-helical region involved in protein interactions .
Key Function: By phosphorylating eEF2, EEF2K slows translation elongation during energy deprivation or stress, conserving cellular energy . This process consumes 30–50% of cellular ATP under normal conditions .
Activation and Regulatory Mechanisms
EEF2K activation occurs via a two-step process:
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Ca²⁺/Calmodulin Binding: Induces autophosphorylation of Thr-348, enhancing kinase activity .
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Metabolic Signaling:
Phosphorylation Sites and Effects
Role in Cancer: Dual Regulatory Effects
EEF2K exhibits context-dependent roles in tumorigenesis:
Pro-Tumorigenic Roles
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Upregulated in breast, pancreatic, and lung cancers, promoting survival under hypoxia/nutrient stress .
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Enhances autophagy and chemoresistance in glioblastoma and triple-negative breast cancer .
Anti-Tumorigenic Roles
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Downregulated in colorectal cancer (COAD), where its loss increases autophagy and tumor growth .
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Overexpression in COAD cells reduces viability and synergizes with oxaliplatin .
Pan-Cancer Expression Analysis (TCGA)
Neurological Implications
EEF2K regulates synaptic plasticity and cognitive function:
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Knockout (KO) Mice: Show impaired long-term trace fear conditioning but normal spatial memory .
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Alzheimer’s Disease: Elevated EEF2K activity correlates with tau hyperphosphorylation .
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Ketamine’s Antidepressant Effect: Linked to transient EEF2K inhibition and BDNF synthesis .
Key Pathways:
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EEF2K modulates dendritic protein synthesis (e.g., NSF, MAP2) critical for neuronal architecture .
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Hippocampal EEF2K suppression enhances neurogenesis and memory in aged mice .
Inhibitors in Development
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Nelfinavir: Activates EEF2K, inducing cancer cell death via translation suppression .
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A-484954: Selective inhibitor reduces tumor growth in preclinical models .
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Deep Generative Models: Recently identified novel EEF2K inhibitors with high binding affinity (e.g., compound 12b) .
Challenges
Product Specs
Product Science Overview
eEF2K is structurally and functionally distinct from other protein kinases. It phosphorylates eukaryotic elongation factor 2 (eEF2) on a conserved threonine residue, which inhibits the function of eEF2. This phosphorylation event is critical because eEF2 is essential for the translocation step during protein synthesis, where it facilitates the movement of the ribosome along the mRNA .
eEF2K is involved in various cellular processes, including:
- Regulation of Protein Synthesis: By phosphorylating eEF2, eEF2K inhibits protein synthesis, which is a vital response to cellular stress conditions such as nutrient deprivation and hypoxia .
- Stress Response: eEF2K plays a significant role in the cellular response to stress. For instance, during starvation, eEF2K helps cells survive by shutting down protein synthesis and conserving energy .
- Neurodegenerative Diseases: Increased activity of eEF2K has been observed in the brains of patients with Parkinson’s disease. Inhibition of eEF2K has been shown to reduce alpha-synuclein toxicity, suggesting a potential therapeutic target for neurodegenerative diseases .
eEF2K is a target of interest in cancer research due to its role in regulating protein synthesis and cell survival. Inhibitors of eEF2K are being explored as potential therapeutic agents for cancer treatment . Additionally, the role of eEF2K in neurodegenerative diseases highlights its potential as a target for therapeutic intervention in conditions such as Parkinson’s disease .
