SIRT2 - Sirtuin 2 | Elisa - Clia - Antibody - Protein

Background:

SIRT2, the NAD-dependent protein deacetylase sirtuin-2, is a critical enzyme in cellular regulation and homeostasis. As a member of the sirtuin family, SIRT2 is involved in a wide array of cellular processes, from metabolism to cell cycle control, and even to the regulation of aging.SIRT2 is predominantly found in the cytoplasm of cells, although it can shuttle between the nucleus and cytoplasm depending on cellular conditions and stimuli. This localization suggests its involvement in cytoplasmic processes, such as the regulation of cytoskeletal dynamics and the modulation of signaling pathways. One of the primary functions of SIRT2 is its ability to remove acetyl groups from target proteins, a process known as deacetylation. This post-translational modification can profoundly influence the activity, stability, and localization of target proteins, thereby impacting various cellular processes. SIRT2-mediated deacetylation has been implicated in the regulation of metabolic pathways, including gluconeogenesis and fatty acid metabolism, as well as in the control of cell cycle progression. SIRT2 has emerged as a key player in cellular stress responses and the maintenance of genomic stability. It is involved in DNA repair mechanisms and has been linked to the regulation of oxidative stress and apoptosis. Dysregulation of SIRT2 activity has been associated with various human diseases, including cancer, neurodegenerative disorders like Parkinson's and Alzheimer's diseases, and metabolic conditions such as obesity and diabetes.

Protein Structure:

• Composition: SIRT2 is a protein consisting of 389 amino acids.
• Domains:
• N-terminal Domain: Contains nuclear localization signals and interaction sites for other proteins.
• Catalytic Core: This domain includes the NAD+-binding site and the deacetylase domain, crucial for SIRT2's enzymatic activity.
• C-terminal Domain: Contains nuclear export signals and contributes to protein stability and subcellular localization.
• Post-translational Modifications: SIRT2 undergoes various post-translational modifications, such as phosphorylation, sumoylation, and acetylation, which regulate its activity and localization.

Classification and Subtypes:

• Family: SIRT2 belongs to the sirtuin family, comprising seven members (SIRT1-7) in mammals.
• Subtypes: While there are no subtypes of SIRT2, its functions often overlap with other sirtuins, particularly SIRT1 and SIRT3, which also play roles in metabolism and stress responses.

Function and Biological Significance:

• Deacetylation: SIRT2 deacetylates various protein substrates, including histones (H3K16Ac), tubulin, and transcription factors, thereby modulating their activity, stability, and interactions.
• Cell Cycle Regulation: SIRT2 is involved in the regulation of the cell cycle, particularly during mitosis. It deacetylates histone H4K16, contributing to chromatin condensation and proper chromosome segregation.
• Metabolic Regulation: SIRT2 influences metabolic processes by deacetylating key metabolic enzymes and regulators. It plays a role in lipid metabolism, gluconeogenesis, and insulin sensitivity.
• Neuroprotection: SIRT2 is implicated in neuroprotection and neuronal health. It has been studied in the context of neurodegenerative diseases such as Parkinson's disease, where it may help protect neurons from oxidative stress and protein aggregation.
• Inflammation and Aging: SIRT2 regulates inflammatory responses and has been associated with aging. It modulates the activity of transcription factors like NF-κB, influencing the expression of pro-inflammatory genes.

Interactions:

• Transcription Factors: SIRT2 interacts with and deacetylates transcription factors such as p53, FOXO3, and NF-κB, thereby modulating their transcriptional activity and cellular responses.
• Cytoskeletal Proteins: SIRT2 deacetylates α-tubulin, affecting microtubule dynamics and stability, which is essential for cell division and intracellular transport.
• Enzymes: It interacts with various enzymes involved in metabolic pathways, influencing their activity and function. For example, SIRT2 deacetylates and activates acetyl-CoA synthetase.

Clinical Issues:

• Neurodegenerative Diseases: SIRT2 has been extensively studied in the context of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and Huntington's disease. Inhibitors of SIRT2 have shown potential in reducing neurotoxicity and improving neuronal survival in models of these diseases.
• Cancer: The role of SIRT2 in cancer is complex and context-dependent. In some cancers, SIRT2 acts as a tumor suppressor by regulating cell cycle checkpoints and genomic stability. However, in other contexts, SIRT2 may promote tumorigenesis by enhancing cell survival and metabolic adaptation.
• Metabolic Disorders: Dysregulation of SIRT2 activity is linked to metabolic disorders such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). Modulating SIRT2 activity could be a therapeutic strategy for these conditions.
• Aging: SIRT2 is associated with the aging process and age-related diseases. Its activity influences cellular senescence, oxidative stress responses, and inflammation, which are critical factors in aging.

Summary:

Sirtuin 2 (SIRT2) is a versatile NAD+-dependent deacetylase involved in regulating cell cycle, metabolism, neuroprotection, and inflammation. By deacetylating various protein substrates, including histones, tubulin, and transcription factors, SIRT2 modulates their activity and function. It plays crucial roles in cell cycle regulation, particularly during mitosis, influences metabolic processes, and contributes to neuronal health and protection. Clinically, SIRT2 is implicated in neurodegenerative diseases, cancer, metabolic disorders, and aging. Its complex roles in these conditions make it a promising target for therapeutic interventions aimed at modulating its activity for disease treatment and healthy aging.