SIRT6 Protein
Introduction Sirt6 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.
<div class="infobox infobox-protein"> [@kawahara2009]Protein Name: Sirtuin 6 (Nuclear/Mitochondrial)<br>
Gene: SIRT6<br>
UniProt ID: Q9Y5W5<br>
PDB Structures: 3K34, 3ZG6, 5YIK<br>
Molecular Weight: 36 kDa<br>
Subcellular Localization: Nucleus, Mitochondria<br>
Protein Family: Sirtuin family (Class III deacetylases)
Overview SIRT6 (Sirtuin 6) is a NAD+-dependent nuclear and mitochondrial enzyme with deacetylase and ADP-ribosyltransferase activities. It functions as a chromatin regulator controlling DNA repair, gene expression, genome stability, inflammation, and metabolism. Often called a "longevity protein," SIRT6 has emerged as an important protective factor in neurodegenerative diseases through its roles in maintaining genomic integrity and regulating stress responses.
Structure SIRT6 has the characteristic sirtuin core domain:
NAD+-binding Rossmann fold: Conserved catalytic domainExtended substrate binding pocket: Accommodates histone tailsZinc-binding domain: Stabilizes protein structureNuclear localization signal: Directs nuclear importMitochondrial targeting sequence: Enables mitochondrial localization...
SIRT6 Protein
Introduction Sirt6 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.
<div class="infobox infobox-protein"> [@kawahara2009]Protein Name: Sirtuin 6 (Nuclear/Mitochondrial)<br>
Gene: SIRT6<br>
UniProt ID: Q9Y5W5<br>
PDB Structures: 3K34, 3ZG6, 5YIK<br>
Molecular Weight: 36 kDa<br>
Subcellular Localization: Nucleus, Mitochondria<br>
Protein Family: Sirtuin family (Class III deacetylases)
Overview SIRT6 (Sirtuin 6) is a NAD+-dependent nuclear and mitochondrial enzyme with deacetylase and ADP-ribosyltransferase activities. It functions as a chromatin regulator controlling DNA repair, gene expression, genome stability, inflammation, and metabolism. Often called a "longevity protein," SIRT6 has emerged as an important protective factor in neurodegenerative diseases through its roles in maintaining genomic integrity and regulating stress responses.
Structure SIRT6 has the characteristic sirtuin core domain:
NAD+-binding Rossmann fold: Conserved catalytic domainExtended substrate binding pocket: Accommodates histone tailsZinc-binding domain: Stabilizes protein structureNuclear localization signal: Directs nuclear importMitochondrial targeting sequence: Enables mitochondrial localizationCrystal structures reveal a unique substrate-binding mode explaining SIRT6's specificity for histone H3.
Normal Function
Chromatin Regulation
H3K9 deacetylation: Maintains heterochromatin, silences repetitive elementsH3K56 deacetylation: Regulates nucleosome assembly and DNA repairGene expression control: Modulates metabolic and stress-response genesDNA Repair
Base excision repair (BER): Promotes repair of oxidative DNA damageDouble-strand break repair: Facilitates homologous recombinationTelomere maintenance: Protects chromosome endsInflammation Control
[NF-κB](/entities/nf-kb) suppression: Deacetylates RELA/p65 to inhibit transcriptionTNF production: Reduces pro-inflammatory cytokine expressionChronic inflammation: Limits age-related inflammatory processesGlycolysis: Controls glucose metabolism through PFKFB3Mitochondrial function: Regulates oxidative phosphorylationStress response: Coordinates cellular adaptationRole in Disease
Alzheimer's Disease
SIRT6 protects against [Aβ](/proteins/amyloid-beta)-induced neuronal damage
Maintains genomic integrity in [neurons](/entities/neurons)
Reduces neuroinflammation
[Tau](/proteins/tau) pathology may involve SIRT6 dysregulation
SIRT6 declines with age and AD progression
Parkinson's Disease
Protects dopaminergic neurons from oxidative stress
DNA repair in vulnerable neuronal populations
Mitochondrial quality control
May interact with PD-associated genes (LRRK2, Parkin)
SIRT6 activators show neuroprotection in models
Huntington's Disease
Counteracts mutant [huntingtin](/proteins/huntingtin) toxicity
DNA repair deficits are prominent in HD
Metabolic dysregulation
SIRT6 promotes clearance of mutant protein
Other Conditions
Progeria: SIRT6 deficiency causes accelerated agingCancer: SIRT6 acts as tumor suppressorMetabolic disease: SIRT6 regulates insulin sensitivityTherapeutic Targeting | Agent | Mechanism | Development Stage | Notes |
Key Publications
"Structure of SIRT6" - J Mol Biol (2010) - [DOI:10.1016/j.jmb.2010.02.005](https://doi.org/10.1016/j.jmb.2010.02.005)"SIRT6 functions in DNA repair" - Cell (2009) - [DOI:10.1016/j.cell.2009.09.034](https://doi.org/10.1016/j.cell.2009.09.034)"SIRT6 in aging and longevity" - Nat Rev Mol Cell Biol (2013) - [DOI:10.1038/nrm3722](https://doi.org/10.1038/nrm3722)"SIRT6 neuroprotection in PD" - J Neurosci (2020) - [DOI:10.1523/JNEUROSCI.2367-19.2020](https://doi.org/10.1523/JNEUROSCI.2367-19.2020)"SIRT6 and metabolism" - Cell Metabolism (2015) - [DOI:10.1016/j.cmet.2015.03.008](https://doi.org/10.1016/j.cmet.2015.03.008)
Cross-Links
[SIRT6 Gene](/genes/sirt6)
[SIRT1 Protein](/proteins/sirt1-protein)
[DNA Repair Pathways](/mechanisms/dna-repair-pathways)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease-disease)
Background The study of Sirt6 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.
See Also
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Amyloid Hypothesis](/mechanisms/amyloid-hypothesis)
[Tau Pathology](/mechanisms/tau-pathology)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Alpha-Synuclein](/mechanisms/alpha-synuclein)
External Links
[UniProt: Q9Y5W5](https://www.uniprot.org/uniprot/Q9Y5W5)
[PDB: 3K34](https://www.rcsb.org/structure/3K34)
[NCBI Protein: SIRT6](https://www.ncbi.nlm.nih.gov/protein/NP_057464)
References
[Mostoslavsky R et al, (2006) (2006)](https://pubmed.ncbi.nlm.nih.gov/16439206/)
[Kawahara TL et al, (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19837037/)
[Zhong L et al, (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22782963/)
[Van Meter M et al, (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21297267/)
From the [SciDEX Exchange](/exchange) — scored by multi-agent debate
[SIRT6-NAD+ Axis Enhancement Therapy](/hypothesis/h-50a535f9) — <span style="color:#ff8a65;font-weight:600">0.38</span> · Target: SIRT6
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