Journal: Elife / Year: 2024 Title: Binding to nucleosome poises human SIRT6 for histone H3 deacetylation. Authors: Ekaterina Smirnova / Emmanuelle Bignon / Patrick Schultz / Gabor Papai / Adam Ben Shem / Abstract: Sirtuin 6 (SIRT6) is an NAD-dependent histone H3 deacetylase that is prominently found associated with chromatin, attenuates transcriptionally active promoters and regulates DNA repair, metabolic ...Sirtuin 6 (SIRT6) is an NAD-dependent histone H3 deacetylase that is prominently found associated with chromatin, attenuates transcriptionally active promoters and regulates DNA repair, metabolic homeostasis and lifespan. Unlike other sirtuins, it has low affinity to free histone tails but demonstrates strong binding to nucleosomes. It is poorly understood how SIRT6 docking on nucleosomes stimulates its histone deacetylation activity. Here, we present the structure of human SIRT6 bound to a nucleosome determined by cryogenic electron microscopy. The zinc finger domain of SIRT6 associates tightly with the acidic patch of the nucleosome through multiple arginine anchors. The Rossmann fold domain binds to the terminus of the looser DNA half of the nucleosome, detaching two turns of the DNA from the histone octamer and placing the NAD binding pocket close to the DNA exit site. This domain shows flexibility with respect to the fixed zinc finger and moves with, but also relative to, the unwrapped DNA terminus. We apply molecular dynamics simulations of the histone tails in the nucleosome to show that in this mode of interaction, the active site of SIRT6 is perfectly poised to catalyze deacetylation of the H3 histone tail and that the partial unwrapping of the DNA allows even lysines close to the H3 core to reach the enzyme.
Entire : Human Sirtuin 6 in complex with the nucleosome
Entire
Name: Human Sirtuin 6 in complex with the nucleosome
Components
Complex: Human Sirtuin 6 in complex with the nucleosome
Complex: SIRT6
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Supramolecule #1: Human Sirtuin 6 in complex with the nucleosome
Supramolecule
Name: Human Sirtuin 6 in complex with the nucleosome / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#7
Source (natural)
Organism: Xenopus laevis (African clawed frog)
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Supramolecule #2: SIRT6
Supramolecule
Name: SIRT6 / type: complex / ID: 2 / Parent: 1
Source (natural)
Organism: Homo sapiens (human)
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Experimental details
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Structure determination
Method
cryo EM
Processing
single particle reconstruction
Aggregation state
particle
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Sample preparation
Buffer
pH: 7.5
Grid
Model: Quantifoil R3.5/1 / Material: COPPER/RHODIUM / Mesh: 300 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 2
Vitrification
Cryogen name: ETHANE
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Electron microscopy
Microscope
TFS KRIOS
Specialist optics
Energy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Image recording
Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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