Cryo-EM structure of the human Sirtuin 6-nucleosome complex

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Sirtuin 6 (SIRT6) is a key enzyme involved in cellular processes like aging and cancer.
• The precise mechanism by which SIRT6 recognizes and binds to its nucleosomal substrate remains unclear.
• Understanding SIRT6's substrate preference is crucial for developing targeted therapeutics.

Purpose of the Study:

• To elucidate the molecular basis of Sirtuin 6's substrate specificity on nucleosomes.
• To visualize the interaction between human SIRT6 and a nucleosome complex.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to determine the structure of human SIRT6 bound to a nucleosome.
• Structural analysis focused on the interactions between SIRT6 domains and nucleosomal components.

Main Results:

• The cryo-EM structure reveals that SIRT6's catalytic domain interacts with nucleosomal DNA at the entry-exit site, exposing the histone H3 N-terminal helix.
• SIRT6's zinc-binding domain engages with the histone acidic patch via an arginine anchor.
• An inhibitory interaction between SIRT6 and the histone H2A C-terminal tail was identified.

Conclusions:

• The determined structure provides atomic-level insights into how SIRT6 selectively targets and deacetylates histone H3 at specific residues (K9 and K56).
• This structural understanding facilitates the rational design of small-molecule modulators for SIRT6.
• Findings contribute to the development of novel therapeutic strategies for age-related diseases and cancer.