Multivalent Interactions Drive Nucleosome Binding and Efficient Chromatin Deacetylation by SIRT6

The protein deacetylase SIRT6
maintains cellular homeostasis through multiple pathways that include the deacetylation
of histone H3 and repression of transcription. Prior work suggests that SIRT6
is associated with chromatin and can substantially reduce global levels of H3
acetylation, but how SIRT6 is able to accomplish this feat is unknown. Here, we
describe an exquisitely tight interaction between SIRT6 and nucleosome core
particles, in which a 2:1 enzyme:nucleosome
complex assembles via asymmetric binding with distinct affinities. While both SIRT6 molecules
associate with the acidic patch on the nucleosome, we find that the
intrinsically disordered SIRT6 C-terminus promotes binding at the higher
affinity site through recognition of nucleosomal DNA. Together, multivalent
interactions couple productive binding to efficient deacetylation of histones
on endogenous chromatin. Unique among histone
deacetylases, SIRT6 possesses the intrinsic capacity to tightly interact with
nucleosomes for efficient activity. The HDX raw data for this work is provided.