Crystal Structures of Human SIRT3 Displaying Substrate-induced Conformational Changes

AUTOR(ES)

Jin, Lei

FONTE

American Society for Biochemistry and Molecular Biology

RESUMO

SIRT3 is a major mitochondrial NAD+-dependent protein deacetylase playing important roles in regulating mitochondrial metabolism and energy production and has been linked to the beneficial effects of exercise and caloric restriction. SIRT3 is emerging as a potential therapeutic target to treat metabolic and neurological diseases. We report the first sets of crystal structures of human SIRT3, an apo-structure with no substrate, a structure with a peptide containing acetyl lysine of its natural substrate acetyl-CoA synthetase 2, a reaction intermediate structure trapped by a thioacetyl peptide, and a structure with the dethioacetylated peptide bound. These structures provide insights into the conformational changes induced by the two substrates required for the reaction, the acetylated substrate peptide and NAD+. In addition, the binding study by isothermal titration calorimetry suggests that the acetylated peptide is the first substrate to bind to SIRT3, before NAD+. These structures and biophysical studies provide key insight into the structural and functional relationship of the SIRT3 deacetylation activity.

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