Details

Autor(en) / Beteiligte

• Jin, Lei
• Wei, Wentao
• Jiang, Yaobin
• Peng, Hao
• Cai, Jianhua
• Mao, Chen
• Dai, Han
• Choy, Wendy
• Bemis, Jean E.
• Jirousek, Michael R.
• Milne, Jill C.
• Westphal, Christoph H.
• Perni, Robert B.

Titel

Crystal Structures of Human SIRT3 Displaying Substrate-induced Conformational Changes

Ist Teil von

• The Journal of biological chemistry, 2009-09, Vol.284 (36), p.24394-24405

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2009

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.