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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.

Crystal structures of human SIRT3 displaying substrate-induced conformational changes., Jin L, Wei W, Jiang Y, Peng H, Cai J, Mao C, Dai H, Choy W, Bemis JE, Jirousek MR, Milne JC, Westphal CH, Perni RB, J Biol Chem. 2009 Sep 4;284(36):24394-405. Epub 2009 Jun 16. PMID:19535340

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Categories: Homo sapiens | Bemis, J E. | Cai, J. | Dai, H. | Jiang, Y. | Jin, L. | Jirousek, M R. | Mao, C. | Milne, J C. | Peng, H. | Perni, R B. | Wei, W. | Westphal, C H. | Apo structure | Hydrolase | Metal-binding | Mitochondrion | Nad | Nad dependent deacetylase | Sirtuin | Transit peptide