Crystal structures of human SIRT3 displaying substrate-induced conformational changes.
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.
Jin
Lei
L
Sirtris, a GSK Company, Cambridge, Massachusetts 02139, USA. leijin05@yahoo.com
Wei
Wentao
W
Jiang
Yaobin
Y
Peng
Hao
H
Cai
Jianhua
J
Mao
Chen
C
Dai
Han
H
Choy
Wendy
W
Bemis
Jean E
JE
Jirousek
Michael R
MR
Milne
Jill C
JC
Westphal
Christoph H
CH
Perni
Robert B
RB
D000106:Acetate-CoA Ligase / Q000737:chemistry* / Q000378:metabolism; D000107:Acetylation; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism; D009243:NAD / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D020836:Protein Structure, Quaternary; D056566:Sirtuin 3; D037761:Sirtuins / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D024101:Mitochondrial Proteins; D010455:Peptides; D009243:NAD; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D037761:Sirtuins; D000106:Acetate-CoA Ligase