Peptide switch is essential for Sirt1 deacetylase activity.
In mammals, the Sirtuins are composed of seven Sir2 orthologs (Sirt1-7) with a conserved deacetylase core that utilizes NAD(+) as a cofactor. Interestingly, the deacetylase core of Sirt1 by itself has no catalytic activity. We found within the C-terminal domain a 25 aa sequence that is essential for Sirt1 activity (ESA). Our results indicate that the ESA region interacts with and functions as an "on switch" for the deacetylase core. The endogenous Sirt1 inhibitor DBC1, which also binds to the deacetylase core, competes with and inhibits the ESA region from interacting with the deacetylase core. We discovered an ESA mutant peptide that can bind to the deacetylase core and inhibit Sirt1 in trans. By using this mutant peptide, we were able to inhibit Sirt1 activity and to increase the chemosensitivity of androgen-refractory prostate cancer cells. Therefore, the ESA region is a potential target for development of therapies to regulate Sirt1.
Laboratory of Obesity and Aging Research, Genetics and Development Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Hyeog
H
Kang
Jeong-Yong
JY
Suh
Young-Sang
YS
Jung
Jae-Won
JW
Jung
Myung K
MK
Kim
Jay H
JH
Chung
D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C527450:CCAR2 protein, human; D010455:Peptides; D025521:Tumor Suppressor Proteins; D056564:Sirtuin 1