Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins

Hyeog Kang, Shinichi Oka, Duck-Yeon Lee, Junhong Park, Angel M. Aponte, Young-Sang Jung, Jacob Bitterman, Peiyong Zhai, Yi He, Hamed Kooshapur, Rodolfo Ghirlando, Nico Tjandra, Sean B. Lee, Myung K. Kim, Junichi Sadoshima and Jay H. Chung ()
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Hyeog Kang: Laboratory of Obesity and Aging Research, Genetics and Development Biology Center, National Heart Lung and Blood Institute, National Institutes of Health
Shinichi Oka: Cardiovascular Research Institute, Rutgers University, New Jersey Medical School
Duck-Yeon Lee: Biochemistry Core Facility, Biochemistry and Biophysics Center, National Heart, Lung and Blood Institute, National Institutes of Health
Junhong Park: Tulane University School of Medicine
Angel M. Aponte: Proteomics Core Facility, National Heart Lung and Blood Institute, National Institutes of Health
Young-Sang Jung: Integrated Metabolomics Research Group, Western Seoul Center, Korea Basic Science Institute
Jacob Bitterman: Laboratory of Obesity and Aging Research, Genetics and Development Biology Center, National Heart Lung and Blood Institute, National Institutes of Health
Peiyong Zhai: Cardiovascular Research Institute, Rutgers University, New Jersey Medical School
Yi He: Laboratory of Molecular Biophysics, National Heart Lung and Blood Institute, National Institutes of Health
Hamed Kooshapur: Laboratory of Molecular Biophysics, National Heart Lung and Blood Institute, National Institutes of Health
Rodolfo Ghirlando: Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Nico Tjandra: Laboratory of Molecular Biophysics, National Heart Lung and Blood Institute, National Institutes of Health
Sean B. Lee: Tulane University School of Medicine
Myung K. Kim: Laboratory of Obesity and Aging Research, Genetics and Development Biology Center, National Heart Lung and Blood Institute, National Institutes of Health
Junichi Sadoshima: Cardiovascular Research Institute, Rutgers University, New Jersey Medical School
Jay H. Chung: Laboratory of Obesity and Aging Research, Genetics and Development Biology Center, National Heart Lung and Blood Institute, National Institutes of Health

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Sirt1 is an NAD+-dependent protein deacetylase that regulates many physiological functions, including stress resistance, adipogenesis, cell senescence and energy production. Sirt1 can be activated by energy deprivation, but the mechanism is poorly understood. Here, we report that Sirt1 is negatively regulated by ATP, which binds to the C-terminal domain (CTD) of Sirt1. ATP suppresses Sirt1 activity by impairing the CTD’s ability to bind to the deacetylase domain as well as its ability to function as the substrate recruitment site. ATP, but not NAD+, causes a conformational shift to a less compact structure. Mutations that prevent ATP binding increase Sirt1’s ability to promote stress resistance and inhibit adipogenesis under high-ATP conditions. Interestingly, the CTD can be attached to other proteins, thereby converting them into energy-regulated proteins. These discoveries provide insight into how extreme energy deprivation can impact Sirt1 activity and underscore the complex nature of Sirt1 structure and regulation.

Date: 2017
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DOI: 10.1038/ncomms15560

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