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

Author

Listed:
  • 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
    Present address: Center for Genome Integrity, UNIST, Ulsan UNIST-Gil 50, Korea)

  • 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
    Present address: Center for Veterinary Medicine, Office of Foods and Veterinary Medicine, U.S. Food and Drug Administration, Rockville, Maryland 20855, USA)

  • 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)

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.

Suggested Citation

  • 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, 2017. "Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins," Nature Communications, Nature, vol. 8(1), pages 1-11, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15560
    DOI: 10.1038/ncomms15560
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