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

Nature Communications
Hyeog KangJay H Chung

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.

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Citations

May 18, 2019·Clinical Epigenetics·Shizhao LiTrygve O Tollefsbol
Sep 23, 2019·Protein Expression and Purification·Yi HeNico Tjandra
Oct 30, 2020·Frontiers in Cell and Developmental Biology·Guo LiWei-Guo Zhu
Apr 23, 2020·Mechanisms of Ageing and Development·Patricia S Pardo, Aladin M Boriek
Mar 16, 2019·Current Opinion in Chemical Biology·Tatsiana KosciukHening Lin
Oct 14, 2020·Molecular Metabolism·Carmen Escalona-GarridoÁngela M Valverde
Apr 14, 2021·Annual Review of Biochemistry·Miao Wang, Hening Lin

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Methods Mentioned

BETA
gel-filtration
pull-down
acetylation
transfection
PCR

Software Mentioned

SEDFIT
R
ImageJ
GraphPad Prism

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