SIRT1 Contains N- and C-terminal Regions That Potentiate Deacetylase Activity

Pan, Min; Yuan, Hua; Brent, Michael; Ding, Emily Chen; Marmorstein, Ronen

doi:10.1074/jbc.m111.285031

Cited by 65 publications

(58 citation statements)

References 36 publications

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“…Furthermore, the SIRT1 N terminus has previously been reported to affect its activity (38), and we therefore also tested inhibition of an N-terminally truncated SIRT1(⌬1-234). Inhibition of SIRT1(⌬1-234) as well as ySir2 and SIRT3 at 50 M compound was relatively mild, with 65-80% remaining activity for MAL deacetylation (Fig.…”

Section: Resultsmentioning

confidence: 99%

A Novel Sirtuin 2 (SIRT2) Inhibitor with p53-dependent Pro-apoptotic Activity in Non-small Cell Lung Cancer

Hoffmann

Breitenbücher

Schüler

et al. 2014

Journal of Biological Chemistry

126

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Section: Resultsmentioning

confidence: 99%

A Novel Sirtuin 2 (SIRT2) Inhibitor with p53-dependent Pro-apoptotic Activity in Non-small Cell Lung Cancer

Hoffmann

Breitenbücher

Schüler

et al. 2014

Journal of Biological Chemistry

126

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“…In this homotrimer, the N-terminal segment from one Hst2 subunit occupies the acetyllysine substrate-binding site of another subunit, and a C-terminal helix partially overlaps with the NAD ϩ -binding site of still another subunit, thereby locking Hst2 in an inactive homotrimeric conformation. A more recent biochemical study of SIRT1 reveals that the N-and C-terminal segments promote catalysis, although the molecular basis for this is unknown (52). Structures of other sirtuins that contain flanking N-and C-terminal segments may reveal other autoregulatory functions, particularly in the mammalian sirtuins that have the most divergent N-and C-terminal regions.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Structural Basis for Sirtuin Activity and Inhibition

Yuan

Marmorstein

2012

Journal of Biological Chemistry

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130

100

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Sir2 proteins, or sirtuins, are a family of enzymes that catalyze NAD ؉ -dependent deacetylation reactions and can also process ribosyltransferase, demalonylase, and desuccinylase activities. More than 40 crystal structures of sirtuins have been determined, alone or in various liganded forms. These high-resolution architectural details lay the foundation for understanding the molecular mechanisms of catalysis, regulation, substrate specificity, and inhibition of sirtuins. In this minireview, we summarize these structural features and discuss their implications for understanding sirtuin function.Sirtuins, also known as Sir2 (silent information regulator 2) proteins, are NAD ϩ -dependent deacetylases but may have other related activities and are broadly conserved in all three kingdoms of life. Bacteria and archaea typically contain one or two sirtuin proteins that target DNA regulatory proteins and metabolic enzymes such as the chromatin protein Alba (1) and acetyl-CoA synthetase (2), whereas eukaryotes typically contain multiple sirtuins with more diverse protein targets (3). Yeast has five sirtuins, including the Sir2p founding member and Hst1-4. Mammals have seven sirtuins (SIRT1-7), of which SIRT1 is the most extensively studied. SIRT1 targets a broad range of substrates, including p53, FOXO, PGC1a, UCP2, liver X receptor, and others, and therefore is implicated in a variety of biological functions such as cell survival, apoptosis, and stress resistance (reviewed in Refs. 4 and 5).Sirtuins employ a conserved catalytic core domain to catalyze deacetylation by transferring the acetyl group from the acetyllysine N⑀ of proteins to NAD ϩ (6, 7), forming 2Ј-Oacetyl-ADP-ribose and free nicotinamide products (8, 9). The nicotinamide product is also a noncompetitive inhibitor of sirtuins (10) and inhibits the enzyme through a base-exchange process by reacting with a catalytic intermediate to reform ␤-NAD ϩ at the expense of deacetylation (11,12 It appears that not all sirtuins carry out deacetylation as their primary activity. For example, several mammalian sirtuins, including SIRT4, SIRT5, and SIRT7, have very weak or no detectable deacetylase activity (22), SIRT6 has both ADP-ribosyltransferase and deacetylase activities (23), and SIRT5 has been shown to be a more active demalonylase and desuccinylase than deacetylase (24,25). Thermotoga maritima Sir2 exhibits deacetylase activity but also harbors depropionylation activity at a slightly reduced rate (26).Despite the many known sirtuin substrates (3), no consensus sequences or substrate determinants have been identified. Hst2 deacetylates acetyllysine within unstructured regions of proteins, displaying conformational rather than sequence specificity (27). In addition, more detailed enzymatic studies of yeast Sir2 and Hst2 and human SIRT2 and SIRT1 show certain peptide substrate preferences but also suggest that sirtuins discriminate their substrates in a local context-based fashion with no sequence consensus (19,28). Notably, many sirtuins, especially those from mamma...

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“…They include the ∼260-residue CD located in the middle, an ∼25-residue C-terminal ESA sequence, and an ∼50-residue NTD ( Fig. 1A; Kang et al 2011;Pan et al 2012;Hubbard et al 2013). In particular, Glu230 in NTD was shown to be critical for stimulation by resveratrol (Hubbard et al 2013).…”

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confidence: 99%

Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol

et al. 2015

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Sirtuins with an extended N-terminal domain (NTD), represented by yeast Sir2 and human SIRT1, harbor intrinsic mechanisms for regulation of their NAD-dependent deacetylase activities. Elucidation of the regulatory mechanisms is crucial for understanding the biological functions of sirtuins and development of potential therapeutics. In particular, SIRT1 has emerged as an attractive therapeutic target, and the search for SIRT1-activating compounds (STACs) has been actively pursued. However, the effectiveness of a class of reported STACs (represented by resveratrol) as direct SIRT1 activators is under debate due to the complication involving the use of fluorogenic substrates in in vitro assays. Future efforts of SIRT1-based therapeutics necessitate the dissection of the molecular mechanism of SIRT1 stimulation. We solved the structure of SIRT1 in complex with resveratrol and a 7-amino-4-methylcoumarin (AMC)-containing peptide. The structure reveals the presence of three resveratrol molecules, two of which mediate the interaction between the AMC peptide and the NTD of SIRT1. The two NTD-bound resveratrol molecules are principally responsible for promoting tighter binding between SIRT1 and the peptide and the stimulation of SIRT1 activity. The structural information provides valuable insights into regulation of SIRT1 activity and should benefit the development of authentic SIRT1 activators.

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SIRT1 Contains N- and C-terminal Regions That Potentiate Deacetylase Activity

Cited by 65 publications

References 36 publications

A Novel Sirtuin 2 (SIRT2) Inhibitor with p53-dependent Pro-apoptotic Activity in Non-small Cell Lung Cancer

A Novel Sirtuin 2 (SIRT2) Inhibitor with p53-dependent Pro-apoptotic Activity in Non-small Cell Lung Cancer

Structural Basis for Sirtuin Activity and Inhibition

Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol

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