Structure of Sir2Tm bound to a propionylated peptide

Bheda, Poonam; Wang, Jennifer T.; Escalante‐Semerena, Jorge C.; Wolberger, Cynthia

doi:10.1002/pro.544

Cited by 22 publications

(38 citation statements)

References 65 publications

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“…1). As a comparison, we also tested the bacterial sirtuin, TmSir2, from Thermotoga maritima , whose active site cannot accommodate larger acyl groups and is thus predicted to be a bona fide deacetylase,46,47 and E. coli CobB, which desuccinylates peptides in vitro 13…”

Section: Resultsmentioning

confidence: 99%

“…Structures of TmSir2 bound to both acetylated46 and propionylated peptides47 have been reported, showing that the modified lysine fits snugly into a tight hydrophobic pocket. In addition, TmSir2 was previously shown to catalyze depropionylation more slowly than deacetylation 47. Consistent with previous data, TmSir2 preferentially removed acetyl groups, with relatively lower activity on all other acyl modifications tested [Fig.…”

Section: Resultsmentioning

confidence: 99%

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Alternate deacylating specificities of the archaeal sirtuins Sir2Af1 and Sir2Af2

2014

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Sirtuins were originally shown to regulate a wide array of biological processes such as transcription, genomic stability, and metabolism by catalyzing the NAD+-dependent deacetylation of lysine residues. Recent proteomic studies have revealed a much wider array of lysine acyl modifications in vivo than was previously known, which has prompted a reevaluation of sirtuin substrate specificity. Several sirtuins have now been shown to preferentially remove propionyl, succinyl, and long-chain fatty acyl groups from lysines, which has changed our understanding of sirtuin biology. In light of these developments, we revisited the acyl specificity of several well-studied archaeal and bacterial sirtuins. We find that the Archaeoglobus fulgidus sirtuins, Sir2Af1 and Sir2Af2, preferentially remove succinyl and myristoyl groups, respectively. Crystal structures of Sir2Af1 bound to a succinylated peptide and Sir2Af2 bound to a myristoylated peptide show how the active site of each enzyme accommodates a noncanonical acyl chain. As compared to its structure in complex with an acetylated peptide, Sir2Af2 undergoes a conformational change that expands the active site to accommodate the myristoyl group. These findings point to both structural and biochemical plasticity in sirtuin active sites and provide further evidence that sirtuins from all three domains of life catalyze noncanonical deacylation.PDB Code(s): 4TWI; 4TWJ

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Alternate deacylating specificities of the archaeal sirtuins Sir2Af1 and Sir2Af2

2014

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“…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).…”

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confidence: 99%

Structural Basis for Sirtuin Activity and Inhibition

Yuan

Marmorstein

2012

Journal of Biological Chemistry

135

112

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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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“…Altogether, these observations lay the foundation for a hypothesis that protein acylation may be one form of non-enzymatic chemical damage that impedes protein function and compromises cellular homeostasis [33]. Meanwhile, the members of sirtuin family, a class of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases [34], have been found to act as erasers of lysine acylation (Table 1) [35][36][37][38][39][40]. For examples, Sirt5 catalyzes the hydrolysis of Ksucc and Kmal (Table 1, Entries 4 and 5).…”

Section: Detection Of Novel Histone Ptmsmentioning

confidence: 99%

Chemical proteomics approaches to examine novel histone posttranslational modifications

2015

Current Opinion in Chemical Biology

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Structure of Sir2Tm bound to a propionylated peptide

Cited by 22 publications

References 65 publications

Alternate deacylating specificities of the archaeal sirtuins Sir2Af1 and Sir2Af2

Alternate deacylating specificities of the archaeal sirtuins Sir2Af1 and Sir2Af2

Structural Basis for Sirtuin Activity and Inhibition

Chemical proteomics approaches to examine novel histone posttranslational modifications

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