Crystal Structure of a SIR2 Homolog–NAD Complex

Min, Jinrong; Landry, Joseph W.; Sternglanz, Rolf; Xu, Rui

doi:10.1016/s0092-8674(01)00317-8

Cited by 298 publications

(436 citation statements)

References 55 publications

Supporting

Mentioning

407

Contrasting

Unclassified

Order By: Relevance

“…Another interesting link of O-acetyl-ADP ribose to heterochromatin has been observed in mammalian systems, as it can bind to macroH2A, a specific H2A variant characteristic of certain forms of heterochromatin, as in the case of the mammalian inactivated X-chromosome (Kustatscher et al, 2005). The region of Sir2 that defines homology in the family is its catalytic domain, a region of approximately 250 residues containing two different motifs, an NAD þ binding reverse Rossman-fold domain at the active site and a small zinc ribbon organized by two pairs of cysteine residues that bind a zinc ion and stabilize the structure (Min et al, 2001;Marmorstein, 2004). Several factors have been found to bind to the catalytic domain such as NcoR, E2F1 and Ku70 (Cohen et al, 2004;Picard et al, 2004;Wang et al, 2006).…”

Section: The Sir2 Familymentioning

confidence: 99%

NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs

2007

View full text Add to dashboard Cite

Histone deacetylases (HDACs) catalyse the removal of acetyl groups from the N-terminal tails of histones. All known HDACs can be categorized into one of four classes (I-IV). The class III HDAC or silencing information regulator 2 (Sir2) family exhibits characteristics consistent with a distinctive role in regulation of chromatin structure. Accumulating data suggest that these deacetylases acquired new roles as genomic complexity increased, including deacetylation of non-histone proteins and functional diversification in mammals. However, the intrinsic regulation of chromatin structure in species as diverse as yeast and humans, underscores the pressure to conserve core functions of class III HDACs, which are also known as Sirtuins. One of the key factors that might have contributed to this preservation is the intimate relationship between some members of this group of proteins (SirT1, SirT2 and SirT3) and deacetylation of a specific residue in histone H4, lysine 16 (H4K16). Evidence accumulated over the years has uncovered a unique role for H4K16 in chromatin structure throughout eukaryotes. Here, we review the recent findings about the functional relationship between H4K16 and the Sir2 class of deacetylases and how that relationship might impact aging and diseases including cancer and diabetes.

show abstract

Section: The Sir2 Familymentioning

confidence: 99%

NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs

2007

View full text Add to dashboard Cite

show abstract

“…Although the known eukaryotic members of the NAD-dependent protein deacetylase SIR2 family often contains the N-and/or C-terminal extensions outside of a conserved core region, none of these contains a PWWP domain. A CXXC zinc-binding motif is found in the structure of an Archaeoglobus fulgidus SIR2 homolog, which contains a CXXC-X 15-20 -CXXC zinc-binding sequence motif 52 .…”

Section: Coordinatesmentioning

confidence: 99%

The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds

et al. 2002

View full text Add to dashboard Cite

The PWWP domain is a weakly conserved sequence motif found in >60 eukaryotic proteins, including the mammalian DNA methyltransferases Dnmt3a and Dnmt3b. These proteins often contain other chromatin-association domains. A 135-residue PWWP domain from mouse Dnmt3b (amino acids 223-357) has been structurally characterized at 1.8 Å resolution. The N-terminal half of this domain resembles a barrel-like five-stranded structure, whereas the C-terminal half contains a five-helix bundle. The two halves are packed against each other to form a single structural module that exhibits a prominent positive electrostatic potential. The PWWP domain alone binds DNA in vitro, probably through its basic surface. We also show that recombinant Dnmt3b2 protein (a splice variant of Dnmt3b) and two N-terminal deletion mutants (Δ218 and Δ369) have approximately equal methyl transfer activity on unmethylated and hemimethylated CpG-containing oligonucleotides. The Δ218 protein, which includes the PWWP domain, binds DNA more strongly than Δ369, which lacks the PWWP domain.Genomic patterns of cytosine methylation at the C5 position play key roles in the organization and control of mammalian chromatin (reviewed in refs 1-3). Mammalian DNA methyltransferases (MTases) all contain a C-terminal catalytic region that is structurally and functionally homologous to bacterial MTases. The eukaryotic DNA MTases have been grouped into three families based on (i) distinctive properties of their N-terminal regions and (ii) intriguing differences in DNA substrate preferences. The first eukaryotic DNA MTase, Dnmt1, contains a large N-terminal regulatory region of ~1,000 amino acids and shows a preference for hemimethylated DNA in vitro [4][5][6] . Dnmt2, a relatively small protein, contains only the MTase domain, and its function is still unclear 7 . Recombinant Dnmt3 acts on unmethylated and hemimethylated DNA at equal rates in vitro 8,9 .The task of dissecting the functional roles of the N-terminal region of the different MTase families is just beginning. These regions vary widely in size and are probably responsible for the diverse biological functions of eukaryotic DNA MTases. These functions include the © 2002 Nature Publishing Group Correspondence should be addressed to X.C. xcheng@emory.edu. Competing interests statementThe authors declare that they have no competing financial interests. HHS Public Access Dnmt3 contains a PWWP domainThe sequences of Dnmt3 orthologs have been determined from human and mouse. They all contain an N-terminal variable region (~280 amino acids in Dnmt3a and ~220 amino acids in Dnmt3b), followed by three stretches of conserved regions: the PWWP motif, six repeats of a CXXC motif and a set of 10 motifs conserved among DNA MTase catalytic regions (Fig. 1a). The PWWP motif 28 was first identified in a gene family related to the hepatomaderived growth factor (HDGF) 29 and WHSC1 genes (Wolf-Hirschhorn Syndrome Candidate) 30 . The corresponding sequence in Dnmt3 is SWWP (Fig. 1b); only the last two positions of the motif...

show abstract

“…This core domain is formed by a Rossmann-fold structure characteristic of NAD(P) 1 /NAD(P)H-binding proteins (Finnin et al, 2001;Min et al, 2001), a zinc-binding module containing a structural zinc atom coordinated by four conserved cysteines and a flexible loop forming a hydrophobic pocket, which may represent a class-specific protein-protein interaction domain that gives a distinct substrate specificity to each sirtuin (Finnin et al, 2001;Min et al, 2001). In addition, differences at the N-and C-termini, which can be identified from the Conserved Domain Database (Marchler-Bauer et al, 2011), account for the variation in binding partners and substrates, subcellular localization and expression pattern, as well as different enzymatic activities (Sherman et al, 1999;Borra et al, 2004;Haigis and Sinclair, 2010).…”

Section: Structurementioning

confidence: 99%

Potential role of sirtuins in livestock production

Ghinis-Hozumi

Antaramián

Villarroya

et al. 2013

Animal

View full text Add to dashboard Cite

Sirtuins are NAD+-dependent histone and protein deacetylases, which have been studied during the last decade with a focus on their role in lifespan extension and age-related diseases under normal and calorie-restricted or pathological conditions. However, sirtuins also have the ability to regulate energy homeostasis as they can sense the metabolic state of the cell through the NAD+/NADH ratio; hence, changes in the diet can modify the expression of these enzymes. Dietary manipulations are a common practice currently being used in livestock production with favorable results, probably due in part to the enhanced activity of sirtuins. Nevertheless, sirtuin expression in livestock species has not been a research target. For these reasons, the goal of this review is to awaken interest in these enzymes for future detailed characterization in livestock species by presenting a general introduction to what sirtuins are, how they work and what is known about their role in livestock.

show abstract

Crystal Structure of a SIR2 Homolog–NAD Complex

Cited by 298 publications

References 55 publications

NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs

NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs

The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds

Potential role of sirtuins in livestock production

Contact Info

Product

Resources

About