Structural basis for allosteric stimulation of Sir2 activity by Sir4 binding

Hsu, Hao Chi; Wang, Chia Lin; Wang, Mingzhu; Yang, Na; Chen, Zhi; Sternglanz, Rolf; Xu, Rui

doi:10.1101/gad.208140.112

Cited by 37 publications

(37 citation statements)

References 57 publications

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“…This arrangement of the ESA β hairpin is reminiscent of that of the C-terminal β hairpin in yeast Sir2, indicating a largely structural role of the ESA sequence in the Sir2-SIRT1 clade of sirtuins ( Fig. 2C; Hsu et al 2013). The SIRT1 NTD is mainly composed of a core of three helices (amino acids 184-229)-a feature that can also be identified in Sir2 (although the Sir2 NTD has two extra helices)-and, when bound by another protein (Sir4) assumes a distinct spatial position ( Fig.…”

Section: Overall Structurementioning

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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Section: Overall Structurementioning

confidence: 99%

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

et al. 2015

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“…Mutations at the protein-protein interface disrupt silencing at the HM loci but not at the rDNA where Sir2 acts as a subunit of RENT (Cuperus et al 2000). Sir4 binding stimulates the deacetylase activity of Sir2 (Tanny et al 2004;Cubizolles et al 2006;Hsu et al 2013). Allosteric regulation of this kind may limit Sir2 activity until a targeting factor, like Sir4, brings the enzyme to nucleation sites on chromatin.…”

Section: Sir4mentioning

confidence: 99%

“…Thus, substrate lysines must reside within a relatively flexible region of the target protein ( Figure 4A) (Min et al 2001;Avalos et al 2002). The core of S. cerevisiae Sir2 differs from other sirtuins by a 30 amino acid insertion following the four cysteines that changes the zinc ribbon into a motif that more closely resembles a plant homeodomain finger ( Figure 4B) (Hsu et al 2013). The function of this insertion remains unclear.…”

Section: Sir2 Protein Structurementioning

confidence: 99%

“…A more central domain of Sir4 (amino acids 737-893) makes extensive contacts with Sir2 (Moazed et al 1997;Cockell et al 2000;Ghidelli et al 2001;Hoppe et al 2002;Hsu et al 2013). Mutations at the protein-protein interface disrupt silencing at the HM loci but not at the rDNA where Sir2 acts as a subunit of RENT (Cuperus et al 2000).…”

Section: Sir4mentioning

confidence: 99%

“…These flanking domains associate with secondary proteins that confer substrate specificity to the sirtuins. The extended N-terminal domain of Sir2 interacts with a Sir2-interacting domain (SID) within Sir4 (amino acids 737-893), which stabilizes the Sir2 core structure and allosterically stimulates the histone deacetylase activity ( Figure 4B) (Hsu et al 2013).…”

Section: Sir2 Protein Structurementioning

confidence: 99%

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The Nuts and Bolts of Transcriptionally Silent Chromatin in Saccharomyces cerevisiae

2016

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Transcriptional silencing in Saccharomyces cerevisiae occurs at several genomic sites including the silent mating-type loci, telomeres, and the ribosomal DNA (rDNA) tandem array. Epigenetic silencing at each of these domains is characterized by the absence of nearly all histone modifications, including most prominently the lack of histone H4 lysine 16 acetylation. In all cases, silencing requires Sir2, a highly-conserved NAD + -dependent histone deacetylase. At locations other than the rDNA, silencing also requires additional Sir proteins, Sir1, Sir3, and Sir4 that together form a repressive heterochromatin-like structure termed silent chromatin. The mechanisms of silent chromatin establishment, maintenance, and inheritance have been investigated extensively over the last 25 years, and these studies have revealed numerous paradigms for transcriptional repression, chromatin organization, and epigenetic gene regulation. Studies of Sir2-dependent silencing at the rDNA have also contributed to understanding the mechanisms for maintaining the stability of repetitive DNA and regulating replicative cell aging. The goal of this comprehensive review is to distill a wide array of biochemical, molecular genetic, cell biological, and genomics studies down to the "nuts and bolts" of silent chromatin and the processes that yield transcriptional silencing.

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Heterochromatin structure: Lessons from the budding yeast

2014

IUBMB Life

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The eukaryotic genome can be roughly divided into euchromatin and heterochromatin domains that are structurally and functionally distinct. Heterochromatin is characterized by its high compactness and its inhibitory effect on DNA transactions such as gene expression. Formation of heterochromatin involves special histone modifications and the recruitment and spread of silencing complexes and causes changes in the primary and higher order structures of chromatin. The past two decades have seen dramatic advances in dissecting the molecular aspects of heterochromatin because of the identification of the histone code for heterochromatin as well as its writers and erasers (histone-modifying enzymes) and readers (silencing factors recognizing histone modifications). How heterochromatic histone modifications and silencing factors contribute to the special primary and higher order structures of heterochromatin has begun to be understood. The budding yeast Saccharomyces cerevisiae has long been used as a model organism for heterochromatin studies. Results from these studies have contributed significantly to the elucidation of the general principles governing the formation, maintenance, and function of heterochromatin. This review is focused on investigations into the structural aspects of heterochromatin in S. cerevisiae. Current understanding of other aspects of heterochromatin including how it promotes gene silencing and its epigenetic inheritance is briefly summarized.

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Structural basis for allosteric stimulation of Sir2 activity by Sir4 binding

Cited by 37 publications

References 57 publications

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

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

The Nuts and Bolts of Transcriptionally Silent Chromatin in Saccharomyces cerevisiae

Heterochromatin structure: Lessons from the budding yeast

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