The Methionine-aromatic Motif Plays a Unique Role in Stabilizing Protein Structure

Valley, Christopher C.; Cembran, Alessandro; Perlmutter, Jason D.; Lewis, Andrew K.; Labello, Nicholas P.; Gao, Jiali; Sachs, Jonathan N.

doi:10.1074/jbc.m112.374504

Cited by 281 publications

(351 citation statements)

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“…S5), suggesting similar K36M preference by the lysine access pocket. Besides hydrophobic contacts, the K36M side chain stacks against the aromatic ring of Y1666 and is further stabilized by sulfur-aromatic (Valley et al 2012) as well as CH-π interactions (Fig. 5B, panel i; Brandl et al 2001).…”

Section: Structural Basis For Trans Inhibition Of Setd2 Activity By Hmentioning

confidence: 99%

Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase

et al. 2016

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High-frequency point mutations of genes encoding histones have been identified recently as novel drivers in a number of tumors. Specifically, the H3K36M/I mutations were shown to be oncogenic in chondroblastomas and undifferentiated sarcomas by inhibiting H3K36 methyltransferases, including SETD2. Here we report the crystal structures of the SETD2 catalytic domain bound to H3K36M or H3K36I peptides with SAH (S-adenosylhomocysteine). In the complex structure, the catalytic domain adopts an open conformation, with the K36M/I peptide snuggly positioned in a newly formed substrate channel. Our structural and biochemical data reveal the molecular basis underying oncohistone recognition by and inhibition of SETD2.Supplemental material is available for this article.Received May 16, 2016; revised version accepted June 20, 2016. Histone post-translational modifications (PTMs) are linked to tumorigenesis, mostly via dysfunction of their regulators (e.g., readers, writers, and erasers) that are frequently mutated in tumors (Dawson and Kouzarides 2012). Recently, high-frequency mutations in genes encoding histones themselves, rather than the histone regulators, were identified in a number of cancer types. Exome sequencing studies have identified recurrent hot spot missense mutations in histone H3. Notably, these mutations are located at or adjacent to H3 lysine residues that undergo acetylation and/or methylation. For example, the H3K27M mutation was identified in the majority of pediatric diffuse intrinsic pontine gliomas (Schwartzentruber et al. 2012;Wu et al. 2012), and the H3K36M mutation was found to occur predominantly in chondroblastomas (Behjati et al. 2013) and rarely in other cancer types such as head and neck squamous cell carcinoma and colorectal cancer (Shah et al. 2014). In addition, the H3K36-neighboring G34 mutations, such as G34R/V and G34W/L, have been detected in pediatric non-brain stem gliomas (Schwartzentruber et al. 2012;Wu et al. 2012) and giant cell tumors of the bone (Behjati et al. 2013), respectively.Biochemical and cellular studies showed that H3K27M reduced global H3K27 methylation in vitro and in vivo by inhibiting the methyltransferase activity of polycombrepressive complex 2 (PRC2) (Chan et al. 2013;Lewis et al. 2013;Justin et al. 2016). Recently, we and others identified a similar "poisoning" mechanism underlying H3K36M-driven tumorigenesis involving the inactivation of H3K36 methyltransferases (Fang et al. 2016;Lu et al. 2016). H3K36 can be methylated by enzymes such as NSD1/2/3, ASH1L, and SETD2 (Wagner and Carpenter 2012). Among them, SETD2 serves as the major H3K36 methyltransferase that is able to generate the trimethylated H3K36 from the unmethylated, monomethylated, or dimethylated states in vitro and in cells (Edmunds et al. 2008;Hu et al. 2010). SETD2 plays important roles in cellular processes such as transcription elongation (Yoh et al. 2008), RNA splicing (de Almeida et al. 2011;Kim et al. 2011), and DNA damage repair (Li et al. 2013;Pai et al. 2014). However, due to the lack...

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Section: Structural Basis For Trans Inhibition Of Setd2 Activity By Hmentioning

confidence: 99%

Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase

et al. 2016

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“…In general, methionine is assumed to play a simple structural role in the hydrophobic cores of proteins, in a similar way to the other hydrophobic amino acids (valine, leucine and isoleucine). Additionally, S/p interactions between the side chain sulfur atom and aromatic amino acids have recently been identified as prevalent and important stabilizing interactions in one-third of all known protein structures (Valley et al, 2012). In a handful of proteins, methionine also plays a functional role as a redox sensor (Bigelow & Squier, 2005).…”

Section: Introductionmentioning

confidence: 99%

Bacterial methionine biosynthesis

2014

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Methionine is essential in all organisms, as it is both a proteinogenic amino acid and a component of the cofactor, S-adenosyl methionine. The metabolic pathway for its biosynthesis has been extensively characterized in Escherichia coli; however, it is becoming apparent that most bacterial species do not use the E. coli pathway. Instead, studies on other organisms and genome sequencing data are uncovering significant diversity in the enzymes and metabolic intermediates that are used for methionine biosynthesis. This review summarizes the different biochemical strategies that are employed in the three key steps for methionine biosynthesis from homoserine (i.e. acylation, sulfurylation and methylation). A survey is presented of the presence and absence of the various biosynthetic enzymes in 1593 representative bacterial species, shedding light on the non-canonical nature of the E. coli pathway. This review also highlights ways in which knowledge of methionine biosynthesis can be utilized for biotechnological applications. Finally, gaps in the current understanding of bacterial methionine biosynthesis are noted. For example, the paper discusses the presence of one gene (metC) in a large number of species that appear to lack the gene encoding the enzyme for the preceding step in the pathway (metB), as it is understood in E. coli. Therefore, this review aims to move the focus away from E. coli, to better reflect the true diversity of bacterial pathways for methionine biosynthesis.

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“…Oxidation of Met to MetO decreases hydrophobicity [5] and disrupts both dispersion and electrostatic interactions present in the sulfur-aromatic motif [7]. Such oxidation-induced post-translational modifications may cause proteins to change conformations and lose functions [8][9][10], and are related to pathophysiological conditions such as cancer, aging, and neurodegenerative diseases [3,11].…”

mentioning

confidence: 99%

“…Moreover, Met has the propensity to interact with aromatic residues, and the resulting Met sulfur-aromatic motif provides additional stabilization over hydrophobic interactions [7]. Oxidation of Met to MetO decreases hydrophobicity [5] and disrupts both dispersion and electrostatic interactions present in the sulfur-aromatic motif [7].…”

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confidence: 99%

Mechanistic and Kinetic Study of Singlet O₂ Oxidation of Methionine by On-Line Electrospray Ionization Mass Spectrometry

Liu

Yin

2015

J. Am. Soc. Mass Spectrom.

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Abstract. We report a reaction apparatus developed to monitor singlet oxygen ( 1 O 2 ) reactions in solution using on-line ESI mass spectrometry and spectroscopy measurements. 1O 2 was generated in the gas phase by the reaction of H 2 O 2 with Cl 2 , detected by its emission at 1270 nm, and bubbled into aqueous solution continuously. O 2 oxidation were monitored by UV-Vis absorption and positive/negative ESI mass spectra, and product structures were elucidated using collision-induced dissociation-tandem mass spectrometry. To suppress electrical discharge in negative ESI of aqueous solution, methanol was added to electrospray via in-spray solution mixing using theta-glass ESI emitters. Capitalizing on this apparatus, the reaction of 1 O 2 with methionine was investigated. We have identified methionine oxidation intermediates and products at different pH, and measured reaction rate constants.1 O 2 oxidation of methionine is mediated by persulfoxide in both acidic and basic solutions. Persulfoxide continues to react with another methionine, yielding methionine sulfoxide as end-product albeit with a much lower reaction rate in basic solution. Density functional theory was used to explore reaction potential energy surfaces and establish kinetic models, with solvation effects simulated using the polarized continuum model. Combined with our previous study of gas-phase methionine ions with 1 O 2 , evolution of methionine oxidation pathways at different ionization states and in different media is described.

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The Methionine-aromatic Motif Plays a Unique Role in Stabilizing Protein Structure

Cited by 281 publications

References 57 publications

Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase

Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase

Bacterial methionine biosynthesis

Mechanistic and Kinetic Study of Singlet O₂ Oxidation of Methionine by On-Line Electrospray Ionization Mass Spectrometry

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The Methionine-aromatic Motif Plays a Unique Role in Stabilizing Protein Structure

Cited by 281 publications

References 57 publications

Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase

Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase

Bacterial methionine biosynthesis

Mechanistic and Kinetic Study of Singlet O2 Oxidation of Methionine by On-Line Electrospray Ionization Mass Spectrometry

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Mechanistic and Kinetic Study of Singlet O₂ Oxidation of Methionine by On-Line Electrospray Ionization Mass Spectrometry