Yeast Ataxin-2 Forms an Intracellular Condensate Required for the Inhibition of TORC1 Signaling during Respiratory Growth

Yang, Y.; Kato, Masato; Wu, Xi; Litsios, Athanasios; Sutter, Benjamin M.; Wang, Yun; Hsu, Chien Hsiang; Wood, N. Ezgi; Lemoff, Andrew; Mirzaei, Hamid; Heinemann, Matthias; Tu, Benjamin P.

doi:10.1016/j.cell.2019.02.043

Cited by 82 publications

(98 citation statements)

References 61 publications

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“…In a previous work, ataxin‐2 was identified as a putative candidate to be regulated via cross talk between methionine sulfoxidation and serine phosphorylation in response to oxidative stress . More recently, the group led by Benjamin Tu has unraveled a prominent role for methionyl residues from Pbp1 (the yeast orthologous of ataxin‐2) in the formation of intracellular drop‐like condensates required for the inhibition of TORC1 signaling during respiratory growth …”

Section: Reversible Oxidation Of Methionine and The Regulation Of Liqmentioning

confidence: 99%

“…38 More recently, the group led by Benjamin Tu has unraveled a prominent role for methionyl residues from Pbp1 (the yeast orthologous of ataxin-2) in the formation of intracellular drop-like condensates required for the inhibition of TORC1 signaling during respiratory growth. 42,43 In the presence of fermentable carbon sources, yeast cells activate anabolic pathways and growth. On the other hand, under conditions of limiting carbon source, yeast mitochondria adopt a state of intense respiration.…”

Section: Reversible Oxidation Of Methionine and The Regulation Of Lmentioning

confidence: 99%

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Methionine in proteins: The Cinderella of the proteinogenic amino acids

Aledo

2019

Protein Science

111

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Methionine in proteins, apart from its role in the initiation of translation, is assumed to play a simple structural role in the hydrophobic core, in a similar way to other hydrophobic amino acids such as leucine, isoleucine, and valine. However, research from a number of laboratories supports the concept that methionine serves as an important cellular antioxidant, stabilizes the structure of proteins, participates in the sequence‐independent recognition of protein surfaces, and can act as a regulatory switch through reversible oxidation and reduction. Despite all these evidences, the role of methionine in protein structure and function is largely overlooked by most biochemists. Thus, the main aim of the current article is not so much to carry out an exhaustive review of the many and diverse processes in which methionine residues are involved, but to review some illustrative examples that may help the nonspecialized reader to form a richer and more precise insight regarding the role‐played by methionine residues in such processes.

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Section: Reversible Oxidation Of Methionine and The Regulation Of Liqmentioning

confidence: 99%

Section: Reversible Oxidation Of Methionine and The Regulation Of Lmentioning

confidence: 99%

Methionine in proteins: The Cinderella of the proteinogenic amino acids

Aledo

2019

Protein Science

111

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“…PAB1 is an essential gene in yeast (Sachs et al, 1986;Sachs et al, 1987), but its absence can be studied in several suppressor mutants. Pbp1 was identified as a Pab1-interacting protein and pbp1Δ cells suppress a pab1Δ allele without having significant effects on mRNA translation or decay Mangus et al, 1998a;Yang et al, 2019). Accordingly, we generated pab1Δ pbp1Δ upf1Δ yeast cells and transformed them with the pRS316-LUC-PTC reporters and control plasmids equivalent to those analyzed in the experiments of Figure 1.…”

Section: Poly(a) Binding Protein Restricts Ptc Readthrough and Maintamentioning

confidence: 99%

Nonsense suppression position effect implicates poly(A)-binding protein in the regulation of translation termination

Roy

et al. 2019

Preprint

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Readthrough of translation termination codons, also known as nonsense suppression, is a relatively inefficient process mediated by ribosomal A site recognition and insertion of near-cognate tRNAs. Multiple factors influence readthrough efficiency, including nonsense codon specificity and context. To determine whether nonsense codon position in a gene influences the extent of readthrough, we generated a series of LUC nonsense alleles and quantitated both readthrough and termination efficiencies at each nonsense codon in yeast cells lacking nonsense-mediated mRNA decay (NMD) activity.Readthrough efficiency for premature termination codons (PTCs) manifested a marked dependence on PTC proximity to the mRNA 3'-end, decreasing progressively across the LUC ORF but increasing with 3'-UTR lengthening. These effects were eliminated, and translation termination efficiency decreased considerably, in cells harboring pab1 mutations. Our results support a critical role for poly(A)-binding protein in the regulation of translation termination and suggest that inefficient termination is the trigger for NMD.3

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“…TDP43 polymers are sensitive to H 2 O 2 -mediated disassembly wherein methionine residues are converted to the methionine sulfoxide state. In this regard, the behavior and biological properties of the TDP43 LC domain are reminiscent of the LC domain specified by the yeast ataxin--2 protein Yang et al, 2019). We hypothesize that both the ataxin--2 and TDP43 LC domains assemble into oligomeric structures specifying redox sensors that constitute proximal receptors to the action of reactive oxygen species.…”

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confidence: 99%

Redox-mediated regulation of a labile, evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain

Lin

Zhou

Kato

et al. 2019

Preprint

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An evolutionarily conserved low complexity (LC) domain is found within a 152 residue segment localized to the carboxyl--terminal region of the TDP43 RNA--binding protein. This TDP43 LC domain contains ten conserved methionine residues. Self--association of this domain leads to the formation of liquid--like droplets composed of labile, cross--β polymers. Exposure of polymers to low concentrations of H 2 O 2 leads to a phenomenon of droplet melting that can be reversed upon exposure of the oxidized protein to the MsrA and MsrB methionine sulfoxide reductase enzymes, thioredoxin, thioredoxin reductase and NADPH. Morphological features of the cross--β polymers were revealed by a method of H 2 O 2 --mediated footprinting. Similar TDP43 LC domain footprints were observed in highly polymerized, hydrogel samples, liquid--like droplet samples, and living cells. The ability of H 2 O 2 to impede cross--β polymerization was abrogated by a prominent ALS--causing mutation that changes methionine residue 337 to valine. These observations offer potentially useful insight into the biological role of TDP43 in facilitating synapse--localized translation, as well as aberrant aggregation of the protein in neurodegenerative disease.

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Yeast Ataxin-2 Forms an Intracellular Condensate Required for the Inhibition of TORC1 Signaling during Respiratory Growth

Cited by 82 publications

References 61 publications

Methionine in proteins: The Cinderella of the proteinogenic amino acids

Methionine in proteins: The Cinderella of the proteinogenic amino acids

Nonsense suppression position effect implicates poly(A)-binding protein in the regulation of translation termination

Redox-mediated regulation of a labile, evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain

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