Determinants and Regulation of Protein Turnover in Yeast

Martín-Pérez, Miguel; Villén, Judit

doi:10.1016/j.cels.2017.08.008

Cited by 97 publications

(144 citation statements)

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“…This is likely due, at least in part, to limited proteome coverage (relative to the protein abundance dataset). However, a recent study also suggested that protein half-life is strongly affected by factors other than sequence characteristics [48], which would likely further dampen trends observed between compositional enrichment and protein half-life. Finally, protein half-life is generally less-conserved than protein abundance [49], perhaps suggesting that specific relationships between conserved sequence features and protein half-life may not be particularly strong.…”

Section: Resultsmentioning

confidence: 99%

Proteome-Scale Relationships Between Local Amino Acid Composition and Protein Fates and Functions

Cascarina

Ross

2018

Preprint

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1Proteins with low-complexity domains continue to emerge as key players in both normal 2 and pathological cellular processes. Although low-complexity domains are often grouped into a 3 single class, individual low-complexity domains can differ substantially with respect to amino 4 acid composition. These differences may strongly influence the physical properties, cellular 5 regulation, and molecular functions of low-complexity domains. Therefore, we developed a 6 bioinformatic approach to explore relationships between amino acid composition, protein 7 metabolism, and protein function. We find that local compositional enrichment within protein 8 sequences affects the translation efficiency, abundance, half-life, subcellular localization, and 9 molecular functions of proteins on a proteome-wide scale. However, these effects depend upon 10 the type of amino acid enriched in a given sequence, highlighting the importance of 11 distinguishing between different types of low-complexity domains. Furthermore, many of these 12 effects are discernible at amino acid compositions below those required for classification as low-13 complexity or statistically-biased by traditional methods and in the absence of homopolymeric 14 amino acid repeats, indicating that thresholds employed by classical methods may not reflect 15 biologically relevant criteria. Application of our analyses to composition-driven processes, such 16 as the formation of membraneless organelles, reveals distinct composition profiles even for 17 closely related organelles. Collectively, these results provide a unique perspective and detailed 18 insights into relationships between amino acid composition, protein metabolism, and protein 19 functions. 20 21 Author Summary 22Low-complexity domains in protein sequences are regions that are composed of only a 23 few amino acids in the protein "alphabet". These domains often have unique chemical 24properties and play important biological roles in both normal and disease-related processes. 25 While a number of approaches have been developed to define low-complexity domains, these 26 methods each possess conceptual limitations. Therefore, we developed a complementary 27 approach that focuses on local amino acid composition (i.e. the amino acid composition within 28 small regions of proteins). We find that high local composition of individual amino acids is 29 associated with pervasive effects on protein metabolism, subcellular localization, and molecular 30 function on a proteome-wide scale. Importantly, the nature of the effects depend on the type of 31 amino acid enriched within the examined domains, and are observable in the absence of 32 classically-defined low-complexity (and related) domains. Furthermore, we define the 33 compositions of proteins involved in the formation of membraneless, protein-rich organelles 34 such as stress granules and P-bodies. Our results provide a coherent view and unprecedented 35 resolution of the effects of local amino acid enrichment on protein biology. 36 37 the local Shannon entropy...

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Section: Resultsmentioning

confidence: 99%

Proteome-Scale Relationships Between Local Amino Acid Composition and Protein Fates and Functions

Cascarina

Ross

2018

Preprint

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“…recently measured protein turnover rates for 3160 proteins in exponentially growing yeast and determined that protein localization, protein complex formation, and connectivity greatly influence protein half‐lives . Assessing PTM profiles, they found that proteins with faster turnover showed higher ubiquitination site occupancy while occupancy for other PTMs was similar between proteins with short or longer half‐lives . In addition, Basisty et al.…”

Section: Protein Aggregation Modifications and Damage Of Aged Proteinsmentioning

confidence: 99%

“…influence protein half-lives. [12] Assessing PTM profiles, they found that proteins with faster turnover showed higher ubiquitination site occupancy while occupancy for other PTMs was similar between proteins with short or longer half-lives. [12] In addition, Basisty et al recently investigated age-related increases in accumulation of long-lived aggregating proteins and correlated their ubiquitination status and insolubility.…”

Section: Protein Aggregation Modifications and Damage Of Aged Proteinsmentioning

confidence: 99%

“…[12] Assessing PTM profiles, they found that proteins with faster turnover showed higher ubiquitination site occupancy while occupancy for other PTMs was similar between proteins with short or longer half-lives. [12] In addition, Basisty et al recently investigated age-related increases in accumulation of long-lived aggregating proteins and correlated their ubiquitination status and insolubility. [13] They also reported that age-related decline in proteostasis led to accumulation of ubiquitinated proteins in aggregates, and that a large proportion of ubiquitinated proteins were not turned over in aged animals.…”

Section: Protein Aggregation Modifications and Damage Of Aged Proteinsmentioning

confidence: 99%

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Accumulation of “Old Proteins” and the Critical Need for MS‐based Protein Turnover Measurements in Aging and Longevity

2019

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Aging and age‐related diseases are accompanied by proteome remodeling and progressive declines in cellular machinery required to maintain protein homeostasis (proteostasis), such as autophagy, ubiquitin‐mediated degradation, and protein synthesis. While many studies have focused on capturing changes in proteostasis, the identification of proteins that evade these cellular processes has recently emerged as an approach to studying the aging proteome. With advances in proteomic technology, it is possible to monitor protein half‐lives and protein turnover at the level of individual proteins in vivo. For large‐scale studies, these technologies typically include the use of stable isotope labeling coupled with MS and comprehensive assessment of protein turnover rates. Protein turnover studies have revealed groups of highly relevant long‐lived proteins (LLPs), such as the nuclear pore complexes, extracellular matrix proteins, and protein aggregates. Here, the role of LLPs during aging and age‐related diseases and the methods used to identify and quantify their changes are reviewed. The methods available to conduct studies of protein turnover, used in combination with traditional proteomic methods, will enable the field to perform studies in a systems biology context, as changes in proteostasis may not be revealed in studies that solely measure differential protein abundances.

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“…Finally, it is well established that protein stability and degradation plays an important role in regulated protein turnover during environmental shifts. 16,17 In addition to protein abundance changes, PTMs are well known to regulate protein activity and/or stability during environmental shifts. For example, stress-activated protein kinases coordinate phospho-signal transduction cascades that are largely conserved from yeast through humans.…”

Section: Introductionmentioning

confidence: 99%

Accurate and Sensitive Quantitation of the Dynamic Heat Shock Proteome using Tandem Mass Tags

Storey

Hardman

Byrum

et al. 2019

Preprint

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Cells respond to environmental perturbations and insults through modulating protein abundance and function. However, the majority of studies have focused on changes in RNA abundance because quantitative transcriptomics has historically been more facile than quantitative proteomics. Modern Orbitrap mass spectrometers now provide sensitive and deep proteome coverage, allowing direct, global quantification of not only protein abundance, but also posttranslational modifications (PTMs) that regulate protein activity. We implemented, and validated using the well-characterized heat shock response of budding yeast, a tandem mass tagging (TMT), triple-stage mass spectrometry (MS 3 ) strategy to measure global changes in the proteome during the yeast heat shock response over nine timepoints. We report that basic pH, ultra-high performance liquid chromatography (UPLC) fractionation of tryptic peptides yields superfractions of minimal redundancy, a crucial requirement for deep coverage and quantification by subsequent LC-MS 3 . We quantified 2,275 proteins across 3 biological replicates, and found that differential expression peaked near 90 minutes following heat shock (with 868 differentially expressed proteins at 5% FDR). The sensitivity of the approach also allowed us to detect changes in the relative abundance of ubiquitination and phosphorylation PTMs over time. Remarkably, relative quantification of post-translationally modified peptides revealed striking evidence of regulation of the heat shock response by protein PTMs. These data demonstrate that the high precision of TMT-MS 3 enables peptide-level quantification of samples, which can reveal important regulation of protein abundance and regulatory PTMs under various experimental conditions.

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Determinants and Regulation of Protein Turnover in Yeast

Cited by 97 publications

References 65 publications

Proteome-Scale Relationships Between Local Amino Acid Composition and Protein Fates and Functions

Proteome-Scale Relationships Between Local Amino Acid Composition and Protein Fates and Functions

Accumulation of “Old Proteins” and the Critical Need for MS‐based Protein Turnover Measurements in Aging and Longevity

Accurate and Sensitive Quantitation of the Dynamic Heat Shock Proteome using Tandem Mass Tags

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