N-Terminal Acetylation Inhibits Protein Targeting to the Endoplasmic Reticulum

Forte, Gabriella; Pool, Martin; Stirling, Colin J.

doi:10.1371/journal.pbio.1001073

Cited by 172 publications

(165 citation statements)

References 64 publications

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“…For some proteins, N-terminal acetylation may act as a degradation signal (88), whereas for others N-terminal acetylation may protect from proteolytic degradation and subsequently increases their half-life (89). N-terminal acetylation was also shown to be involved in protein sorting and addressing to cellular organelles (90) or to membrane (91). Indeed, although Adh1p is frequently described as a cytoplasmic protein, it is also associated with the plasma membrane (92) like many other fermentation enzymes (Pgi1p, Tpi1p, Eno1p, Eno2p, Tdh1p, Tdh2p, Tdh3p, Pgk1p, Pyk1p).…”

Section: Discussionmentioning

confidence: 99%

Linking Post-Translational Modifications and Variation of Phenotypic Traits

Albertin

Marullo

Bely

et al. 2013

Molecular & Cellular Proteomics

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Enzymes can be post-translationally modified, leading to isoforms with different properties. The phenotypic consequences of the quantitative variability of isoforms have never been studied. We used quantitative proteomics to dissect the relationships between the abundances of the enzymes and isoforms of alcoholic fermentation, metabolic traits, and growth-related traits in Saccharomyces cerevisiae. Although the enzymatic pool allocated to the fermentation proteome was constant over the culture media and the strains considered, there was variation in abundance of individual enzymes and sometimes much more of their isoforms, which suggests the existence of selective constraints on total protein abundance and trade-offs between isoforms. Variations in abundance of some isoforms were significantly associated to metabolic traits and growth-related traits. In particular, cell size and maximum population size were highly correlated to the degree of N-terminal acetylation of the alcohol dehydrogenase. The fermentation proteome was found to be shaped by human selection, through the differential targeting of a few isoforms for each food-processing origin of strains. These results highlight the importance of posttranslational modifications in the diversity of metabolic and life-history traits. Molecular & Cellular Proteomics 12: 10.1074/mcp.M112.024349, 720 -735, 2013.The key problem in understanding genotype-phenotype relationships is the complexity arising from multiple levels of cellular functioning. Among them, metabolic networks involve series of interconnected chemical reactions catalyzed by enzymes, allowing the transformation of input substrates into intermediate or final metabolites. These networks play an essential role in an organism's growth, reproduction, and ability to maintain cell integrity and to respond to environmental changes (1, 2). The metabolic fluxes, as well as the metabolite concentrations, are governed by the activity of the enzymes, which depends on three types of factors: kinetic parameters, enzyme abundance, and activation state of the enzyme. The kinetic parameters are determined by the sequence and the three-dimensional structure of the protein (3). The abundance of the enzymes is the result of numerous molecular processes taking place from the transcriptional to the translational level, including epigenetic modifications of the DNA and chromatin (4), transcriptional regulation by transcription factors (5), mRNA capping and splicing and small RNA regulation (6), protein turnover (7), etc. The enzyme activation state is primarily because of post-translational modifications of the native protein, themselves highly regulated (8, 9). Other mechanisms involved in enzyme activity are proteinprotein interactions and allosteric regulation, such mechanisms being sometimes mediated through post-translational modifications (10, 11). The resulting isoforms can display differences in activity, affinity for partners (protein or effectors), and stability (12). The most studied modification is the reversibl...

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Section: Discussionmentioning

confidence: 99%

Linking Post-Translational Modifications and Variation of Phenotypic Traits

Albertin

Marullo

Bely

et al. 2013

Molecular & Cellular Proteomics

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“…However, an increasing number of reports indicate that Nt-acetylation is essential for higher eukaryotes, but less critical for normal growth in yeast (9)(10)(11)(12). Functionally, Nt-acetylation was found to regulate a variety of protein features (13), including the degradation (at least in yeast) of some Nt-acetylated proteins by a new branch of the Nend-rule pathway (14) and the ability of Nt-acetylation to inhibit protein translocation into the endoplasmic reticulum (15). The major NATs, NatA, -B, and -C are heterodimers or heterotrimers.…”

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confidence: 99%

N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB

Damme

Lasa²,

Polevoda

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

179

203

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Protein N-terminal acetylation (Nt-acetylation) is an important mediator of protein function, stability, sorting, and localization. Although the responsible enzymes are thought to be fairly well characterized, the lack of identified in vivo substrates, the occurrence of Nt-acetylation substrates displaying yet uncharacterized N-terminal acetyltransferase (NAT) specificities, and emerging evidence of posttranslational Nt-acetylation, necessitate the use of genetic models and quantitative proteomics. NatB, which targets Met-Glu-, Met-Asp-, and Met-Asn-starting protein N termini, is presumed to Nt-acetylate 15% of all yeast and 18% of all human proteins. We here report on the evolutionary traits of NatB from yeast to human and demonstrate that ectopically expressed hNatB in a yNatB-Δ yeast strain partially complements the natB-Δ phenotypes and partially restores the yNatB Nt-acetylome. Overall, combining quantitative N-terminomics with yeast studies and knockdown of hNatB in human cell lines, led to the unambiguous identification of 180 human and 110 yeast NatB substrates. Interestingly, these substrates included Met-Gln-N-termini, which are thus now classified as in vivo NatB substrates. We also demonstrate the requirement of hNatB activity for maintaining the structure and function of actomyosin fibers and for proper cellular migration. In addition, expression of tropomyosin-1 restored the altered focal adhesions and cellular migration defects observed in hNatB-depleted HeLa cells, indicative for the conserved link between NatB, tropomyosin, and actin cable function from yeast to human.

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“…Most recently two studies have significantly revisited the field of acetylation function and regulation. First, it was suggested that NAA contributes to cell sorting by inhibiting protein to target the endoplasmic reticulum (39). Thus, proteins devoid of NAA signal would be preferentially guided to the secretory pathway in yeast.…”

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confidence: 99%