Nα-terminal Acetylation of Eukaryotic Proteins

Polevoda, Bogdan; Sherman, Fred

doi:10.1074/jbc.r000023200

Cited by 318 publications

(306 citation statements)

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“…Occurrence of particular amino acid residues at the NH 2 termini of proteins thus determines the prevalence of the acetylated form by this mechanism; 95% of all N-acetylated termini comprise only a handful of amino acids: N-acetyl serine, alanine, glycine, and methionine. The next most common are valine and aspartate (34). In the present dataset of hibernator blood plasma, despite being listed in the metabolite database, there were no measurable amounts of N-acetylated serine, alanine, valine or aspartate.…”

Section: Discussionmentioning

confidence: 92%

Metabolic cycles in a circannual hibernator

Epperson¹,

Karimpour-Fard

Hunter

et al. 2011

Physiological Genomics

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nation as manifested in ground squirrels is arguably the most plastic and extreme of physiological phenotypes in mammals. Homeostasis is challenged by prolonged fasting accompanied by heterothermy, yet must be facilitated for survival. We performed LC and GC-MS metabolomic profiling of plasma samples taken reproducibly during seven natural stages of the hibernator's year, three in summer and four in winter (each n Ն 5), employing a nontargeted approach to define the metabolite shifts associated with the phenotype. We quantified 231 named metabolites; 106 of these altered significantly, demarcating a cycle within a cycle where torpor-arousal cycles recur during the winter portion of the seasonal cycle. A number of robust hibernation biomarkers that alter with season and winter stage are identified, including specific free fatty acids, antioxidants, and previously unpublished modified amino acids that are likely to be associated with the fasting state. The major pattern in metabolite levels is one of either depletion or accrual during torpor, followed by reversal to an apparent homeostatic level by interbout arousal. This finding provides new data that strongly support the predictions of a long-standing hypothesis that periodic arousals are necessary to restore metabolic homeostasis. Ictidomys tridecemlineatus; Spermophilus; ␥-glutamyl; biliverdin; NacetylA YEAR IN THE LIFE OF A HIBERNATOR begins with reproduction in spring, followed by growth in summer, and then massive storage of fat as fall approaches. Hibernation, characterized by months of fasting and dramatic oscillations between states of cold and warm body temperature (T b ), ensues only after adequate fat stores are deposited (7). Most of the fall and winter months are spent in a state of deep torpor in which metabolic, heart, and respiratory rates are reduced to Ͻ5% of their summer equivalents, and body temperature declines to as low as 0°C, or even below (5). However, all hibernating mammals spontaneously reverse torpor at regular intervals by elevating metabolic rate and employing strictly endogenous mechanisms of heat production including shivering and nonshivering thermogenesis. In the thirteen-lined ground squirrel, Ictidomys tridecemlineatus, elevated metabolic rate and T b (ϳ37°C) are maintained in each interbout arousal for ϳ10 -12 h before dropping again to initiate the next ϳ2 wk bout of torpor. Thus, the circannual hibernation rhythm can be viewed as a cycle between summer homeothermy and winter heterothermy, the latter of which is itself a cycle between torpor and arousal (see Fig. 1). These dramatic physiological shifts of hibernation have been postulated to result from intrinsic metabolic cycles (41) that may be revealed by metabolic profiling (42).Previous work to measure metabolite changes in hibernators documents a number of alterations in liver (2, 32, 36), brain (21, 40), brown adipose tissue (13), bile (4), and blood (1, 9, 24, 31) that begin to assess the metabolites cycling in association with hibernation. These data suggest a two-s...

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Section: Discussionmentioning

confidence: 92%

Metabolic cycles in a circannual hibernator

Epperson¹,

Karimpour-Fard

Hunter

et al. 2011

Physiological Genomics

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“…NatA is composed of two main subunits (Nat1p and Ard1p), whose mutants are related to the disappearance of acetylated isoforms of several enzymes, including Adh1p and Pdc1p (85). N-terminal acetylation is one of the most common protein modifications in eukaryotes, as 85% of the proteins have an acetylated isoform (86), but it displays several specificities. Unlike other post-translational modifications, N-terminal acetylation is irreversible and occurs during protein synthesis after about 50 amino acid residues have emerged from the ribosome (87).…”

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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“…These last two residues may be a classical Nacetyltransferase (Nat) substrate sequence because they resemble a motif from a subclass of NatA substrates in higher eukaryotes, which is designated as NatD substrates in yeast [36]. After methionine cleavage, the most common N-terminal residue for N-acetylation by NatA is S, A, or T. The addition of the amino acid E or D penultimate to that N-terminal residue then classifies them as NatD substrates.…”

Section: Dissection Of the Pexel Motifmentioning

confidence: 99%

N-terminal processing of proteins exported by malaria parasites

Chang

Falick

Carlton

et al. 2008

Molecular and Biochemical Parasitology

169

172

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Malaria parasites utilize a short N-terminal amino acid motif termed the Plasmodium export element (PEXEL) to export an array of proteins to the host erythrocyte during blood stage infection. Using immunoaffinity chromatography and mass spectrometry, insight into this signalmediated trafficking mechanism was gained by discovering that the PEXEL motif is cleaved and N-acetylated. PfHRPII and PfEMP2 are two soluble proteins exported by Plasmodium falciparum that were demonstrated to undergo PEXEL cleavage and N-acetylation, thus indicating that this Nterminal processing may be general to many exported soluble proteins. It was established that PEXEL processing occurs upstream of the brefeldin A-sensitive trafficking step in the P. falciparum secretory pathway, therefore cleavage and N-acetylation of the PEXEL motif occurs in the endoplasmic reticulum (ER) of the parasite. Furthermore, it was shown that the recognition of the processed N-terminus of exported proteins within the parasitophorous vacuole may be crucial for protein transport to the host erythrocyte. It appears that the PEXEL may be defined as a novel ER peptidase cleavage site and a classical N-acetyltransferase substrate sequence.

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Nα-terminal Acetylation of Eukaryotic Proteins

Cited by 318 publications

References 50 publications

Metabolic cycles in a circannual hibernator

Metabolic cycles in a circannual hibernator

Linking Post-Translational Modifications and Variation of Phenotypic Traits

N-terminal processing of proteins exported by malaria parasites

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