Post-Translational Modifications in Health and Disease: 13 (Protein Reviews)

Post Translational Modifications: An Overview

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However, technical difficulties limit these studies, leaving many unanswered questions. Notably, though, a sampling of the proteome in a given organism or cell provides only a snapshot of a highly dynamic process, confounding the analytical problem and ultimately arguing for time-resolved inventories [ 20 ]. Thus, while many tools are currently available for the study of PTMs, new methods are needed to further advance the study of these modifications.

Generally, protein PTMs occur as a result of either modifying enzymes related to posttranslational processing such as glycosylation or signaling pathway activation such as phosphorylation. Moreover, PTM patterns are known to be affected by disease conditions [ 46 ]. Similarly, the dysregulation of PTM is associated with the aging process [ 18 , 47 — 49 ]. In this context, both enzymatic and nonenzymatic PTMs can undergo age-related alterations.

Alteration in the pattern of nonenzymatic PTMs depends mainly on the nature of the modifying substances, such as metabolites and free radicals. For instance, reactive oxygen species can lead to oxidation of amino acid side chains oxidation of thiols to different forms, oxidation of methionine, formation of carbonyl groups, etc.

In contrast, changes in the nature of enzymatic PTMs rely primarily on the activities of modifying enzymes. In this review, we provide an overview of some of the most well-characterized PTMs implicated in aging and aging-associated pathologies across different levels of biological complexity. Protein PTMs fall under two broad categories Scheme 1.

The first category encompasses covalent additions of some chemical group by enzymatic catalysis. Typically, an electrophilic fragment of a cosubstrate is added to an electron-rich protein side chain, which acts as a nucleophile in the transfer. The other category of PTMs encompasses covalent cleavage of peptide backbones. This cleavage occurs by one of two mechanisms: Common covalent protein PTMs include phosphorylation, acylation, alkylation, glycosylation, and oxidation.

These PTMs, catalyzed by dedicated mechanisms Scheme 2 , play roles in aging and age-related diseases. A brief description of the main types of PTMs associated with aging and age-related diseases is provided below. Two categories of posttranslational modifications of proteins: Reproduced with permission from Walsh et al. Five major types of covalent additions to protein side chains: The most common posttranslational modification, protein phosphorylation, is the reversible addition of a phosphoryl group from adenosine triphosphate ATP principally to serine, threonine, or tyrosine residues.

Phosphorylated proteins have critical and well-known functions in diverse cellular processes across eukaryotes, but phosphorylation also occurs in prokaryotic cells. In humans, about one-third of proteins are estimated to be substrates for phosphorylation [ 53 ]. Indeed, phosphorylated proteins are now identified and characterized by high-throughput phosphoproteomics studies. The reversibility of protein phosphorylation is attributed to the actions of kinases and phosphatases, which phosphorylate and dephosphorylate substrates, respectively.

The temporal and spatial balance of kinase and phosphatase concentrations within a cell mediates the size of its phosphoproteome [ 54 ]. N-Acetylation is the reversible or irreversible transfer of an acetyl group to a nitrogen molecule through the actions of cleavage of methionine by methionine aminopeptidase MAP and the addition of an acetyl group from acetyl-CoA by N-acetyltransferase NAT.

In the case of histone proteins, which make up chromatin, lysine acetylation regulates gene transcription, thereby affecting the cell's transcriptome. Histone acetylation typically results in transcriptional activation; deacetylation typically results in transcriptional suppression. One group of histone deacetylases are the sirtuins silent information regulator , which maintain gene silencing via hypoacetylation.

Sirtuins have been reported to aid in maintaining genomic stability [ 57 ]. Although first described in histones, acetylation is also observed in cytoplasmic proteins. Acetylated proteins can also be modulated by the cross-talk with other posttranslational modifications, including phosphorylation, ubiquitination, and methylation [ 58 ]. Therefore, acetylation may contribute to cell biology beyond transcriptional regulation [ 59 ]. Protein glycosylation involves the addition of a diverse set of sugar moieties.

This major type of PTM has significant implications for protein folding, conformation, distribution, stability, and activity. Glycosylated proteins can have additions of simple monosaccharides e. More than half of all mammalian proteins are believed to be glycosylated [ 60 ]. However, glycoprotein functions, at both molecular and cellular levels, remain unclear. While proteins exhibit improved stability and trafficking after glycosylation in vivo, glycan structures can alter protein functions or activities.

These structures often result from the activities of glycan-processing enzymes working within a cell at any given time. However, the structures are sometimes protein-specific, depending on protein trafficking properties and interactions with other cellular factors [ 61 ]. There are three types of protein glycosylation in higher eukaryotes: N-linked, O-linked, and C-linked. These types reflect their glycosidic linkages to amino acid side chains [ 62 ]. N-linked glycans have multiple functions.

While they act as ligands for glycan-binding proteins in cell-cell communication, they also can regulate glycoprotein aggregation in the plasma membrane and affect the half-life of antibodies, cytokines, and hormones in serum [ 64 ]. O-linked glycosylation in higher eukaryotes occurs through several different mechanisms. Aberrant expression of mucin-type O-linked glycans occurs in cancer cells [ 65 ] and may provide targets for anticancer vaccines [ 67 ].

This glycosylation modulates Notch signaling during eukaryotic development [ 71 , 72 ]. The addition of one ubiquitin is followed by the formation of a ubiquitin polymer. The resultant polyubiquitinated proteins are recognized by the 26S proteasome in the protein degradation pathway [ 81 ].

Protein sumoylation is a reversible posttranslational modification whereby a small ubiquitin-like modifier SUMO is covalently attached to proteins [ 82 ]. Accordingly, protein sumoylation is mediated by a reversible enzymatic cascade in a manner similar to protein ubiquitination [ 83 ]. Like ubiquitin, SUMO is conjugated to the lysine side chains of target proteins via a cascade of activating, conjugating, and ligating enzymes, and it is removed by SUMO-specific isopeptidases [ 82 ].

Introduction

Over the last few decades, it has been well established that sumoylation controls many aspects of nuclear function [ 84 ]. However, recent research has started to unveil a determinant role of protein sumoylation in many extranuclear neuronal processes and potentially in a wide range of neuropathological conditions [ 85 ].

Nitrosylation is a reversible addition of a nitric oxide NO to cysteine residues, forming S-nitrosothiols SNOs , via redox-mediated reactions. S-Nitrosylation is used by cells to stabilize proteins, regulate gene expression, and provide NO donors.

Indeed, these molecules have a short half-life because of the action of enzymes like glutathione GSH and thioredoxin that denitrosylate proteins [ 88 ]. S-Nitrosylation is increasingly recognized as a ubiquitous regulatory reaction comparable to phosphorylation. SNOs may play an important role in many processes ranging from signal transduction, DNA repair, host defense, and blood pressure control to ion channel regulation and neurotransmission [ 89 ].

S-Nitrosylation specificity can mainly be achieved by two strategies. The existence of a consensus nitrosylation acid-based motif has been postulated [ 90 ]. S-Nitrosylation specificity may also be achieved through the subcellular localization of the NOSs, which may be in proximity to potential targets. The effect of NO on cells depends on its local concentration, the redox status of its immediate environment, and the susceptibility of target sites for modification [ 91 ].

Different degrees of accessibility to NO RSNO or different reaction rates with NO, as well as important functional differences in the -SH group being modified by NO, might explain why and how specific S-nitrosylation of precise cysteine residues induces protein modulation [ 92 ]. A classical example of SNOs is caspases, which mediate apoptosis. Stored in the mitochondrial intermembrane space as SNOs, caspases are then released into the cytoplasm and denitrosylated. The activated caspase then induces apoptosis [ 93 ]. Alkyl substituents are attached to specific regions of proteins by PTM enzymes.

The introduction of such alkyl groups results in the alteration of the hydrophobicity of the modified protein [ 94 ]. The most common type of protein alkylation is protein methylation. Methylation is a well-known PTM mediated by methyltransferases. One-carbon methyl groups are added to nitrogen or oxygen N- and O-methylation, resp. While N-methylation is irreversible, O-methylation is potentially reversible. Methylation occurs so often that its primary methyl donor, S-adenosyl methionine SAM , is suggested as the most-used enzymatic substrate after ATP [ 56 ].

A common theme with methylated proteins, as is also the case with phosphorylated proteins, is the role this modification plays in the regulation of protein-protein interactions. For instance, the arginine methylation of proteins can either inhibit or promote protein-protein interactions depending on the type of methylation [ 95 , 96 ].

Protein methylation has been most studied in the histones. The transfer of methyl groups from S-adenosyl methionine to histones is catalyzed by enzymes known as histone methyltransferases. The N-terminal tails of histones H3 and H4 receive methyl groups on specific lysines. Methylation then determines if gene transcription is activated or repressed, thus leading to different biological outcomes [ 97 ]. Histone methylation was traditionally thought to be irreversible.

However, histone demethylases demonstrate the reversibility of this PTM [ 98 ]. Indeed, chromatin modification dynamic changes were imposed by an ability or inability to maintain equilibrium in the opposing effects of methylases and demethylases. The simultaneous removal of one histone methylation mark and an addition of another enable transcriptional tuning [ 99 , ]. Further, methylation works in concert with other types of PTMs, as well as with histone and nonhistone proteins, to exert influence on not only chromatin remodeling but also gene transcription, protein synthesis, and DNA repair [ ].

The reaction of proteins with a variety of free radicals and reactive oxygen species ROS leads to oxidative protein modifications such as formation of protein hydroperoxides, hydroxylation of aromatic groups and aliphatic amino acid side chains, oxidation of sulfhydryl groups, oxidation of methionine residues, conversion of some amino acid residues into carbonyl groups, cleavage of the polypeptide chain, and formation of cross-linking bonds. Aromatic and sulfur-containing residues are particularly susceptible to oxidative modification [ 66 — 68 ].

Unless repaired or removed from cells, oxidized proteins are often toxic and can impair cellular viability [ ], since oxidatively modified proteins can form large aggregates [ ]. Oxidatively damaged proteins undergo selective proteolysis, primarily by the 20S proteasome in an ubiquitin- and ATP-independent way. Ultimately, upon extensive protein oxidation, these aggregates can become progressively resistant to proteolytic digestion and actually bind the 20S proteasome and irreversibly inhibit its activity [ 70 — 72 ]. Protein carbonylation is defined as an irreversible posttranslational modification PTM whereby a reactive carbonyl moiety, such as an aldehyde, ketone, or lactam, is introduced into a protein.

The first identified source of protein-bound carbonyls was metal-catalyzed oxidation MCO [ ]. MCO results from the Fenton reaction when transition metal ions are reduced in the presence of hydrogen peroxide, generating the highly reactive hydroxyl radicals in the process [ ]. These hydroxyl radicals can oxidize amino acid side chains or cleave the protein backbone, leading to numerous modifications including reactive carbonyls [ ].

For example, oxidation of proline and arginine results in the production of glutamic semialdehyde, while lysine is oxidized to aminoadipic semialdehyde and threonine to 2-aminoketobutyric acid [ ]. Direct oxidation of other amino acid residues can also lead to protein-bound carbonyls. Tryptophan oxidation by ROS produces at least seven oxidation products. Among them are kynurenine and N-formyl kynurenine, as well as their hydroxylated analogs, which contain aldehyde or keto groups formed by oxidative cleavage of the indole ring [ ].

Another important source of protein-bound carbonyls is reactive lipid peroxidation products, which are produced during oxidation of polyunsaturated fatty acids [ 78 — 81 ]. Protein carbonylation can also occur via glycoxidation. These glycated residues can be further decomposed by ROS into advanced glycation end products AGE carrying carbonylated moieties that can also contribute for protein carbonylation [ ]. As individuals age, control of gene expression, which is orchestrated by multiple epigenetic factors, deteriorates.

Epigenetic control of chromatin remodeling, through histone acetylation, is associated with cellular metabolism [ , ]. Changes in metabolism with aging affect the concentration of acetyl-CoA and of citrate; this, in turn, alters the cytosolic level of acetyl-CoA. Altered acetyl-CoA levels, then, affect other metabolic processes such as the synthesis of fatty acids, exerting downstream effects on other physiological functions.

Moreover, altered acetyl-CoA levels affect histone acetylation, thereby dysregulating transcription [ , ]. These transcriptional changes occur with aging or with the progression of aging-related diseases. Thus, chromatin may act to sense changes in cellular metabolism [ ]. In fact, lifespan can be extended by several manipulations that reverse age-dependent changes in chromatin structure, indicating the pivotal role of chromatin structure during aging [ ]. Protein acetylation has been suggested to play a key role in the process of aging by enhancing the function of certain genes, most notably the AMPK regulatory subunit, which can promote longevity [ ].

Likewise, it is widely accepted that sirtuins, a class of proteins that modulate stress responses and metabolism by removing the acetyl groups from target proteins, have an impact on lifespan and the aging process [ , ]. More recently, it has been found that caloric restriction CR , an intervention known to extend the lifespan in many organisms ranging from budding yeast to mammals, is associated with dramatic changes in mitochondrial acetylation.

Many proteins are altered by acetylation in response to CR [ , ]. These changes may contribute to mitochondrial adaptation to reduced caloric intake and may help to promote longevity. Likewise, regular exercise has been found to reduce oxidatively modified proteins in the brain with improved cognitive functions [ ], through processes involving PTMs in histone tails controlled by HATs, HDACs, and histone demethylases [ ]. Many pathways and processes appear to regulate the rate of aging and organismal susceptibility to age-related diseases such as neurodegeneration, atherosclerosis, and cancer.

One process that is increasingly implicated is autophagy. First described in yeast, autophagy is a tightly regulated process stimulated by stressful conditions, such as starvation. Once activated, autophagy involves the recycling of old and damaged proteins and organelles to provide building blocks for new cellular components. Accordingly, disruption of this process results in diseased phenotypes and decreased lifespan, as revealed by studies using mouse models [ 96 — 98 ], Caenorhabditis elegans , Drosophila melanogaster , and Saccharomyces cerevisiae [ 90 — 93 ].

While the core components that regulate autophagy have been widely studied e. Understanding the mechanisms of autophagy regulation will provide biogerontologists deeper insight into the process and point to new therapeutic avenues [ ]. One of the earliest mentions of the effects of oxidative stress in cells can be found in a description of the chemical nature of pro-oxidant and antioxidant molecules [ ]. A balance between oxidative and antioxidative effects maintains cellular health, whereas an imbalance is associated with diseases and aging.

ROS are hallmarks of oxidative damage. The effects of an imbalanced redox status of cells primarily involve the modification of redox-sensitive molecules, such as the oxidation of cysteine and methionine in proteins, the peroxidation of lipids, and the oxidation of DNA bases [ 13 ].

Several studies have identified proteins involved in mediating or countering reactive oxygen species production and action. A recent review [ ] focusing on aging-related oxidative damage in the context of the damage accumulation theory of aging has stated that chronic oxidative damage is the primary cause of age-related diseases. Cellular senescence, defined as a loss of cell division, motility, and protein turnover, occurs as a result of damage accumulation over time and is considered an important feature of aging [ 13 ].

Morphological changes due to the accumulation of protein aggregates in the cells are also considered as a feature of cellular senescence induced by oxidative protein damage. A wide range of aging-related diseases is at least in part associated with protein oxidative damage. These include eye diseases, metabolic disorders such as diabetes and obesity, inflammatory conditions such as arthritis, cardiovascular complications such as atherosclerosis, kidney disorders, respiratory disease, cancer, and neurodegenerative disorders such as Alzheimer's [ ] and Parkinson's [ ] diseases.

Accordingly, Radman [ ] recently proposed that aging and age-related diseases could be phenotypic consequences of proteome damage patterns. Eye lens cataracts are a common affliction of aging populations that result in the progressive worsening of vision. One of the primary underlying changes during cataract formation is protein aggregation in the eye lens. While environmental factors like smoke, UV radiation, and chemical fumes contribute to the formation of cataracts, protein PTMs also play a significant role in the structure and stability of lens proteins, resulting in their aggregation within the lens [ ].

Protein oxidation plays a particularly important role in lens protein aggregation, and antioxidants are often prescribed in the clinical management of cataracts [ ]. Experimental studies using both human and mouse models have identified cysteine oxidation at the critical sites of several enzymes in human and mouse lens, including several metabolic enzymes, namely glyceraldehyde 3-phosphate dehydrogenase GAPDH , glutathione synthase, aldehyde dehydrogenase, and sorbitol dehydrogenase, as well as protein deglycase DJ-1 Parkinson disease protein 7 or PARK7 [ ].

Extensive oxidation of intermediate filament proteins such as BFSP1 and BFSP12, vimentin, and cytokeratins, as well as the microfilament and microtubule filament proteins such as tubulin and actin, has also been reported [ ]. Alzheimer's disease AD is one of the major aging-related disorders that severely impact the quality of life of elderly individuals [ ].

The clinical symptoms of AD include a decline in cognitive function and memory and a state of confusion. At the cellular level, AD is associated primarily with two proteins: Dissociation of the microtubule-associated protein, tau, from the cytoskeleton in neuronal cells leads to its subsequent intracellular aggregation into paired helical filaments known as neurofibrillary tangles.

Under normal circumstances, the peptide is degraded by proteases, including zinc proteases called neprilysins, endothelin-converting enzymes, and insulin-degrading enzyme [ ]. The progression of AD is accompanied by hyperphosphorylation of tau. Hyperphosphorylated tau protein is found in degradation-resistant helical filament cores of neurofibrillary tangles [ ].

Intriguingly, a recent report has shown that hydrogen peroxide-mediated oxidative stress can cause a temporary reduction in tau phosphorylation [ ]. The study of these PTMs is key to the understanding of the molecular mechanisms associated with disease onset and also provides new opportunities for therapeutic strategies and drug development.

Parkinson's disease PD is another neurodegenerative disorder of unknown origin that affects approximately 6. Several of the identified modification sites appear to be conserved from yeast to humans [ ]. Aging is also a risk factor for cardiovascular diseases, such as hypertension, coronary heart disease, stroke, and heart failure.

Several experimental and clinical observations support the hypothesis that excessive oxidative stress or reactive oxygen species ROS production plays a role in the pathogenesis of these diseases [ ]. For instance, oxidative damage in cardiovascular disease is primarily related to low-density lipoproteins LDL , which produce lipid peroxidation products such as lipid peroxides, isoprostanes, oxysterols, hydroxyl fatty acids, and aldehydes [ ].

These mice also showed an aging-related decline in cardiac function, characterized by changes in ventricular diameter and ejection fraction [ ].

Overview of Post-Translational Modifications (PTMs)

Treatment with the antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidinoxyl TEMPOL prevented compromised cardiac function in these mice. Protection of cardiac telomeres from the oxidation by TEMPOL in BMAL1-deficient mice was also observed, further supporting the therapeutic relevance of targeting protein oxidation in aging [ ]. Studies of acute kidney injury and chronic kidney disease during aging have also highlighted the role of oxidatively damaged proteins and protein aggregates [ ].

In this context, a balance between oxidative stress and autophagy has been recognized as an important factor controlling inflammation and cell death in kidney disorders [ ]. Various metabolic disorders, such as obesity, insulin resistance, and diabetes are characterized by increased body weight, high glucose levels, and reduced energy levels. Environmental and nutritional stresses are considered to be the main drivers of such metabolic disorders, potentially involving oxidative damage.

The accumulation of reactive oxygen species mediates oxidative modification of metabolic enzymes and proteins, as does the consumption of high-carbohydrate or high-fat diets [ ]. The enzyme methionine sulfoxide reductase A MsrA is an antioxidant enzyme in cells that is involved in countering the effects of oxidative stress and has been implicated significantly in developing protection against oxidative stress and protein maintenance, two crucial factors in the aging process [ ].

A recent study [ ] using transgenic mice has found that MsrA affects lifespan and ameliorates some of the effects of age-associated metabolic disorders, such as insulin resistance. Taken together, these results highlight the role of protein oxidative damage in the process of aging and aging-related pathologies. Thus, pharmacological and nonpharmacological strategies that influence the oxidative stress balance of the cell are important as proximal strategies in the road towards extending healthspan.

Reactive chlorine species are considered a primary source of enzymatically catalyzed protein chlorination [ ]. The free-hydroxyl-containing tyrosine is the primary amino acid target for halogen modification. The enzyme myeloperoxidase catalyzes the formation of 3-chlorotyrosine [ ]. An early study on protein chlorination [ ] found that a tyrosine residue in apolipoprotein A-I apoA-I serves as a site for either chlorination or nitration depending on the action of either myeloperoxidase or peroxynitrite, respectively.

Interestingly, chlorination but not nitration affected apoA-I function and markedly reduced its cholesterol efflux activity. Elevated levels of myeloperoxidase are associated with chronic heart failure, and its expression increases in cardiac endothelial cells following exposure to hydrogen peroxide [ ]. A recent study found that inhibition of myeloperoxidase using 2-thioxanthines resulted in a reduction of protein chlorination in a mouse model of peritonitis [ ].

Skin aging is typically used as a physiological parameter to assess age-related changes in the body. A recent report on photoaging of the skin [ ] proposed a link between inflammation-induced protein denitration and light-induced skin aging. The authors found elevated levels of halogenated tyrosine and inflammatory cells in skin samples both exposed to and protected from light, indicating that halogenation is likely a part of the normal aging process. Neurodegeneration is another major consequence of aging that occurs due to a combination of factors, including oxidative stress.

Intriguingly, the biphasic removal of HOCl and subsequent prevention of 2-thionitrobenzoate oxidation involves HOCl-induced chlorination of serotonin as well as the formation of inactive aggregates of chlorinated serotonin, implicating a feedback process. Furthermore, selective serotonin reuptake inhibitors, such as fluoxetine, reduce protein chlorination in the brain, suggesting a potential therapeutic approach against age-related protein chlorination effects [ ].

Nitration is an oxidative protein modification that occurs on tyrosine residues. Excess levels of reactive nitrogen species RNS are the primary source of nitrating reactions [ ]. The excessive presence of ROS, along with RNS, leads to the formation of additional nitrating entities, namely peroxynitrite. One common example of RNS-induced protein nitration is the formation of 3-nitrotyrosine, which is associated with increased nitroxidative stress during the aging process [ ].

Tyrosine nitration modifies the biochemical properties of the amino acid, including its pKa, redox potential, hydrophobicity, and size, subsequently leading to significant changes in the structure and function of affected proteins. Alterations in protein biochemistry provoke the cellular and physiological manifestations of nitration in aging.

1. Introduction

Additionally, protein tyrosine nitration is mediated by nonenzymatic free radical reactions involving the formation of an intermediate tyrosyl radical. Studies using fast reaction kinetics and bioanalytical methods as well as structural assessments using electron paramagnetic resonance have enabled the comprehensive characterization of tyrosine nitration [ ]. Recent studies have shown that membrane-associated protein tyrosine nitration involves oxidation by lipid peroxyl radicals, a by-product of membrane lipid peroxidation, which is also associated with aging [ ].

Moreover, several studies have revealed that protein tyrosine nitration occurs site-specifically to a few tyrosine residues within the target proteins and, thereby, is restricted to a fraction of the proteome [ ]. The spatial and temporal localization of nitrating entities plays an important role in selecting the tyrosine residue within a target protein. Studies on mitochondrial proteins that are homogenously nitrated have further supported the site-specific selectivity as well as the overall effects of protein tyrosine nitration in aging and age-associated diseases [ 58 , 59 ].

While protein tyrosine nitration was initially thought to be irreversible, recent studies have identified a denitrase enzyme [ ]. Denitrase activity is found in a range of tissues and cells but not in smooth muscle cells. Another recent study [ ] regarding the effect of protein nitration in age-related systemic inflammation systemic inflammatory response syndrome or SIRS has shown that toxemia-induced lung injury increases the level of protein tyrosine nitration and reduces the activity of superoxide dismutase in mouse lung.

Additionally, aged mice showed higher protein nitration in the vascular endothelia compared to younger mice. The specific proteins that maintain pulmonary vascular permeability also showed higher tyrosine nitration, including profilin-1, transgelin-2, LASP 1, tropomyosin, and myosin [ ]. The observations of senescence in unicellular organisms in the absence of genetic or environmental variability opened the door to suggestions that such organisms could be used as simple quantitative experimental systems to address molecular mechanisms underlying aging [ 79 , ]. Bacterial aging seems to share some common features with the process of eukaryotic aging, namely, the role of oxidative damage, and the effect of protein quality control systems to trigger senescence [ ].

For instance, as in eukaryotes, bacterial aging is associated with the accumulation of oxidized proteins in the form of aggregates in the older poles of cells [ 76 , 78 ] Figure 1. This accumulation resembles many known age-related eukaryotic protein folding diseases [ , ], and at least in eukaryotes, increased protein aggregation and altered cell proteostasis have been associated with oxidative stress-related posttranslational modifications [ ].

Whether this process also plays a role in the accumulation of protein aggregates in bacteria remains unclear. The patterns of oxidative protein damage and aggregation accompanying aging in E. In fact, the similarity between the biological effects of radiation and aging is easily observed in survival curves plotted as a function of radiation dose or time: Thus, bacteria are now being considered as useful model organisms in aging studies, particularly in understanding the effects of aging and aging-related stress on protein stability and function [ ].

Accumulation of protein aggregates and inclusion bodies in E. Reproduced with permission from Lindner et al. Schematic relationship between survival and protein carbonylation for different species A, B, and C as a function of radiation dose or age. Blue lines depict survival. Red lines depict protein carbonyl levels. Reproduced with permission from Radman [ ]. In the case of E.

Misfolded proteins can passively and spontaneously aggregate at the cell poles in E. Thus, misfolded proteins freely diffuse in the cytoplasm and tend to stick to each other owing to the exposure of hydrophobic patches on their surface. As the amorphous aggregates grow by the addition of more misfolded peptides, they are excluded from the nucleoid and accumulate at the cell poles where they can expand further. Supporting this model, in silico simulations have demonstrated that the passive diffusion of a particle, its intrinsic ability to multimerize, and the absence of nucleoids at the poles are sufficient to obtain a polar localization pattern by entropy alone [ ].

Aggregate distribution and associated fluorescence levels along the cell axis in E. Aging correlation with the presence of protein aggregation. The aging effect was calculated from the relative growth rate difference between old-pole and new-pole offspring of newborn mother cells where inclusion bodies are inherited by the old pole cell population 1 or the new pole cell population 2. Additionally, a variety of posttranslational modifications, such as changes in phosphorylation state or nucleotide binding, can control the complex intracellular distribution of several proteins that are involved in cell cycle regulation, signal transduction, polarized motility, and adhesion [ , ] Figure 5 a.

Although most of the examples known to date are related to proteins that are at some point recruited to the poles through protein-protein interactions, similar modifications could also influence the ability of some proteins to multimerize, thereby impacting their spontaneous polar accumulation.

If the presence and the activity of cognate kinases, such as phosphatases and GTPase-activating proteins GAPs , is under the temporal regulation, this can provide a way to regulate an otherwise spontaneous polar localization in time Figure 5 b , as reported in the case of Streptomyces coelicolor [ — ]. Protein cleavage by specific proteases might also represent a strategy to modulate polar localization in space and time, as proposed for the polar beacon PodJ. PodJ is converted from a long form PodJL to a shorter form PodJS by a cell-cycle-regulated proteolytic sequence that eventually degrades PodJS, ensuring its proper localization and subsequently its function [ , ] Figure 5 c.

However, the precise mechanisms whereby both forms of PodJ differentially localize at the poles remain to be determined. Possible strategies for spatial and temporal regulation of polar localization. Misfolded proteins produced in the progeny accumulate onto the existing polar aggregate. Eventually, de novo polar accretions can appear in progeny that did not acquire a polar focus top cell , for example, after new protein synthesis.

The question mark indicates a hypothetical step. In step 1, the protein blue has an asymmetric distribution inherent to a cell cycle event. The concentration of the diffusing protein oligomer red increases locally owing to interaction with the asymmetric protein. In step 2, the self-assembly of a protein or oligomer leads to the formation of a large structure at the pole. This provides spatial and temporal regulation to a multimerization-dependent polar localization.

Reproduced with permission from Laloux and Jacobs-Wagner [ ]. Recently, acetylation has also been found to be prevalent among bacteria. Bacteria contain hundreds of acetylated proteins that affect diverse cellular pathways. Still, little is known about the regulation or biological relevance of nearly all of these modifications. To uncover the potential regulatory roles of acetylation, a recent study analyzed how acetylation patterns and abundances change between growth phases in B.

The authors discovered a subset of critical acetylation events that are temporally regulated during cell growth. Furthermore, they demonstrated a stationary-phase-enriched acetylation on the essential shape-determining protein MreB, which led them to propose a role for MreB acetylation in controlling cell width by restricting cell wall growth [ ]. Lysine acetylation also coordinates carbon source utilization and metabolic flux in Salmonella in a reversible manner, so that cells are able to respond to environmental changes by promptly sensing cellular energy status and flexibly altering reaction rates or directions [ ].

Thus, lysine acetylation may represent a metabolic regulatory mechanism that is conserved from bacteria to mammals. As evidence supporting the conservation of at least some of the hallmarks of aging in bacteria continues to emerge [ 74 , , , ], it will be interesting to investigate the role of PTMs in regulating bacterial aging. As awareness of the role of PTMs in aging and aging-related diseases grows, there is an urgent need for the development of methods to detect protein PTMs more rapidly and accurately.

Post Translational Modifications: An Overview | Proteintech Group

Furthermore, the recent finding of rare and unconventional modifications in age-related pathologies calls for the development of more specific and sensitive methods to detect such modifications [ 27 ]. The recent rapid progress in large-scale genomics and proteomics technologies is likely to be a catalyzing factor for such studies. Drugs that target PTMs, such as phosphorylation, acetylation, methylation, and ubiquitination, will serve as useful tools in exploring the basic mechanism of PTM modulation and provide a pharmacological platform to combat the detrimental effects of aging [ ].

From a nonpharmacological perspective, exercise interventions are known to be an effective means of delaying the negative effects of aging at the physical and metabolic level. Several lines of evidence have shown that exercise can bring about benefits for elderly people through the modulation of both inflammatory and redox status, with impacts on proteostasis, insulin sensitivity, body composition e. Likewise, caloric restriction is another nongenetic and almost universal process known to delay the onset of aging and extend maximum lifespan [ ].

However, the influence of exercise and diet on protein PTMs remains relatively underexplored. Studies covering this particular area have the potential to develop widely accessible and affordable intervention strategies to fight aging-related diseases. Finally, the utility of prokaryotic models in understanding the biology of aging is noteworthy, given the possibility of the conservation of aging-associated molecular mechanisms throughout evolution. As research progresses in the field of microbiogerontology, it will be interesting to discover to what extent such molecular mechanisms are conserved.

This might open a completely new window of opportunities to search for ways to slow aging and extend healthy lifespan. The funders had no role in study design, data collection, and analysis; decision to publish; or preparation of the manuscript. The authors declare that there is no conflict of interest regarding the publication of this paper.

National Center for Biotechnology Information , U. Oxid Med Cell Longev. Published online Aug Author information Article notes Copyright and License information Disclaimer. Received Apr 3; Accepted May Santos and Ariel B. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Protein phosphorylation Figure 2 is the most commonly studied post-translational modification. It has been estimated that one-third of mammalian proteins may be phosphorylated, and this modification often plays a key role in modulating protein function.

Recent developments in mass-spectrometry MS methods have enabled the identification of thousands of PTM sites. Consequently, novel enrichment strategies have uncovered the global cellular importance of several types of modifications e. More than diverse types of PTMs are currently known 5,6 , ranging from small chemical modifications e. WB result of phospho-Marcks antibody AP , 1: The analysis of proteins and their PTMs is particularly important for the study of heart disease, cancer, neurodegenerative diseases, and diabetes 7.

The main challenges in studying post-translationally modified proteins are the development of specific detection and purification methods. Fortunately, these technical obstacles are being overcome with a variety of new and refined proteomics technologies. A brief overview How does post translational modification work?

Types of post-translational modifications PTMs. Most common post-translational modifications Protein phosphorylation Figure 2 is the most commonly studied post-translational modification. PTMs impact on health and disease The analysis of proteins and their PTMs is particularly important for the study of heart disease, cancer, neurodegenerative diseases, and diabetes 7. Proteomic analysis in the neurosciences.

The Roles of Post-translational Modifications in the Context of Protein Interaction Networks Deciphering a global network of functionally associated post-translational modifications.

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