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Protein modification in aging: An update
Experimental Gerontology 41 (2006) 807–812 www.elsevier.com/locate/expgero
Mini Review
Protein modification in aging: An update Christian Scho¨neich
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Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047, USA Received 27 May 2006; received in revised form 14 July 2006; accepted 17 July 2006 Available online 26 September 2006
Abstract Post-translational modifications of proteins are an important biologic tool for the production of various protein species from a single gene, which may vary in conformation, function, biologic half-life and complex formation with other proteins. The present minireview summarizes a few selected research observations important for the role of post-translational modifications in biologic aging and age-related diseases, including farnesylation, methylglyoxal-derivatization, transglutaminase pathways and the formation of 3-nitrotyrosine and 2-oxo-histidine in vivo. Ó 2006 Elsevier Inc. All rights reserved. Keywords: Aging; Protein; Post-translational modifications; Oxidation; Nitrotyrosine; Farnesylation; Transglutaminase; 2-Oxo-histidine
1. Introduction Post-translational protein modifications play an important role in the regulation of protein function through the modulation of protein structure, activity, turnover, localization, and the nature of protein–protein complexes. Today more than 200 different post-translational modifications are known (Khidekel and Hsieh-Wilson, 2004), which are the result of both enzymatic and non-enzymatic processes. There is increasing evidence that post-translational modifications of specific proteins accompany pathologic processes and biological aging. An important goal of global and targeted proteomic experiments must, therefore, be the identification and functional characterization of posttranslationally modified proteins in vivo, and to resolve the question whether such post-translational modifications are mechanistically related (in contrast to merely being associated with) to a disease process or a specific phenotype of aging. Such studies could eventually lead to the discovery of specific biomarkers for diagnostic purposes and/or the design of therapies or preventive measures. Recently, much emphasis has been placed on the search for biomarkers for aging and/or age-dependent pathologies. Such stud*
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ies require a careful experimental design and accurate validation with respect to specificity and predictive value and few, if any, useful biomarkers have evolved (Ong and Mann, 2005; Gillette et al., 2005; LaBaer, 2005). An experimental limitation can the accessibility of biological material, for example, if the biomarker cannot be found in biological fluids. On the other hand, significantly more progress has been made in the mechanistic evaluation of post-translational protein modifications and their potential link to aging and age-dependent pathologies. Several selected examples of these will be presented below, covering enzymatic and non-enzymatic pathways, including protein modifications induced through oxidative stress. Rather comprehensive reviews on protein modifications during oxidative stress and aging have been published recently (Cloos and Christgau, 2004; Scho¨neich, 2005; Dalle-Donne et al., 2005, 2006). Therefore, this minireview shall be a true update focusing on a few selected areas rather than a comprehensive treatment. 2. Prelamin A farnesylation and Hutchinson–Gilford progeria syndrome Mechanistic studies have recently provided a causal relationship between the etiology of Hutchinson–Gilford progeria syndrome (HGPS) and the aberrant processing of
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post-translationally modified prelamin A into mature lamin A (Mallampalli et al., 2005). HGPS represents a genetic disorder, which results in premature aging of children leading to death within their early teenage years. Prelamin A contains a C-terminal farnesylation motif (CSIM). In the general mechanism of farnesylation, farnesyl transferase catalyzes the reaction of the cysteine mercapto group with farnesyl diphosphate, an intermediate product of the cholesterol biosynthetic pathway (Liao, 2002; Bowers and Fierke, 2004; Greenwood et al., 2006). The natural processing of prelamin A involves farnesylation of the Cys residue within the CSIM sequence, followed by proteolytic removal of the SIM tag and methylation of the carboxylate group of the resulting C-terminal Cys residue. Subsequently, zinc metalloprotease Ste24 (Zmpste24) removes the C-terminal 15 amino acid residues, generating non-farnesylated lamin A. In a cell culture model, lamin A localizes to nuclear foci and the nucleoplasm. In HGPS, the most common mutation of the prelamin A gene, LMNA, leads to a deletion of 50 codons, which include the Zmpste24 processing site. In contrast, the farnesylation motif remains intact causing retention of the farnesyl chain in the protein, which is now termed progerin. The retention of the farnesyl chain leads to a primary localization of progerin at the nuclear envelope, different from the localization of wild-type lamin A to nuclear foci. Further evidence for a critical role of Zmpste24 in prelamin processing and farnesyl chain removal comes from several experimental mutants, lacking either the Zmpste24 cleavage site or the Cys residue of the C-terminal CSIM motiv (mutation to SSIM). While the former results in aberrant lamin A localization, the latter restores the correct localization to nuclear foci. Importantly, the aberrant cellular compartmentalization of progerin was also prevented pharmacologically through the exposure of cells in culture to farnesyl transferase inhibitors (FTI). More recently, similar experiments showed beneficial effects in a mouse model of HGPS, deficient in the gene for Zmpste24, Zmpste24 (Fong et al., 2006), demonstrating that aberrant processing of a single farnesylation site in progerin may be critical for the pathogenesis of HGPS. It will be interesting to explore in the future whether low levels of farnesylated lamin A, increasing with age, may accompany also the slow process of normal aging. 3. Methylglyoxal and the regulation of gene expression The reaction of methylglyoxal (MG) with proteins represents one pathway leading to the formation of advanced glycation end products (AGEs), prominent protein modifications accompanying, e.g., biological aging and diabetes. While increased levels of MG-derived protein modifications are generally observed under pathologic conditions, significant amounts are detectable also in healthy tissue (Ahmed et al., 2003). Proteomic studies identified a series of mitochondrial proteins as targets of MG-dependent modification in the diabetic rat kidney (Rosca et al., 2005). MG forms various stable adducts with arginine
residues such as Nd-(5-hydro-5-methyl-4-imidazolon2-yl)ornithin (MG-H1), Nd-[5-(2,3,4-trihydroxybutyl)-5hydro-4- imidazolon-2-yl]ornithin and argpyrimidine (Ahmed et al., 2005). The inactivation of proteins through the accumulation of AGEs had been reported (Ahmed et al., 2005). Recent data (Yao et al., 2006) provide now evidence for a physiological role of MG (Ramasamy et al., 2006), where the modification of a corepressor, mSin3A, directly leads to an increased expression of angiopoietin-2. Usually, mSin3A is part of a protein complex with the repressor Sp3, which binds to the promoter region of angiopoetin-2. MG-modification of mSin3A results in the recruitment of O-GlcNAc transferase (OGT) to this complex and modification of Sp3 by OGT, followed by dissociation from the promoter region, which permits expression of angiopoietin-2. Considering the manifold of AGE structures formed through the reaction of reactive carbonyls with Arg and Lys, one should expect that future experiments will uncover additional mechanisms where AGE formation regulates specific biologic pathways. Here, the sensitivity of protein Arg residues towards MG in vivo may not only be defined by their chemical microenvironment (controlling accessibility and protonation equilibria) but also by the action of protein arginine methyl transferase (PRMT). The latter class of enzymes can transfer one and/or two methyl groups onto protein Arg residues, where dimethylation would prohibit the reaction with MG. Hence, dimethylation could protect protein Arg residues against the formation of MG-H1 (Fackelmayer, 2005), analogous to a mechanism characterized for human crystallins, where Cys methylation protects these proteins against oxidative modification/aggregation (Lapko et al., 2003). 4. Transglutaminase pathways of protein cross-linking and neurodegenerative diseases Transglutaminases (TGs) are Ca2+-dependent enzymes that catalyze the deamidation and transamination of protein glutamine residues. While deamidation results in the formation of glutamic acid, transamination usually leads to c-glutamyl-e-lysine (GGEL) cross-links. Increasing evidence is accumulating that TG-dependent protein crosslinking plays an important role in oxidative stress (Shin et al., 2004) and the pathologies of neurodegenerative diseases and aging. For example, the microtubule-associated protein tau represents a target for TG in vitro and in vivo, where, in vitro, TG-dependent cross-linking affects primarily protein domains located in close proximity to microtubule-binding domains (Tucholski et al., 1999). TG-dependent tau cross-linking is specifically increased in a transgenic mouse model with a higher tendency for the formation of neurofibrillary tangles, expressing the tau mutant P301L (Halverson et al., 2005). Increased TG activity appears to correlate with increased neuronal death in Alzheimer’s disease (AD) (Bonelli et al., 2002) and Huntington’s disease (HD), as crossing HD R6/1 transgenic
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mice with TG knock-out mice results in a large reduction of cell death (Mastroberardino et al., 2002). Chemically, the formation of GGEL cross-links is consistent with the formation of largely insoluble protein precipitates in the brain; however, little is known to date about the biological and pathological significance of (i) individual GGEL crosslinks, (ii) the yields of individual and multiple GGEL crosslinks, (iii) the occurrence of intra- vs. intermolecular GGEL cross-links, and (iv) the protein targets of GGEL cross-links, i.e., the nature of the individual cross-linked proteins. Moreover, GGEL-cross-linked proteins may form different aggregates compared to amyloidogenic proteins, which do not contain GGEL-cross-links. For example, the exposure to TG of a four-repeat domain of human tau, s4RD, human a-synuclein, and the N-terminal domain of the yeast prion protein Sup35, SupNM, abolished the tendency of these proteins to amyloid formation (Konno et al., 2005). This is most likely due to the formation of intramolecular GGEL cross-links, which then may reduce the conformational freedom of these polypeptides to aggregate intermolecularly en route to fibril formation. Much emphasis has been placed on the characterization of protein targets for TG; for example, the AD amyloidb peptide undergoes facile cross-linking with small heat shock proteins (Boros et al., 2004) and high molecular weight aggregates of mitochondrial aconitase appear to be the result of transglutamination in HD brain (Kim et al., 2005). Another area of emphasis is the development of appropriate techniques to detect TG-dependent crosslinks in tissue (Nemes et al., 2005). The specificity of antibodies against the GGEL cross-link has been questioned based on the hypothesis that it is not only the GGEL domain but the peptide sequences around the GGELcross-link, which constitute the epitope (Nemes et al., 2005). Mass spectrometric methods, on the other hand, provide a more powerful tool for the identification and direct sequencing of GGEL cross-linked protein domains. Here, it is important to note that higher energies are required for the collision-induced dissociation of the GGEL amide bond compared with the peptide backbone (Nemes et al., 2005). In a mixture of known proteins, peptides containing the GGEL cross-link may be identified by MALDI-TOF mass spectrometry using a multipoint recalibration strategy (Emanuelsson et al., 2005). 5. Protein tyrosine nitration targets selected proteins in vivo: structural consequences Pathologic and aging tissue often shows increased levels of 3-nitrotyrosine (3-NY) (Greenacre and Ischiropoulos, 2001; Turko and Murad, 2002; Ischiropoulos, 2003; Ischiropoulos and Beckman, 2003). In addition, 3-NY levels may serve as an indicator for the progression of cardiovascular disease and its modulation by statin therapy (Shishehbor et al., 2003). In general, the formation of 3-NY is taken as evidence that tissue is exposed to some sort of oxidative (or nitrative) stress. Proteomics has been increasingly
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applied to the identification of nitrated proteins in tissue (Aulak et al., 2001; Greenacre and Ischiropoulos, 2001; Turko and Murad, 2002; Ischiropoulos and Beckman, 2003; Turko et al., 2003; Kanski et al., 2003; Radi, 2004; Zhan and Desiderio, 2004; Casoni et al., 2005; Kanski et al., 2005a,b) revealing that (i) protein nitration is usually confined to a small subproteome, (ii) does not necessarily depend on the abundance of a given protein and (iii) is highly dynamic in nature possibly due to a highly efficient turnover (Koeck et al., 2004) and/or repair (Irie et al., 2003). The apparent selectivity of protein nitration in vivo has spurred interest in defining the rationale behind this selectivity, and several in vitro studies have addressed the parameters which control the susceptibility of a tyrosine residue to nitration by defined nitrating agents such as peroxynitrite (Ischiropoulos, 2003). Interestingly, though, the nitration patterns of a given protein in model reactions in vitro may differ significantly from that obtained in vivo, illustrated in the following for two protein examples of age-dependent nitration in skeletal muscle, the cytosolic creatine kinase and glycogen phosphorylase. In vivo, the skeletal muscle creatine kinase suffers nitration of both Tyr14 and Tyr20, but not measurably of any of the other seven Tyr residues at positions 39, 82, 125, 140, 173, 174, and 279 (Kanski et al., 2005b). Tryptic peptides containing all these remaining Tyr residues were covered by MS/MS analysis of the protein, indicating the validity of the analytical method. In contrast, the in vitro exposure of creatine kinase to peroxynitrite in the presence of CO2 resulted in the exclusive nitration of Tyr82 (Kanski et al., 2005b). Again, tryptic peptides containing all of the other eight Tyr residues were covered by MS/MS analysis. These distinctly different patterns are likely caused by one or more of the following mechanisms occurring in vivo: (i) a selective turnover or repair of specific nitrated creatine isoforms in vivo, (ii) the existence of additional nitrating species in vivo different from peroxynitrite, and (iii) the existence of creatine kinase in complexes with small molecules and/ or proteins. A comparable observation was made for the skeletal muscle glycogen phosphorylase: in vivo nitration targets Tyr113, Tyr161, and Tyr573 (Kanski et al., 2005b; Sharov et al., 2006). In the crystal structure of pyridoxalphosphate-bound glycogen phosphorylase, the phenolic ˚ ) to the oxygen of Tyr573 is located rather close (5.67 A phosphate group of pyridoxalphosphate (Barford et al., 1991), suggesting that electrostatic interactions between a deprotonated 3-NY residue (pKa 7.1) at this position and pyridoxalphosphate may cause some conformational changes of the protein. In contrast, the exposure of glycogen phosphorylase to peroxynitrite in vitro targeted Tyr at positions 51, 52, 113, 155, 185, 203, 262, 280, 404, 473, 731, and 732, but not Tyr161 and Tyr573. Hence, in vitro models may not necessarily be good predictors of both targets and selectivities of protein nitration in vivo if only selected nitrating species such as peroxynitrite are used in the model experiments. Some advances have been made with regard to the biochemical consequences of protein tyrosine
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nitration. For example, the crystal structure of MnSOD nitrated at Tyr34 shows evidence for a bifurcation of a hydrogen bond between the Ne2 of Gln143 and both the phenolic hydroxyl group and the nitro group of Tyr(NO2)34 (Quint et al., 2006). Hence, nitration appears to perturb the hydrogen bond network within the protein besides additional sterical and electrostatic consequences. In another example, nitration of tyrosine residues within the glutathione disulfide binding site of glutathione reductase resulted in a nearly 1000-fold decrease in catalytic efficiency of the enzyme (Savvides et al., 2002). 6. Evidence for metal-catalyzed oxidation of histidine to 2-oxo-histidine in vivo The sensitivity of protein His residues towards metalcatalyzed oxidation in vitro has been known for years (Lewisch and Levine, 1995). Surprisingly, little analytical data are available that stable His oxidation products, specifically 2-oxo-histidine, are formed and can accumulate in vivo. For example, while Santa Maria et al. reported that Cu,ZnSOD isolated from the aged liver (Santa Maria et al., 1995) showed an age-dependent loss of His, monitored by the diethylpyrocarbonate method, these findings could neither be substantiated by mass spectrometry of Cu,ZnSOD isolated from the liver nor could 2-oxo-histidine be detected (Ghezzo-Scho¨neich et al., 2001). Similarly, while the amino acid analysis of the Alzheimer’s disease b-amyloid peptide extracted from brain showed some loss of His residues (Atwood et al., 2000), the mass spectrometry analysis of the peptide showed 2-oxo-histidine formation only after exposure to metal-catalyzed oxidation in vitro (Scho¨neich and Williams, 2002; Inoue et al., 2006). These findings raised the question whether specifically 2-oxo-histidine is actually formed during protein oxidation in vivo or whether it only escapes detection due to a potentially rapid degradation of the product itself or of proteins containing 2-oxohistidine. New data on the metal-catalyzed oxidation of the PerR transcription factor in Bacillus subtilis provide a partial answer to this question (Lee and Helmann, 2006). Purification of the protein in the absence of a metal-chelator and the in vitro exposure to H2O2 resulted in the oxidation of His-containing peptides but not of Cys-containing sequences, which are part of the binding site for the structurally important Zn2+. More importantly, when FLAG epitope-tagged PerR (PerR-FLAG) was expressed in B. subtilis and the intact cells were exposed to either H2O2 or H218O2, oxidized PerR-FLAG could be purified, where 16 O or 18O were incorporated into His37 or His91, confirmed by electrospray ionization-tandem mass spectrometry. These experiments show that 2-oxo-histidine can be formed in vivo and suggest that 2-oxo-histidine can be sufficiently stable for chemical analysis. We note, though, that the affinity-purification of a FLAG-tagged protein from a cell lysate represents a rather efficient purification procedure compared with the potential multiple steps in the purification of a non-tagged protein from tissue homogenate.
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Mini Review
Protein modification in aging: An update Christian Scho¨neich
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Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047, USA Received 27 May 2006; received in revised form 14 July 2006; accepted 17 July 2006 Available online 26 September 2006
Abstract Post-translational modifications of proteins are an important biologic tool for the production of various protein species from a single gene, which may vary in conformation, function, biologic half-life and complex formation with other proteins. The present minireview summarizes a few selected research observations important for the role of post-translational modifications in biologic aging and age-related diseases, including farnesylation, methylglyoxal-derivatization, transglutaminase pathways and the formation of 3-nitrotyrosine and 2-oxo-histidine in vivo. Ó 2006 Elsevier Inc. All rights reserved. Keywords: Aging; Protein; Post-translational modifications; Oxidation; Nitrotyrosine; Farnesylation; Transglutaminase; 2-Oxo-histidine
1. Introduction Post-translational protein modifications play an important role in the regulation of protein function through the modulation of protein structure, activity, turnover, localization, and the nature of protein–protein complexes. Today more than 200 different post-translational modifications are known (Khidekel and Hsieh-Wilson, 2004), which are the result of both enzymatic and non-enzymatic processes. There is increasing evidence that post-translational modifications of specific proteins accompany pathologic processes and biological aging. An important goal of global and targeted proteomic experiments must, therefore, be the identification and functional characterization of posttranslationally modified proteins in vivo, and to resolve the question whether such post-translational modifications are mechanistically related (in contrast to merely being associated with) to a disease process or a specific phenotype of aging. Such studies could eventually lead to the discovery of specific biomarkers for diagnostic purposes and/or the design of therapies or preventive measures. Recently, much emphasis has been placed on the search for biomarkers for aging and/or age-dependent pathologies. Such stud*
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ies require a careful experimental design and accurate validation with respect to specificity and predictive value and few, if any, useful biomarkers have evolved (Ong and Mann, 2005; Gillette et al., 2005; LaBaer, 2005). An experimental limitation can the accessibility of biological material, for example, if the biomarker cannot be found in biological fluids. On the other hand, significantly more progress has been made in the mechanistic evaluation of post-translational protein modifications and their potential link to aging and age-dependent pathologies. Several selected examples of these will be presented below, covering enzymatic and non-enzymatic pathways, including protein modifications induced through oxidative stress. Rather comprehensive reviews on protein modifications during oxidative stress and aging have been published recently (Cloos and Christgau, 2004; Scho¨neich, 2005; Dalle-Donne et al., 2005, 2006). Therefore, this minireview shall be a true update focusing on a few selected areas rather than a comprehensive treatment. 2. Prelamin A farnesylation and Hutchinson–Gilford progeria syndrome Mechanistic studies have recently provided a causal relationship between the etiology of Hutchinson–Gilford progeria syndrome (HGPS) and the aberrant processing of
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post-translationally modified prelamin A into mature lamin A (Mallampalli et al., 2005). HGPS represents a genetic disorder, which results in premature aging of children leading to death within their early teenage years. Prelamin A contains a C-terminal farnesylation motif (CSIM). In the general mechanism of farnesylation, farnesyl transferase catalyzes the reaction of the cysteine mercapto group with farnesyl diphosphate, an intermediate product of the cholesterol biosynthetic pathway (Liao, 2002; Bowers and Fierke, 2004; Greenwood et al., 2006). The natural processing of prelamin A involves farnesylation of the Cys residue within the CSIM sequence, followed by proteolytic removal of the SIM tag and methylation of the carboxylate group of the resulting C-terminal Cys residue. Subsequently, zinc metalloprotease Ste24 (Zmpste24) removes the C-terminal 15 amino acid residues, generating non-farnesylated lamin A. In a cell culture model, lamin A localizes to nuclear foci and the nucleoplasm. In HGPS, the most common mutation of the prelamin A gene, LMNA, leads to a deletion of 50 codons, which include the Zmpste24 processing site. In contrast, the farnesylation motif remains intact causing retention of the farnesyl chain in the protein, which is now termed progerin. The retention of the farnesyl chain leads to a primary localization of progerin at the nuclear envelope, different from the localization of wild-type lamin A to nuclear foci. Further evidence for a critical role of Zmpste24 in prelamin processing and farnesyl chain removal comes from several experimental mutants, lacking either the Zmpste24 cleavage site or the Cys residue of the C-terminal CSIM motiv (mutation to SSIM). While the former results in aberrant lamin A localization, the latter restores the correct localization to nuclear foci. Importantly, the aberrant cellular compartmentalization of progerin was also prevented pharmacologically through the exposure of cells in culture to farnesyl transferase inhibitors (FTI). More recently, similar experiments showed beneficial effects in a mouse model of HGPS, deficient in the gene for Zmpste24, Zmpste24 (Fong et al., 2006), demonstrating that aberrant processing of a single farnesylation site in progerin may be critical for the pathogenesis of HGPS. It will be interesting to explore in the future whether low levels of farnesylated lamin A, increasing with age, may accompany also the slow process of normal aging. 3. Methylglyoxal and the regulation of gene expression The reaction of methylglyoxal (MG) with proteins represents one pathway leading to the formation of advanced glycation end products (AGEs), prominent protein modifications accompanying, e.g., biological aging and diabetes. While increased levels of MG-derived protein modifications are generally observed under pathologic conditions, significant amounts are detectable also in healthy tissue (Ahmed et al., 2003). Proteomic studies identified a series of mitochondrial proteins as targets of MG-dependent modification in the diabetic rat kidney (Rosca et al., 2005). MG forms various stable adducts with arginine
residues such as Nd-(5-hydro-5-methyl-4-imidazolon2-yl)ornithin (MG-H1), Nd-[5-(2,3,4-trihydroxybutyl)-5hydro-4- imidazolon-2-yl]ornithin and argpyrimidine (Ahmed et al., 2005). The inactivation of proteins through the accumulation of AGEs had been reported (Ahmed et al., 2005). Recent data (Yao et al., 2006) provide now evidence for a physiological role of MG (Ramasamy et al., 2006), where the modification of a corepressor, mSin3A, directly leads to an increased expression of angiopoietin-2. Usually, mSin3A is part of a protein complex with the repressor Sp3, which binds to the promoter region of angiopoetin-2. MG-modification of mSin3A results in the recruitment of O-GlcNAc transferase (OGT) to this complex and modification of Sp3 by OGT, followed by dissociation from the promoter region, which permits expression of angiopoietin-2. Considering the manifold of AGE structures formed through the reaction of reactive carbonyls with Arg and Lys, one should expect that future experiments will uncover additional mechanisms where AGE formation regulates specific biologic pathways. Here, the sensitivity of protein Arg residues towards MG in vivo may not only be defined by their chemical microenvironment (controlling accessibility and protonation equilibria) but also by the action of protein arginine methyl transferase (PRMT). The latter class of enzymes can transfer one and/or two methyl groups onto protein Arg residues, where dimethylation would prohibit the reaction with MG. Hence, dimethylation could protect protein Arg residues against the formation of MG-H1 (Fackelmayer, 2005), analogous to a mechanism characterized for human crystallins, where Cys methylation protects these proteins against oxidative modification/aggregation (Lapko et al., 2003). 4. Transglutaminase pathways of protein cross-linking and neurodegenerative diseases Transglutaminases (TGs) are Ca2+-dependent enzymes that catalyze the deamidation and transamination of protein glutamine residues. While deamidation results in the formation of glutamic acid, transamination usually leads to c-glutamyl-e-lysine (GGEL) cross-links. Increasing evidence is accumulating that TG-dependent protein crosslinking plays an important role in oxidative stress (Shin et al., 2004) and the pathologies of neurodegenerative diseases and aging. For example, the microtubule-associated protein tau represents a target for TG in vitro and in vivo, where, in vitro, TG-dependent cross-linking affects primarily protein domains located in close proximity to microtubule-binding domains (Tucholski et al., 1999). TG-dependent tau cross-linking is specifically increased in a transgenic mouse model with a higher tendency for the formation of neurofibrillary tangles, expressing the tau mutant P301L (Halverson et al., 2005). Increased TG activity appears to correlate with increased neuronal death in Alzheimer’s disease (AD) (Bonelli et al., 2002) and Huntington’s disease (HD), as crossing HD R6/1 transgenic
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mice with TG knock-out mice results in a large reduction of cell death (Mastroberardino et al., 2002). Chemically, the formation of GGEL cross-links is consistent with the formation of largely insoluble protein precipitates in the brain; however, little is known to date about the biological and pathological significance of (i) individual GGEL crosslinks, (ii) the yields of individual and multiple GGEL crosslinks, (iii) the occurrence of intra- vs. intermolecular GGEL cross-links, and (iv) the protein targets of GGEL cross-links, i.e., the nature of the individual cross-linked proteins. Moreover, GGEL-cross-linked proteins may form different aggregates compared to amyloidogenic proteins, which do not contain GGEL-cross-links. For example, the exposure to TG of a four-repeat domain of human tau, s4RD, human a-synuclein, and the N-terminal domain of the yeast prion protein Sup35, SupNM, abolished the tendency of these proteins to amyloid formation (Konno et al., 2005). This is most likely due to the formation of intramolecular GGEL cross-links, which then may reduce the conformational freedom of these polypeptides to aggregate intermolecularly en route to fibril formation. Much emphasis has been placed on the characterization of protein targets for TG; for example, the AD amyloidb peptide undergoes facile cross-linking with small heat shock proteins (Boros et al., 2004) and high molecular weight aggregates of mitochondrial aconitase appear to be the result of transglutamination in HD brain (Kim et al., 2005). Another area of emphasis is the development of appropriate techniques to detect TG-dependent crosslinks in tissue (Nemes et al., 2005). The specificity of antibodies against the GGEL cross-link has been questioned based on the hypothesis that it is not only the GGEL domain but the peptide sequences around the GGELcross-link, which constitute the epitope (Nemes et al., 2005). Mass spectrometric methods, on the other hand, provide a more powerful tool for the identification and direct sequencing of GGEL cross-linked protein domains. Here, it is important to note that higher energies are required for the collision-induced dissociation of the GGEL amide bond compared with the peptide backbone (Nemes et al., 2005). In a mixture of known proteins, peptides containing the GGEL cross-link may be identified by MALDI-TOF mass spectrometry using a multipoint recalibration strategy (Emanuelsson et al., 2005). 5. Protein tyrosine nitration targets selected proteins in vivo: structural consequences Pathologic and aging tissue often shows increased levels of 3-nitrotyrosine (3-NY) (Greenacre and Ischiropoulos, 2001; Turko and Murad, 2002; Ischiropoulos, 2003; Ischiropoulos and Beckman, 2003). In addition, 3-NY levels may serve as an indicator for the progression of cardiovascular disease and its modulation by statin therapy (Shishehbor et al., 2003). In general, the formation of 3-NY is taken as evidence that tissue is exposed to some sort of oxidative (or nitrative) stress. Proteomics has been increasingly
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applied to the identification of nitrated proteins in tissue (Aulak et al., 2001; Greenacre and Ischiropoulos, 2001; Turko and Murad, 2002; Ischiropoulos and Beckman, 2003; Turko et al., 2003; Kanski et al., 2003; Radi, 2004; Zhan and Desiderio, 2004; Casoni et al., 2005; Kanski et al., 2005a,b) revealing that (i) protein nitration is usually confined to a small subproteome, (ii) does not necessarily depend on the abundance of a given protein and (iii) is highly dynamic in nature possibly due to a highly efficient turnover (Koeck et al., 2004) and/or repair (Irie et al., 2003). The apparent selectivity of protein nitration in vivo has spurred interest in defining the rationale behind this selectivity, and several in vitro studies have addressed the parameters which control the susceptibility of a tyrosine residue to nitration by defined nitrating agents such as peroxynitrite (Ischiropoulos, 2003). Interestingly, though, the nitration patterns of a given protein in model reactions in vitro may differ significantly from that obtained in vivo, illustrated in the following for two protein examples of age-dependent nitration in skeletal muscle, the cytosolic creatine kinase and glycogen phosphorylase. In vivo, the skeletal muscle creatine kinase suffers nitration of both Tyr14 and Tyr20, but not measurably of any of the other seven Tyr residues at positions 39, 82, 125, 140, 173, 174, and 279 (Kanski et al., 2005b). Tryptic peptides containing all these remaining Tyr residues were covered by MS/MS analysis of the protein, indicating the validity of the analytical method. In contrast, the in vitro exposure of creatine kinase to peroxynitrite in the presence of CO2 resulted in the exclusive nitration of Tyr82 (Kanski et al., 2005b). Again, tryptic peptides containing all of the other eight Tyr residues were covered by MS/MS analysis. These distinctly different patterns are likely caused by one or more of the following mechanisms occurring in vivo: (i) a selective turnover or repair of specific nitrated creatine isoforms in vivo, (ii) the existence of additional nitrating species in vivo different from peroxynitrite, and (iii) the existence of creatine kinase in complexes with small molecules and/ or proteins. A comparable observation was made for the skeletal muscle glycogen phosphorylase: in vivo nitration targets Tyr113, Tyr161, and Tyr573 (Kanski et al., 2005b; Sharov et al., 2006). In the crystal structure of pyridoxalphosphate-bound glycogen phosphorylase, the phenolic ˚ ) to the oxygen of Tyr573 is located rather close (5.67 A phosphate group of pyridoxalphosphate (Barford et al., 1991), suggesting that electrostatic interactions between a deprotonated 3-NY residue (pKa 7.1) at this position and pyridoxalphosphate may cause some conformational changes of the protein. In contrast, the exposure of glycogen phosphorylase to peroxynitrite in vitro targeted Tyr at positions 51, 52, 113, 155, 185, 203, 262, 280, 404, 473, 731, and 732, but not Tyr161 and Tyr573. Hence, in vitro models may not necessarily be good predictors of both targets and selectivities of protein nitration in vivo if only selected nitrating species such as peroxynitrite are used in the model experiments. Some advances have been made with regard to the biochemical consequences of protein tyrosine
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nitration. For example, the crystal structure of MnSOD nitrated at Tyr34 shows evidence for a bifurcation of a hydrogen bond between the Ne2 of Gln143 and both the phenolic hydroxyl group and the nitro group of Tyr(NO2)34 (Quint et al., 2006). Hence, nitration appears to perturb the hydrogen bond network within the protein besides additional sterical and electrostatic consequences. In another example, nitration of tyrosine residues within the glutathione disulfide binding site of glutathione reductase resulted in a nearly 1000-fold decrease in catalytic efficiency of the enzyme (Savvides et al., 2002). 6. Evidence for metal-catalyzed oxidation of histidine to 2-oxo-histidine in vivo The sensitivity of protein His residues towards metalcatalyzed oxidation in vitro has been known for years (Lewisch and Levine, 1995). Surprisingly, little analytical data are available that stable His oxidation products, specifically 2-oxo-histidine, are formed and can accumulate in vivo. For example, while Santa Maria et al. reported that Cu,ZnSOD isolated from the aged liver (Santa Maria et al., 1995) showed an age-dependent loss of His, monitored by the diethylpyrocarbonate method, these findings could neither be substantiated by mass spectrometry of Cu,ZnSOD isolated from the liver nor could 2-oxo-histidine be detected (Ghezzo-Scho¨neich et al., 2001). Similarly, while the amino acid analysis of the Alzheimer’s disease b-amyloid peptide extracted from brain showed some loss of His residues (Atwood et al., 2000), the mass spectrometry analysis of the peptide showed 2-oxo-histidine formation only after exposure to metal-catalyzed oxidation in vitro (Scho¨neich and Williams, 2002; Inoue et al., 2006). These findings raised the question whether specifically 2-oxo-histidine is actually formed during protein oxidation in vivo or whether it only escapes detection due to a potentially rapid degradation of the product itself or of proteins containing 2-oxohistidine. New data on the metal-catalyzed oxidation of the PerR transcription factor in Bacillus subtilis provide a partial answer to this question (Lee and Helmann, 2006). Purification of the protein in the absence of a metal-chelator and the in vitro exposure to H2O2 resulted in the oxidation of His-containing peptides but not of Cys-containing sequences, which are part of the binding site for the structurally important Zn2+. More importantly, when FLAG epitope-tagged PerR (PerR-FLAG) was expressed in B. subtilis and the intact cells were exposed to either H2O2 or H218O2, oxidized PerR-FLAG could be purified, where 16 O or 18O were incorporated into His37 or His91, confirmed by electrospray ionization-tandem mass spectrometry. These experiments show that 2-oxo-histidine can be formed in vivo and suggest that 2-oxo-histidine can be sufficiently stable for chemical analysis. We note, though, that the affinity-purification of a FLAG-tagged protein from a cell lysate represents a rather efficient purification procedure compared with the potential multiple steps in the purification of a non-tagged protein from tissue homogenate.
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