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PubMed1988

Neuronal transformations in Alzheimer's disease.

Brains of nine early and four advanced Alzheimer patients have been investigated, utilizing three approaches to specify the threshold state of Alzheimer's disease (AD). Extensive thin sectioning electron microscopy (EM) of frontal lobe biopsies, correlated with stringent clinical assessment, has demonstrated that the neuronal cytoskeleton undergoes specific transformations into paired helical filament-like (PHF-like) strands, which lead to the formation of the insoluble paracrystalline paired helical filaments (PHFs). The neurofilamentous network (NFN) transformation plays an important role in this process, whereby segregation, posttranslational modifications and reassembly of the modified components through autocrosslinking, and phase transition occur. According to our data, the threshold state can be defined as the state of irreversible segregation and posttranslational modification of the NFN and the microtubule-associated proteins. At this state, therapeutic intervention to reverse the disease process may be possible. The results indicate similarities between the formation of the paracrystals of the PHFs and the formation of the tropomyosin-like crystals of the Hirano bodies. Close relationships among PHFs and smooth endoplasmic reticulum and plasma membrane do exist. Enveloped virus-like particles have been observed in neurons containing PHFs. A possible role of these virus-like particles as an etiological agent for AD is discussed.

Alzheimer Disease↗
PubMed1994

Clathrin-dependent localization of alpha 1,3 mannosyltransferase to the Golgi complex of Saccharomyces cerevisiae.

Posttranslational modification of yeast glycoproteins with alpha 1,3-linked mannose is initiated within a Golgi compartment analogous to the medial Golgi cisternae of higher eukaryotes. We have characterized the synthesis, posttranslational modification, and localization of the yeast alpha 1,3 mannosyltransferase (Mnn1p) using antibodies prepared against a segment of this protein expressed in bacteria. Mnn1p is initially synthesized as a 98.5-kD, type II integral membrane glycoprotein that is modified with both N- and O-linked oligosaccharides. It is subject to a slow, incremental increase in molecular mass that is dependent upon protein transport to the Golgi complex. Self-modification of Mnn1p with alpha 1,3 mannose epitopes, primarily on O-linked oligosaccharides, is at least partly responsible for the incremental increase in molecular mass. Mnn1p is a resident protein of the Golgi complex and colocalizes with guanosine diphosphatase to at least two physically distinct Golgi compartments by sucrose gradient fractionation, one of which may be a late Golgi compartment that also contains the Kex2 endopeptidase. Surprisingly, we found that a significant fraction of Mnn1p is mislocalized to the plasma membrane in a clathrin heavy chain temperature sensitive mutant while guanosine diphosphatase remains intracellular. A mutant Mnn1p that lacks the NH2-terminal cytoplasmic tail is properly localized to the Golgi complex, indicating that clathrin does not mediate Mnnlp Golgi retention by a direct interaction with the Mnn1p cytoplasmic tail. These results indicate that clathrin plays a broader role in the localization of Golgi proteins than anticipated.

Amino Acid Sequence↗
PubMed2003

Protein mass analysis of histones.

Posttranslational modification of chromatin-associated proteins, including histones and high-mobility-group (HMG) proteins, provides an important mechanism to control gene expression, genome integrity, and epigenetic inheritance. Protein mass analysis provides a rapid and unbiased approach to monitor multiple chemical modifications on individual molecules. This review describes methods for acid extraction of histones and HMG proteins, followed by separation by reverse-phase chromatography coupled to electrospray ionization mass spectrometry (LC/ESI-MS). Posttranslational modifications are detected by analysis of full-length protein masses. Confirmation of protein identity and modification state is obtained through enzymatic digestion and peptide sequencing by MS/MS. For differentially modified forms of each protein, the measured intensities are semiquantitative and allow determination of relative abundance and stoichiometry. The method simultaneously detects covalent modifications on multiple proteins and provides a facile assay for comparing chromatin modification states between different cell types and/or cellular responses.

Animals↗
PubMed1997

Identification of essential amino acids in phenylalanine ammonia-lyase by site-directed mutagenesis.

The postulated precursor of the prosthetic dehydroalanine of phenylalanine ammonia-lyase (PAL), serine 202, was changed to cysteine by site-directed mutagenesis. After cloning and heterologous expression in Escherichia coli, the gene product was assayed for PAL activity. Mutant S202C showed full catalytic activity, and its kinetic constants and the amount of thiol groups were identical to those of wild-type PAL. It must be concluded that in a posttranslational modification both water and hydrogen sulfide can be eliminated from the amino acid in position 202 to form dehydroalanine. In an attempt to identify further amino acids essential either for the posttranslational modification or for catalysis, arginine 174, glutamine 425, and lysine 499 were changed to isoleucine. Analysis of the heterologously expressed mutated gene products revealed that only the R174I mutant showed a significantly lower Vmax value (1/450) identifying this arginine as important. This finding was supported by treatment of wild-type PAL and mutant R174I with phenylglyoxal and 2,3-butandione. Both react specifically with the guanidino group of arginine. They irreversibly inhibited wild-type PAL but had no influence of the Vmax value of mutant R174I. Preincubation with l-phenylalanine protected wild-type PAL from inhibition by phenylglyoxal indicating that arginine 174 is close to the active site. Incubation with KCN irreversibly abolished the remaining activity of mutant R174I leading to the conclusion that arginine 174 is important in catalysis.

Amino Acids↗
PubMed2003

Identification of S-sulfonation and S-thiolation of a novel transthyretin Phe33Cys variant from a patient diagnosed with familial transthyretin amyloidosis.

Familial transthyretin amyloidosis (ATTR) is an autosomal dominant disorder associated with a variant form of the plasma carrier protein transthyretin (TTR). Amyloid fibrils consisting of variant TTR, wild-type TTR, and TTR fragments deposit in tissues and organs. The diagnosis of ATTR relies on the identification of pathologic TTR variants in plasma of symptomatic individuals who have biopsy proven amyloid disease. Previously, we have developed a mass spectrometry-based approach, in combination with direct DNA sequence analysis, to fully identify TTR variants. Our methodology uses immunoprecipitation to isolate TTR from serum, and electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry (MS) peptide mapping to identify TTR variants and posttranslational modifications. Unambiguous identification of the amino acid substitution is performed using tandem MS (MS/MS) analysis and confirmed by direct DNA sequence analysis. The MS and MS/MS analyses also yield information about posttranslational modifications. Using this approach, we have recently identified a novel pathologic TTR variant. This variant has an amino acid substitution (Phe --> Cys) at position 33. In addition, like the Cys10 present in the wild type and in this variant, the Cys33 residue was both S-sulfonated and S-thiolated (conjugated to cysteine, cysteinylglycine, and glutathione). These adducts may play a role in the TTR fibrillogenesis.

Amino Acid Sequence↗
PubMed2007

Identification of targets of phosphorylation in heart mitochondria.

Whereas most strategies in proteomics deal with changes in protein levels, posttranslational modifications often represent pathological consequences at the molecular level without changes in abundance and, therefore represent a critical phenomenon to study. The present report elucidates an approach to studying one such posttranslational modification, phosphorylation, which is an important event in a variety of signaling cascades initiated in the heart in response to physiological and pathological stimuli. Comparison of phosphorylation profiles in different conditions, including drug treatments, receptor stimulation or blockade, and so forth, may lead to identification of relevant targets of signal transduction cascades. Furthermore, it may be possible to devise similar schemes to detect the subset of proteins modified by ubiquitinylation, lipid acylation, and so forth, and to compare differential patterns. Phosphorylation of mitochondrial targets is increasingly being recognized. Mitochondria are critical targets of a number of signaling pathways and therefore it is important to develop suitable methods to detect phosphorylation of mitochondrial targets. One approach is to perform in vitro phosphorylation in a reconstituted system of cytosol and mitochondria.

Animals↗
PubMed2006

Mapping histone modifications by nucleosome immunoprecipitation.

Studies of histone modification patterns and their role in gene regulation have led to the proposal that there is a "histone code." We have developed a method for nucleosome immunoprecipitation that can precisely identify the specific nucleosomes that carry a posttranslational modification of interest. The process involves the isolation and micrococcal nuclease digestion of minichromosomes to generate nucleosome core particles. These are then used in immunoprecipitation reactions with an antibody directed against the histone modification of interest. Subsequently, nucleosome core particle DNA is purified and end labeled. The original locations of the nucleosomes in the immunoprecipitate can be determined at low resolution (using a modified Southern blot hybridization procedure) or at maximal resolution (using the monomer extension method). Using the latter method, the positions of specific nucleosomes that carry the posttranslational modification of interest can be identified precisely. This method is sensitive, provides maximal resolution, and is inexpensive. The approach described here may serve as a paradigm for the study of histone-modifying patterns.

Animals↗
PubMed1999

Constitutive mdmx expression during cell growth, differentiation, and DNA damage.

The mdmx gene was shown to possess high homology to the mdm-2 gene and to encode a protein that can bind p53 and block p53 transactivation. Because Mdm-2 protein blocks the growth-suppressive activity of the p53 tumor-suppressor protein through similar activities, we examined the expression patterns of mdmx to determine how MdmX expression correlates with p53 protein levels. In this study, the expression pattern and protein levels of mdmx were examined in a number of cell culture systems. Like mdm-2, mdmx gene expression was constitutive during serum deprivation/restimulation of murine fibroblasts and differentiation of either murine teratocarcinoma or preadipocyte cells. In contrast, whereas mdm-2 gene expression was induced after cisplatin damage to ovarian carcinoma cells, mdmx expression remained constitutive. Because p53 transactivation is critical following a genotoxic stress, we examined p53:MdmX complexes after in vitro DNA-PK phosphorylation, a posttranslational modification that blocks p53 association with Mdm-2. The DNA-PK phosphorylation of p53 was capable of inhibiting p53:MdmX association. Thus, whereas DNA damage does not regulate mdmx mRNA levels, posttranslational modifications induced during DNA damage may block p53:MdmX association in vivo. These results demonstrate that, in the cell lines examined, mdmx gene expression remains constitutive during cell proliferation and differentiation or following DNA damage. Taken together, the data suggest that cells retain a constant level of MdmX. Thus, in undamaged cells, there exists the potential for an MdmX:p53 reservoir.

3T3 Cells↗
PubMed2004

A nonenzymatic modification of the amino-terminal domain of histone H3 by bile acid acyl adenylate.

Although it has been proposed that the secondary bile acids, deoxycholic acid and lithocholic acid, increase the number of aberrant crypt foci in the colon and may act as colon tumor promoters, there is little evidence detailing their mechanism of action. Histones play an important role in controlling gene expression, and the posttranslational modification of histones plays a role in regulation of intracellular signal transduction. In particular, the amino-terminal tail domain of histone H3 is sensitive to several posttranslational modifications, and acetylation of this domain changes its electrostatic environment and results in the loss of native folding. Therefore, we studied the modification of epsilon-amino groups on human histone H3 by deoxycholyl adenylate, which is an active intermediate in deoxycholyl thioester biosynthesis. After incubation of recombinant human histone H3 with a smaller amount of acyl adenylate, followed by enzymatic digestion, the peptide fragment mixtures were analyzed by matrix-assisted laser desorption ionization mass spectrometry. These data showed the formation of only one adduct fragment, which corresponded to amino acids 3-8 with a deoxycholate adduct, suggesting that the epsilon-amino group of Lys(4) had the highest reactivity. This novel modification, formation of a bile acid adduct on the histone H3 amino-terminal tail domain through an active acyl adenylate, may relate to the carcinogenesis-promoting effects of secondary bile acids.

Amino Acid Sequence↗
PubMed1989

RNA sequence analysis of a perinatal lethal osteogenesis imperfecta mutation.

The perinatal lethal form of osteogenesis imperfecta often results from mutations which disrupt stable assembly, delay secretion, and cause excessive posttranslational modification of type I procollagen molecules. One such mutation was efficiently characterized by an indirect method of RNA sequence analysis. The mutation initially was localized in procollagen by mapping the distribution of abnormal posttranslational modification within the triple helical domain of mutant molecules. Total RNA was isolated from osteogenesis imperfecta cells in culture, cDNA was synthesized using alpha 1(I) and alpha 2(I) specific primers, and fragments of cDNA suspected to harbor the mutation were amplified by the polymerase chain reaction technique and then cloned in M13 vectors. Sequence analysis of the amplified cDNA revealed a new, heterozygous Gly----Val substitution at residue 256 of the triple helical domain of alpha 1(I) chains produced by the perinatal lethal osteogenesis imperfecta cells. The nature and location of the mutation were confirmed by sequence analysis of amplified genomic DNA. A Gly----Val substitution has not previously been associated with the lethal form of osteogenesis imperfecta, and this mutation has the most amino-terminal location within the alpha 1(I) chain triple helical domain reported to date.

Alleles↗
PubMed2005

Detection and identification of S-nitrosylated proteins in endothelial cells.

Nitric oxide performs some of its direct effects by the induction of various protein posttranslational modifications. Among them, S-nitrosylation of cysteines has gained increasing attention and has been postulated as a signaling mechanism. However, there are still many technical limitations for the detection and identification of this posttranslational modification in cell proteins, and some of them are directly related to the lability of the nitrosothiol bond. We describe protocols for applying a derivatization technique, the biotin switch, which substitutes the S-nitrosylation for a biotinylation in the detection and proteomic identification of S-nitrosylated proteins in intact cells.

Endothelium↗
PubMed2001

Properties of microtubules assembled from mammalian tubulin synthesized in Escherichia coli.

When isolated from tissues, the alpha beta-dimeric protein tubulin consists of multiple isoforms which originate from the expression and subsequent posttranslational modification of multiple polypeptide sequences. Microtubules studied in vitro consist of mixtures of these isoforms. It is therefore not known whether dimers composed of single sequences of alpha- and beta-tubulin can polymerize to form microtubules, or whether posttranslational modifications may be necessary for microtubule assembly. To initiate investigation of these questions, rabbit reticulocyte lysate, which contains the cytoplasmic chaperonin CCT and its cofactors, was employed to prepare substantial quantities (tens of micrograms) of active tubulin by in vitro folding of mouse alpha- and beta-tubulins recombinantly synthesized in E. coli. This recombinant tubulin is composed of only a single alpha-chain and a single beta-chain. When analyzed after folding by isoelectric focusing, each chain yielded only one band, indicating that neither was detectably posttranslationally modified in the course of the folding reaction. When subjected to assembly-promoting conditions, this tubulin formed microtubules without the addition of any exogenous protein. Electron microscopy showed them to be of normal morphology. Analysis of their protein composition showed that they are composed nearly entirely of recombinant tubulin. These results demonstrate that the naturally occurring mixtures of isoforms are not strictly required for the formation of microtubules. They also open a route to other studies, both biomedical and structural, of fully defined tubulin in vitro.

Animals↗
PubMed1992

Lethal perinatal osteogenesis imperfecta due to a type I collagen alpha 2(I) Gly to Arg substitution detected by chemical cleavage of an mRNA:cDNA sequence mismatch.

A single base mismatch was detected by a chemical cleavage method in heteroduplexes formed between patient mRNA and a control collagen alpha 2(I) cDNA probe in a case of osteogenesis imperfecta type II. The region of the mRNA mismatch was amplified using the polymerase chain reaction, cloned and sequenced. A heterozygous point mutation of G to C at base pair 1,774 of the collagen alpha 2(I) mRNA resulted in the substitution of glycine with arginine at amino acid position 457 of the helix. Type I collagen of alpha 1(I)- and alpha 2(I)-chains from the patient migrated slowly on electrophoresis due to increased levels of posttranslational modification of lysine. The parents' fibroblast collagen did not contain the mRNA mismatch and the collagens showed normal electrophoretic behaviour. Two-dimensional electrophoresis of the CNBr peptides from the patient's collagen confirmed the excessive posttranslational modification of the alpha 1(I)- and alpha 2(I)-chains in the CNBr peptides N-terminal to the mutation due to disruption of the obligatory Gly-X-Y triplet repeat of the helix. The mutation led to reduced procollagen secretion and helix destabilization as evidenced by a decreased thermal stability. These data lend further support to the accumulating evidence that type I collagen alpha 2(I) glycine substitution mutations result in the same spectrum of clinical severity as those in the alpha 1(I)-chain.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1991

Functional expression of mammalian adenosine cyclic monophosphate-dependent protein kinase in Saccharomyces cerevisiae.

The heterologous expression of protein kinases in E. coli has proved difficult and unpredictable. Although the v-abl protein kinase is successfully expressed in E. coli, our experiments on expression of yeast C subunits in E. coli produced large amounts of predominantly insoluble and inactive protein. Attempts to refold the protein proved unsuccessful. In contrast, a major fraction of mouse C alpha expressed in E. coli is soluble and the enzyme in the soluble fraction is active; however, certain mutant forms have proved to be unstable, difficult to purify, or insoluble. In addition, the E. coli system cannot be used to study the biological role of posttranslational modifications specific to eukaryotic systems. Several protein kinases have been expressed in soluble form in insect cells using baculovirus, suggesting that this system is generally more reliable than E. coli. However, the presence and nature of posttranslational modifications in insect cells may be different from that found in the natural source and may affect the biochemical function. In addition, baculovirus expression is not particularly useful for studying biological questions. Mouse C alpha and C beta have been overexpressed in NIH3T3 cells. This approach is useful in characterizing the biochemical properties of C alpha versus C beta, but it may not be an ideal system for studying mutant proteins since wild-type C subunits are still expressed from the chromosomal copies in this genetic background. This small level of wild type may make it difficult to analyze weakly functional mutants, which have activities less than 10% that of wild type. Several cell lines with altered subunits of cAMP-dependent protein kinase have been identified but a strain completely devoid of C subunit has not been adequately characterized for protein structure/function studies. Disruption of the genes encoding cAMP-dependent protein kinase in mammalian cells has not yet been accomplished. This chapter describes a method to express a C subunit of mammalian cAMP-dependent kinase in yeast. We have demonstrated that the mouse C alpha subunit can substitute for its yeast counterpart. Since at least one functional C subunit is required for viability, these results suggest that the yeast substrates important for viability are recognized by the mammalian C subunit. Although the sequence conservation between yeast and mouse C subunit is only about 50%, these results demonstrate that heterologous proteins with relatively low sequence conservation with their yeast counterparts can be functional in yeast.(ABSTRACT TRUNCATED AT 400 WORDS)

Alcohol Dehydrogenase↗
PubMed1991

Protein kinase C plays a role in the induction of tyrosine phosphorylation of lymphoid microtubule-associated protein-2 kinase. Evidence for a CD3-associated cascade that includes pp56lck and that is defective in HPB-ALL.

Ligation of the CD3 receptor induces multiple signal transduction events that modify the activation state of the T cell. We have compared two lines that express biologically active CD3 receptors but differ in their biochemical activation pathways during ligation of this receptor. Jurkat cells respond to anti-CD3 with Ca2+ mobilization, PKC activation, induction of protein tyrosine phosphorylation, and activation of newly characterized lymphoid microtubule associated protein-2 kinase (MAP-2K). MAP-2K itself is a 43-kDa phosphoprotein that requires tyrosine phosphorylation for activation. Although ligation of the CD3 receptor in HPB-ALL could stimulate tyrosine phosphorylation of a 59- kDa substrate, there was no associated induction of [Ca2+]i flux, PKC, or MAP-2K activation. A specific PKC agonist, PMA, which bypasses the CD3 receptor, could, however, activate MAP-2K in HPB-ALL cells. This implies that defective stimulation of PKC by the CD3 receptor is responsible for its failure to activate MAP-2K in HPB-ALL. The defect in PKC activation is likely distal to the CD3 receptor as A1F14- failed to activate MAP-2K in HPB-ALL but was effective in Jurkat cells. The stimulatory effect of PMA on MAP-2K activity in HPB-ALL was accompanied by tyrosine phosphorylation of this kinase which implies that PKC may, in some way, regulate tyrosine phosphorylation of MAP-2K. A candidate for this role is pp56lck which underwent posttranslational modification (seen as mobility change on SDS-PAGE) during anti-CD3 and PMA stimulation in Jurkat or PMA treatment in HPB-ALL. There was, in fact, exact coincidence between induction of PKC activity, posttranslational modification of lck and tyrosine phosphorylation/activation of MAP-2K. Lck kinase activity in an immune complex kinase assay was unchanged during PMA treatment. An alternative explanation is that modification of lck may alter its substrate profile. We therefore looked at the previously documented ability of PKC to dissociate lck from the CD4 receptor and found that PMA could reduce the stoichiometry of the lck interaction with CD4 in HPB-ALL and to a lesser extent in Jurkat cells. These results imply the existence of a kinase cascade that is initiated by PKC and, in the course of which, lck and MAP-2K may interact.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1987

Introduction of the human pro alpha 1(I) collagen gene into pro alpha 1(I)-deficient Mov-13 mouse cells leads to formation of functional mouse-human hybrid type I collagen.

The Mov-13 mouse strain carries a retroviral insertion in the pro alpha 1(I) collagen gene that prevents transcription of the gene. Cell lines derived from homozygous embryos do not express type I collagen although normal amounts of pro alpha 2 mRNA are synthesized. We have introduced genomic clones of either the human or mouse pro alpha 1(I) collagen gene into homozygous cell lines to assess whether the human or mouse pro alpha 1(I) chains can associate with the endogenous mouse pro alpha 2(I) chain to form stable type I collagen. The human gene under control of the simian virus 40 promoter was efficiently transcribed in the transfected cells. Protein analyses revealed that stable heterotrimers consisting of two human alpha 1 chains and one mouse alpha 2 chain were formed and that type I collagen was secreted by the transfected cells at normal rates. However, the electrophoretic migration of both alpha 1(I) and alpha 2(I) chains in the human-mouse hybrid molecules were retarded, compared to the alpha (I) chains in control mouse cells. Inhibition of the posttranslational hydroxylation of lysine and proline resulted in comigration of human and mouse alpha 1 and alpha 2 chains, suggesting that increased posttranslational modification caused the altered electrophoretic migration in the human-mouse hybrid molecules. Amino acid sequence differences between the mouse and human alpha chains may interfere with the normal rate of helix formation and increase the degree of posttranslational modifications similar to those observed in patients with lethal perinatal osteogenesis imperfecta. The Mov-13 mouse system should allow us to study the effect specific mutations introduced in transfected pro alpha 1(I) genes have on the synthesis, assembly, and function of collagen I.

Animals↗
PubMed2003

Phylogenetic analyses and expression studies reveal two distinct groups of calreticulin isoforms in higher plants.

Calreticulin (CRT) is a multifunctional protein mainly localized to the endoplasmic reticulum in eukaryotic cells. Here, we present the first analysis, to our knowledge, of evolutionary diversity and expression profiling among different plant CRT isoforms. Phylogenetic studies and expression analysis show that higher plants contain two distinct groups of CRTs: a CRT1/CRT2 group and a CRT3 group. To corroborate the existence of these isoform groups, we cloned a putative CRT3 ortholog from Brassica rapa. The CRT3 gene appears to be most closely related to the ancestral CRT gene in higher plants. Distinct tissue-dependent expression patterns and stress-related regulation were observed for the isoform groups. Furthermore, analysis of posttranslational modifications revealed differences in the glycosylation status among members within the CRT1/CRT2 isoform group. Based on evolutionary relationship, a new nomenclature for plant CRTs is suggested. The presence of two distinct CRT isoform groups, with distinct expression patterns and posttranslational modifications, supports functional specificity among plant CRTs and could account for the multiple functional roles assigned to CRTs.

Amino Acid Sequence↗
PubMed2001

S-nitrosylation is emerging as a specific and fundamental posttranslational protein modification: head-to-head comparison with O-phosphorylation.

Nitric oxide (NO) is a free-radical product of mammalian cell metabolism that plays diverse and important roles in the regulation of cell function. Biological actions of NO arise as a direct consequence of chemical reactions between NO or NO-derived species and protein targets. Reactions of NO with transition metals in target proteins have garnered the most attention to date as the principal mechanism of NO signaling; nonetheless, S-nitrosylation of protein Cys residues is rapidly moving to center stage in importance. In general, however, there has been a delay in adequate appreciation of the role of S-nitrosylation in biological signaling by NO. This lag is attributed to a poor understanding of the basis for selective targeting of NO to particular thiols, and methodological limitations in accurately quantifying this modification--recent breakthroughs in concepts and methods diminish these barriers. Here, we consider the wheres and whys of protein S-nitrosylation and its basis for specificity. Protein S-nitrosylation potentially represents a ubiquitous and fundamental mechanism for posttranslational control of protein activity on a par with that of O-phosphorylation.

Animals↗