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PubMed1981

mRNA for the rat uterine estrogen-induced protein. Translation in vitro and regulation by estrogen.

Poly(A)-rich RNA was isolated from uterus and brain of immature rats and translated in the rabbit reticulocyte lysate cell-free protein-synthesizing system. The translation products were analyzed by 1) specific immunoprecipitation using antibodies directed against purified estrogen-induced protein (IP), 2) two-dimensional gel electrophoresis, and 3) partial protease digestion of selected spots from two-dimensional gels. These analyses showed that IP mRNA from both uterus and brain is faithfully translated in the cell-free system. Comparison of translation products derived from uterine mRNA of untreated and 1-h estrogen-treated rats revealed a specific increase in the ability of mRNA from treated animals to direct the synthesis of IP. Thus, estrogen stimulation of IP synthesis results, at least partly, from increased uterine concentrations of IP mRNA.

Animals↗
PubMed1994

Post-translational protein import and folding.

Significant advances have been made over the past year in analyzing the membrane machineries for the post-translational export of proteins in bacteria and for the import of proteins into mitochondria. Another important development is the identification in mitochondria of homologs of the bacterial heat-shock proteins DnaJ and GrpE, which function together with Hsp70 in membrane translocation and folding of imported proteins. A number of gene products involved in peroxisomal protein uptake have been identified, which are now awaiting biochemical analysis.

Animals↗
PubMed1993

Co-translational protein import into mitochondria: an alternative view.

Recent in vitro and in vivo experiments suggest that the synthesis and import of mitochondrial proteins are very tightly coupled and that a co-translational import reaction may be mandatory for some proteins. These results are entirely consistent with early experiments which suggested that import occurs co-translationally and that cytosolic polysomes synthesizing mitochondrial proteins are bound to protein import sites on isolated mitochondria. This article discusses and seemingly contradictory reports concerning the involvement of co-translational and post-translational mechanisms in the import process and examines the impact of recent developments in the field.

Animals↗
PubMed2007

Post-translational protein modifications in type 1 diabetes: a role for the repair enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase?

AIMS/HYPOTHESIS: Post-translational modifications, such as isomerisation of native proteins, may create new antigenic epitopes and play a role in the development of the autoimmune response. Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PIMT), encoded by the gene PCMT1, is an enzyme that recognises and repairs isomerised Asn and Asp residues in proteins. The aim of this study was to assess the role of PIMT in the development of type 1 diabetes. MATERIALS AND METHODS: Immunohistochemical analysis of 59 normal human tissues was performed with a monoclonal PIMT antibody. CGP3466B, which induces expression of Pcmt1, was tested on MIN6 and INS1 cells, to assess its effect on Pcmt1 mRNA and PIMT levels (RT-PCR and western blot) and apoptosis. Forty-five diabetes-prone BioBreeding (BB) Ottawa Karlsburg (OK) rats were randomised to receive 0, 14 or 500 microg/kg (denoted as the control, low-dose and high-dose group, respectively) of CGP3466B from week 5 to week 20. RESULTS: A high level of PIMT protein was detected in beta cells. CGP3466B induced a two- to threefold increase in Pcmt1 mRNA levels and reduced apoptosis by 10% in MIN6 cells. No significant effect was seen on cytokine-induced apoptosis or PIMT protein levels in INS1 cells. The onset of diabetes in the BB/OK rats was significantly delayed (85.6+/-9.0 vs 84.3+/-6.8 vs 106.6+/-13.5 days, respectively; p<0.01 for high-dose vs low-dose and control groups), the severity of the disease was reduced (glucose 22.2+/-3.2 vs 16.9+/-2.6 vs 15.8+/-2.7 mmol; p<0.01 for high- and low-dose groups vs control group) and residual beta cells were more frequently identified (43% vs 71% vs 86%; p<0.05 for high-dose vs control group) in the treated animals. CONCLUSIONS/INTERPRETATION: The results support a role for post-translational modifications and PIMT in the development of type 1 diabetes in the diabetes-prone BB rat, and perhaps also in humans.

Animals↗
PubMed2005

Post-translational protein modification as the substrate for long-lasting memory.

Prevailing models of memory identify mRNA translation as necessary for long-lasting information storage. However, there are enough instances of memory storage in the virtual absence of protein synthesis to prompt consideration of alternative models. A comprehensive review of the protein synthesis literature leads us to conclude that the translational mechanism is exclusively a permissive, replenishment step. Therefore, we propose that post-translational modification (PTM) of proteins already at the synapse is the crucial instructive mechanism underlying long-lasting memory. A novel feature of this model is that non-random spontaneous (or endogenous) brain activity operates as a regulated positive-feedback rehearsal mechanism, updating network configurations by fine-tuning the PTM state of previously modified proteins. Synapses participating in memory storage are therefore supple, a feature required for networks to alter complexity and update continuously. In analogy with codons for amino acids, a long-lasting memory is represented by a 'degenerate code' - a set of pseudo-redundant networks that can ensure its longevity.

Animals↗
PubMed2004

Fragile X mental retardation protein is necessary for neurotransmitter-activated protein translation at synapses.

Fragile X mental retardation is caused by absence of the RNA-binding protein fragile X mental retardation protein (FMRP), encoded by the FMR1 gene. There is increasing evidence that FMRP regulates transport and modulates translation of some mRNAs. We studied neurotransmitter-activated synaptic protein synthesis in fmr1-knockout mice. Synaptoneurosomes from knockout mice did not manifest accelerated polyribosome assembly or protein synthesis as it occurs in wild-type mice upon stimulation of group I metabotropic glutamate receptors. Direct activation of protein kinase C did not compensate in the knockout mouse, indicating that the FMRP-dependent step is further along the signaling pathway. Visual cortices of young knockout mice exhibited a lower proportion of dendritic spine synapses containing polyribosomes than did the cortices of wild-type mice, corroborating this finding in vivo. This deficit in rapid neurotransmitter-controlled local translation of specific proteins may contribute to morphological and functional abnormalities observed in patients with fragile X syndrome.

Animals↗
PubMed2005

Co-translational protein targeting by the signal recognition particle.

The signal recognition particle (SRP) mediates the co-translational targeting of nascent proteins to the eukaryotic endoplasmic reticulum membrane, or the bacterial plasma membrane. During this process, two GTPases, one in the SRP and one in the SRP receptor (SR), form a complex in which both proteins reciprocally activate the GTPase reaction of one another. The recent crystal structures of the T. aquaticus SRP.SR complex show that the two GTPases associate via an unusually extensive and highly cooperative interaction surface, and form a composite active site at the interface. GTPase activation proceeds through a unique mechanism, stimulated by both interactions between the twinned GTP molecules across the dimer interface and by conformational rearrangements that position catalytic residues in each active site with respect to the bound substrates. Distinct classes of mutations have been isolated that inhibit specific stages during SRP-SR complex formation and activation, suggesting discrete conformational stages during formation of the active SRP.SR complex. Each stage provides a potential control point in the targeting reaction at which regulation by additional components can be exerted, thus ensuring the binding and release of cargo at the appropriate time.

Bacterial Proteins↗
PubMed2004

Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice.

The inhibitor of apoptosis proteins (IAPs) are a family of antiapoptotic proteins that bind and inhibit caspases 3, 7, and/or 9, but not caspase 8. Growing evidence also indicates that IAPs also modulate cell division, cell cycle progression, and signal transduction pathways. As our basic understanding of IAPs has increased, the knowledge is being translated into clinically useful applications in the diagnosis and treatment of malignancy. For example, IAPs such as survivin are being investigated as diagnostic markers for the presence of occult malignancy. In addition, IAP overexpression is a poor prognostic marker in a variety of solid tumors and hematologic malignancies. Finally, IAPs are attractive therapeutic targets, and efforts are under way to develop antisense and chemical IAP inhibitors that may be useful for the treatment of a variety of malignancies. For all of these potential clinical applications, however, the challenge remains to incorporate these findings into actual clinical practice.

Animals↗
PubMed2002

Primary and secondary metabolism, and post-translational protein modifications, as portrayed by proteomic analysis of Streptomyces coelicolor.

The newly sequenced genome of Streptomyces coelicolor is estimated to encode 7825 theoretical proteins. We have mapped approximately 10% of the theoretical proteome experimentally using two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. Products from 770 different genes were identified, and the types of proteins represented are discussed in terms of their annotated functional classes. An average of 1.2 proteins per gene was observed, indicating extensive post-translational regulation. Examples of modification by N-acetylation, adenylylation and proteolytic processing were characterized using mass spectrometry. Proteins from both primary and certain secondary metabolic pathways are strongly represented on the map, and a number of these enzymes were identified at more than one two-dimensional gel location. Post-translational modification mechanisms may therefore play a significant role in the regulation of these pathways. Unexpectedly, one of the enzymes for synthesis of the actinorhodin polyketide antibiotic appears to be located outside the cytoplasmic compartment, within the cell wall matrix. Of 20 gene clusters encoding enzymes characteristic of secondary metabolism, eight are represented on the proteome map, including three that specify the production of novel metabolites. This information will be valuable in the characterization of the new metabolites.

Acetylation↗
PubMed1988

PARA-SITE: a computer algorithm for rapidly analyzing the physical-chemical properties of amino acid sequences at sites of co- and post-translational protein processing.

A new algorithm is presented which can be used to examine the physical-chemical properties of amino acids at sites of co- or post-translational processing. This algorithm has been incorporated into a computer program known as PARA-SITE. Thirty different parameters can be studied for amino acids which occupy comparable positions in naturally occurring proteins. PARA-SITE should aid in the design and interpretation of protein engineering experiments which seek to dissect structure/activity relationships.

Algorithms↗
PubMed1997

Co-translational protein targeting catalyzed by the Escherichia coli signal recognition particle and its receptor.

The Ffh-4.5S ribonucleoprotein particle (RNP) and FtsY from Escherichia coli are homologous to essential components of the mammalian signal recognition particle (SRP) and SRP receptor, respectively. The ability of these E. coli components to function in a bona fide co-translational targeting pathway remains unclear. Here we demonstrate that the Ffh-4.5S RNP and FtsY can efficiently replace their mammalian counterparts in targeting nascent secretory proteins to microsomal membranes in vitro. Targeting in the heterologous system requires a hydrophobic signal sequence, utilizes GTP and, moreover, occurs co-translationally. Unlike mammalian SRP, however, the Ffh-4.5S RNP is unable to arrest translational elongation, which results in a narrow time window for the ribosome nascent chain to interact productively with the membrane-bound translocation machinery. The highly negatively charged N-terminal domain of FtsY, which is a conserved feature among prokaryotic SRP receptor homologs, is important for translocation and acts to localize the protein to the membrane. Our data illustrate the extreme functional conservation between prokaryotic and eukaryotic SRP and SRP receptors and suggest that the basic mechanism of co-translational protein targeting is conserved between bacteria and mammals.

Animals↗
PubMed1983

mRNA species and proteins of adenovirus type 12 transforming regions: identification of proteins translated from multiple coding stretches in 2.2 kb region 1B mRNA in vitro and in vivo.

Analysis of cytoplasmic RNA in Ad12-infected and -transformed cells showed that more than 20 mRNA species are transcribed from regions 1A and 1B. These mRNA species could be classified into four classes according to the extent to which they were expressed in infected and transformed cells under various conditions. The proteins synthesized from the major species of each of these mRNAs were identified by in vitro translation. In region 1A, the 40K (and 38K) proteins were synthesized from three mRNA species that differed from one another in their 5' ends, and in region 1B three proteins with molecular weights of 19,000 (19K), 50K, and 17K were synthesized from a single species of 2.2 kb mRNA. Only the 19K protein was immunoprecipitated by anti-T serum (G serum) from rats bearing GY1 cell tumors, [GY1 cells are rat cells transformed by the Ad12 HindIII-G fragment (0-6.8 map units).] The 19K protein was also detected by immunoprecipitation in extracts from both transformed and infected cells. The 17K protein was immunoprecipitated by anti-T serum (C serum) derived from rats bearing CY1 cell tumors, but was not by G serum. [CY1 cells are rat cells transformed by the Ad12 EcoRI-C fragment (0-16.5 map units).] The 17K protein was also translated in vitro from the 0.5 kb region 1B mRNA. These results suggest that the 19K and 17K proteins correspond to Ad12 T antigen f and polypeptide IX, respectively, and that these two proteins are translated in vivo from different coding regions in 2.2 kb mRNA in CY1 cells.

Adenoviruses, Human↗
PubMed1999

Resistance of ribosomal protein mRNA translation to protein synthesis shutoff induced by poliovirus.

Poliovirus infection induces an overall inhibition of host protein synthesis, although some mRNAs continue to be translated, suggesting different translation requirements for cellular mRNAs. It is known that ribosomal protein mRNAs are translationally regulated and that the phosphorylation of ribosomal protein S6 is involved in the regulation. Here, we report that the translation of ribosomal protein mRNAs resists poliovirus infection and correlates with an increase in p70(s6k) activity and phosphorylation of ribosomal protein S6.

Humans↗
PubMed1996

A novel missense mutation in the amino-terminal domain of the human androgen receptor gene in a family with partial androgen insensitivity syndrome causes reduced efficiency of protein translation.

The role of the androgen receptor (AR) in male sexual differentiation is revealed in part by the analysis of naturally occurring mutations in families with androgen insensitivity syndrome (AIS). We have investigated a family with partial AIS affecting three generations and have identified a G to A substitution in the AR gene at the fourth position 3' from the A of the ATG initiation codon changing the second amino acid residue from glutamic acid to lysine (EK2). Transient expression of the mutant EK2-pCMVhAR expression vector in COS cells revealed decreased translation with a 20-50% reduction in mutant protein relative to wild type AR by immunoblot analysis. The rate of dissociation of [3H]methyltrienolone from the EK2 mutant (half-time [t1/2] = 1.7 +/- 0.08 SE h) was increased compared with wild type AR (t1/2 = 2.4 +/- 0.11 h). Cotransfection studies using an androgen responsive luciferase reporter vector demonstrated a 50% reduction in transcriptional activation by EK2. These functional alterations are consistent with the partial AIS phenotype in affected males, corroborate the AR amino-terminal domain effect on kinetics of androgen binding, and provide physiological evidence for earlier translation experiments identifying the nucleotide sequence for optimal translation initiation.

Adolescent↗
PubMed2000

Non-oxidative modification of lens crystallins by kynurenine: a novel post-translational protein modification with possible relevance to ageing and cataract.

In humans, the crystallin proteins of the ocular lens become yellow-coloured and fluorescent with ageing. With the development of senile nuclear cataract, the crystallins become brown and additional fluorophores are formed. The mechanism underlying crystallin colouration is not known but may involve interaction with kynurenine-derived UV filter compounds. We have recently identified a sulphur-linked glutathionyl-3-hydroxykynurenine glucoside adduct in the lens and speculated that kynurenine may also form adducts with GSH and possibly with nucleophilic amino acids of the crystallins (e.g. Cys). Here we show that kynurenine modifies calf lens crystallins non-oxidatively to yield coloured (365 nm absorbing), fluorescent (Ex 380 nm/Em 450-490 nm) protein adducts. Carboxymethylation and succinylation of crystallins inhibited kynurenine-mediated modification by approx. 90%, suggesting that Cys, Lys and possibly His residues may be involved. This was confirmed by showing that kynurenine formed adducts with GSH as well as with poly-His and poly-Lys. NMR studies revealed that the novel poly-Lys-kynurenine covalent linkage was via the epsilon-amino group of the Lys side chain and the betaC of the kynurenine side chain. Analysis of tryptic peptides of kynurenine-modified crystallins revealed that all of the coloured peptides contained either His, Cys or an internal Lys residue. We propose a novel mechanism of kynurenine-mediated crystallin modification which does not require UV light or oxidative conditions as catalysts. Rather, we suggest that the side chain of kynurenine-derived lens UV filters becomes deaminated to yield an alpha,beta-unsaturated carbonyl which is highly susceptible to attack by nucleophilic amino acid residues of the crystallins. The inability of the lens fibre cells to metabolise their constituent proteins results in the accumulation of coloured/fluorescent crystallins with age.

Aging↗
PubMed2007

Oxidative-nitrosative stress and post-translational protein modifications: implications to lung structure-function relations. Arginase modulates NF-kappaB activity via a nitric oxide-dependent mechanism.

NF-kappaB is a versatile transcription factor that regulates a wide array of processes, including inflammation and survival, and plays a critical role in the etiology of inflammatory lung diseases. Nitric oxide (NO) has been suggested to play an antiinflammatory role through S-nitrosation of components of NF-kappaB pathway. NO production can be modulated by changing the availability of its substrate, L-arginine. Arginases compete with NO synthases (NOSs) for their common substrate, L-arginine, and thereby have the potential to alter the signaling function of NO. The goal of the present study was to determine the impact of arginase manipulation on NO, and subsequent effects on NF-kappaB activation, in lung epithelial cells. Our results demonstrate that reduction of arginase activity enhanced cellular content of NO and S-nitrosated proteins, and resulted in decreases in TNF-alpha- or LPS-stimulated NF-kappaB DNA binding and transcriptional activity, in association with enhanced S-nitrosation of p50. The effects of arginase inhibition on NF-kappaB were reversed by the generic NOS inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), suggesting a causal role for NO in the attenuation of NF-kappaB induced by arginase suppression. Conversely, overexpression of arginase I decreased cellular S-nitrosothiol content and enhanced IkappaB kinase activity and NF-kappaB DNA binding, and decreased S-nitrosation of p50. Collectively, our data point to a regulatory mechanism wherein NF-kappaB is controlled through arginase-dependent regulation of NO levels, which may impact on chronic inflammatory diseases that are accompanied by NF-kappaB activation and upregulation of arginases.

Animals↗