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PubMed2006

Post-translational modification of delta antigen of hepatitis D virus.

The hepatitis delta virus (HDV) genome has only one open reading frame, which encodes the viral small delta antigen. After RNA editing, the same open reading frame is extended 19 amino acids at the carboxyl terminus and encodes the large delta antigen. These two viral proteins escort the HDV genome through different cellular compartments for the complicated phases of replication, transcription and, eventually, the formation of progeny virions. To orchestrate these events, the delta antigens have to take distinct cues to traffic to the right compartments and make correct molecular contacts. In eukaryotes, post-translational modification (PTM) is a major mechanism of dictating the multiple functions of a single protein. Multiple PTMs, including phosphorylation, isoprenylation, acetylation, and methylation, have been identified on hepatitis delta antigens. In this chapter we review these PTMs and discuss their functions in regulating and coordinating the life cycle of HDV.

Acetylation↗

PubMed1991

Mutations and variants of apolipoprotein B that affect plasma cholesterol levels.

Apolipoprotein (apo-) B100 is the exclusive apolipoprotein of low density lipoproteins (LDL0, which transport most of the plasma cholesterol in humans. Mutations in apo-B100 can cause either hypocholesterolemia or hypercholesterolemia. Familial hypobetalipoproteinemia, which leads to hypocholesterolemia, has been shown to be caused by defects in the apo-B gene that terminate translation prematurely and result in the production of truncated proteins. The mutations responsible for the hypocholesterolemia have been either single nucleotide substitutions or deletions. Familial defective apo-B100, which leads to hypercholesterolemia, is caused by a point mutation in the receptor-binding domain of apo-B100. The mutation disrupts the binding of LDL to the LDL receptor, thereby disrupting LDL receptor-mediated catabolism and resulting in hypercholesterolemia. A variant form of apo-B, apo-B48, is also critical for lipoprotein metabolism. Apolipoprotein B48 is obligatory for the secretion of chylomicrons. It is formed from an RNA-edited apo-B mRNA in which codon 2153 has been converted from a CAA (glutamine) codon to a premature UAA (stop) codon. The first cytosine in this codon is deaminated to form uracil. The minimum nucleotide recognition sequence for the editing mechanism has been reported to be between 26 and more than 63 nucleotides surrounding codon 2153. The apo-B mRNA editing mechanism, which appears to be a cytosine deaminase, and its regulation are being actively investigated.

Apolipoprotein B-48↗

PubMed1994

Physical map and gene organization of the mitochondrial genome of Chondrus crispus (Rhodophyta, Gigartinales).

Organellar DNA, i.e. a mixture of plastid and mitochondrial DNAs, was purified from the rhodophyte Chondrus crispus and analysed with restriction endonucleases. Mitochondrial DNA fragments were identified by heterologous hybridization, cloned, mapped and partially sequenced. The mitochondrial genome of C. crispus consists of a 25.9 kb circular molecule on which twenty genes were localized. Compared with other plant mitochondrial genomes, C. crispus mitochondrial DNA appears as a relatively small molecule with a high coding capacity and a specific gene organization. The use of a modified genetic code and the absence of RNA editing, previously reported for the cox3 gene, is a general characteristic of the sequenced genes of this molecule. This is the first detailed description of a red algal mitochondrial genome.

Base Sequence↗

PubMed1996

Regulation of gene expression in plant mitochondria.

Many genes is plant mitochondria have been analyzed in the past 15 years and regulatory processes controlling gene expression can now be investigated. In vitro systems capable of initiating transcription faithfully at promoter sites have been developed for both monocot and dicot plants and will allow the identification of the interacting nucleic acid elements and proteins which specify and guide transcriptional activities. Mitochondrial activity, although required in all plant tissues, is capable of adapting to specific requirements by regulated gene expression. Investigation of the factors governing the quality and quantity of distinct RNAs will define the extent of interorganelle regulatory interference in mitochondrial gene expression.

Gene Expression Regulation, Developmental↗

PubMed1995

Oenothera mitochondrial orf454, a gene involved in cytochrome c biogenesis corresponds to orf169 and orf322 of Marchantia.

We have characterized a mitochondrial gene in Oenothera, designated orf454, capable of encoding a component of the cytochrome c biogenesis system. This open reading frame is interrupted by an intron of 941 nucleotides showing high similarity to a group II intron residing in the rpl2 gene. RNA editing, which is observed at 18 cytidine positions within the orf454 reading frame, improves the similarity to protein-coding sequences in bacteria and higher plants and removes the last 16 amino acids. orf454 also shows high sequence similarity to two overlapping reading frames (orf169 and orf322) of Marchantia mitochondria. These ORFs belong to an operon-like cluster of genes in the liverwort that is not conserved in Oenothera mitochondria. However, in bacteria these reading frames are organized like the Marchantia gene cluster. It has been shown by genetical analysis in Rhodobacter capsulatus that these genes are essential for cytochrome c biogenesis. Genes of bacterial operons-ccl1 in Rhodobacter and yejR and nrfE in Escherichia coli - show high sequence similarity to the mitochondrial reading frames orf577 and orf454 of Oenothera. orf454, which we describe here, is homologous to the C-terminal region of these bacterial genes, while the previously described orf577 is homologous to the N-terminal region.

Amino Acid Sequence↗

PubMedDate not supplied

The sugar beet mitochondrial gene for the ATPase alpha-subunit: sequence, transcription and rearrangements in cytoplasmic male-sterile plants.

We have characterized the mitochondrial atpA (the alpha subunit of F1-ATPase) gene from male-fertile cytoplasm (cv TK81-0) of sugar beet. The gene is 1518-bp long and encodes a polypeptide of 506 amino acids. The atpA mRNA sequence is modified by three C-to-U RNA editing events, all of which alter the encoded protein sequences. In order to examine the genome organization of the atpA locus in cytoplasmic male-sterile (CMS) sugar beet, atpA-containing clones were isolated from Owen CMS (TK81-MS) and a different source of CMS [I-12CMS(2)] cytoplasm respectively. The sequences of the atpA coding region from TK81-MS and I-12CMS(2) are identical to each other and to the corresponding TK81-0 sequence. However, the TK81-0 and TK81-MS loci diverge completely 47 bp upstream of the initiation codon, resulting in different 5' transcript termini for the two genes. On the other hand, the point of divergence between the TK81-0 and I-12CMS(2) atpA genes was found to occur after 393 bp 3' to the TAA stop codon. Our results also show the 3'-flanking sequences of I-12CMS(2) atpA to be present elsewhere in the mitochondrial genomes of TK81-0, TK81-MS and I-12CMS(2), suggesting the possible involvement of these repeated DNA elements in the sequence rearrangements.

Adenosine Triphosphatases↗

PubMedDate not supplied

Plant mitochondrial RNase P.

Molecular investigations in mitochondria of higher plants have to take in account the complicated genomic structure of these organelles and their complex mode of gene expression. Recently tRNA processing activities and particularly RNase P-like activities have been described for mitochondria of mono- and dicot plants. The determined biochemical characteristics of these plant mitochondrial tRNA processing enzymes now allow a comparison to the bacterial prototype from which they evolved. The substrate specificity of the plant mitochondrial RNase P in particular has unique selection parameters distinct from the E. coli RNase P.

Animals↗

PubMed1990

The revised genetic code.

Recent findings on the genetic code are reviewed, including selenocysteine usage, deviations in the assignments of sense and nonsense codons, RNA editing, natural ribosomal frameshifts and non-orthodox codon-anticodon pairings. A multi-stage codon reading process is presented.

Genetic Code↗

PubMed1997

Glutamate, excitotoxicity and amyotrophic lateral sclerosis.

The "glutamate hypothesis" is one of three major pathophysiological mechanisms of motor neurone injury towards which current research effort into amyotrophic lateral sclerosis (ALS) is directed. There is great structural and functional diversity in the glutamate receptor family which results from combinations of 14 known gene products and their splice variants, with or without additional RNA editing. It is possible that motor neurones express a unique molecular profile of glutamate receptors. Abnormal activation of glutamate receptors is one of five main candidates as a final common pathway to neuronal death. In classical acute excitotoxicity, there is influx of Na+ and CI-, and destabilisation of intracellular Ca2+ homeostasis, which activates a cascade of harmful biochemical events. The concept of secondary excitotoxicity, where cellular injury by glutamate is triggered by disturbances in neuronal energy status, may be particularly relevant to a chronic neurodegenerative disease such as ALS. Data are now beginning to emerge on the fine molecular structure of the glutamate receptors present on human motor neurones, which have a distinct profile of AMPA receptors. Two important molecular features of motor neurones have been identified that may contribute to their vulnerability to neurodegeneration. The low expression of calcium binding proteins and the low expression of the GluR2 AMPA receptor subunit by vulnerable motor neurone groups may render them unduly susceptible to calcium-mediated toxic events following glutamate receptor activation. Eight lines of evidence that indicate a disturbance of glutamatergic neurotransmission in ALS patients are reviewed. The links between abnormal activation of glutamate receptors and other potential mechanisms of neuronal injury, including activation of calcium-mediated second messenger systems and free radical mechanisms, are emphasised. Riluzole, which modulates the glutamate neurotransmitter system, has been shown to prolong survival in patients with ALS. Further research may allow the development of subunit-specific therapeutic targeting of glutamate receptors and modulation of "downstream" events within motor neurones, aimed at protecting vulnerable molecular targets in specific populations of ALS patients.

Amyotrophic Lateral Sclerosis↗

PubMed1998

The complete mitochondrial genome of Rhea americana and early avian divergences.

The complete mitochondrial DNA, mtDNA, molecule of the greater rhea, Rhea americana, was sequenced. The size of the molecule is 16,710 nucleotides. The organization of the molecule conforms with that described for the chicken and the ostrich. It has been shown previously that relative to other vertebrates the NADH3 gene of the ostrich has an insertion of one nucleotide in position 174 of the gene. The same observation was made in the rhea and in the newly sequenced NADH3 gene of the emu, Dromaius novaehollandiae. Comparison with the NADH3 gene of the chicken and the rook suggests that the inserted nucleotide may be deleted by RNA editing. The divergence between the two struthioniform species, the ostrich and the rhea, was molecularly dated at approximately 51 million years before present, MYBP. This dating is more recent than commonly acknowledged. Phylogenetic analysis of the complete cytochrome b genes of seven avian orders placed the Passeriformes basal in the avian tree with the Struthioniformes among the remaining Neognathae. These findings challenge the commonly accepted notion that the most basal avian divergence is that between the Palaeognathae and Neognathae.

Animals↗

PubMed2002

Constitutive activity of G-protein-coupled receptors: cause of disease and common property of wild-type receptors.

The aim of this review is to provide a systematic overview on constitutively active G-protein-coupled receptors (GPCRs), a rapidly evolving area in signal transduction research. We will discuss mechanisms, pharmacological tools and methodological approaches to analyze constitutive activity. The two-state model defines constitutive activity as the ability of a GPCR to undergo agonist-independent isomerization from an inactive (R) state to an active (R*) state. While the two-state model explains basic concepts of constitutive GPCR activity and inverse agonism, there is increasing evidence for multiple active GPCR conformations with distinct biological activities. As a result of constitutive GPCR activity, basal G-protein activity increases. Until now, constitutive activity has been observed for more than 60 wild-type GPCRs from the families 1-3 and from different species including humans and commonly used laboratory animal species. Additionally, several naturally occurring and disease-causing GPCR mutants with increased constitutive activity relative to wild-type GPCRs have been identified. Alternative splicing, RNA editing, polymorphisms within a given species, species variants and coupling to specific G-proteins all modulate the constitutive activity of GPCRs, providing multiple regulatory switches to fine-tune basal cellular activities. The most important pharmacological tools to analyze constitutive activity are inverse agonists and Na(+) that stabilize the R state, and pertussis toxin that uncouples GPCRs from G(i)/G(o)-proteins. Constitutive activity is observed at low and high GPCR expression levels, in native systems and in recombinant systems, and has been reported for GPCRs coupled to G(s)-, G(i)- and G(q)-proteins. Constitutive activity of neurotransmitter GPCRs may provide a tonic support for basal neuronal activity. For the majority of GPCRs known to be constitutively active, inverse agonists have already been identified. Inverse agonists may be useful in the treatment of neuropsychiatric and cardiovascular diseases and of diseases caused by constitutively active GPCR mutants.

Animals↗

PubMed2004

The mitochondrial DNA of land plants: peculiarities in phylogenetic perspective.

Land plants exhibit a significant evolutionary plasticity in their mitochondrial DNA (mtDNA), which contrasts with the more conservative evolution of their chloroplast genomes. Frequent genomic rearrangements, the incorporation of foreign DNA from the nuclear and chloroplast genomes, an ongoing transfer of genes to the nucleus in recent evolutionary times and the disruption of gene continuity in introns or exons are the hallmarks of plant mtDNA, at least in flowering plants. Peculiarities of gene expression, most notably RNA editing and trans-splicing, are significantly more pronounced in land plant mitochondria than in chloroplasts. At the same time, mtDNA is generally the most slowly evolving of the three plant cell genomes on the sequence level, with unique exceptions in only some plant lineages. The slow sequence evolution and a variable occurrence of introns in plant mtDNA provide an attractive reservoir of phylogenetic information to trace the phylogeny of older land plant clades, which is as yet not fully resolved. This review attempts to summarize the unique aspects of land plant mitochondrial evolution from a phylogenetic perspective.

DNA, Mitochondrial↗

PubMed2005

The organization of mitochondrial atp6 gene region in male fertile and CMS lines of pepper (Capsicum annuum L.).

The mitochondrial atp6 gene in male fertile (N) and CMS (S) pepper has previously been compared and was found to be present in two copies (Kim et al. in J Kor Soc Hort Sci 42:121-127 2001). In the current study, these atp6 copies were amplified by an inverse PCR technique, and the coding region as well as the 5' and 3' flanking regions were sequenced. The atp6 copies in CMS pepper were detected as one intact gene and one pseudogene, truncated at the 3' coding region. When the atp6 genes in pepper were compared to other plant species, pepper, potato, and petunia all possessed a sequence of 12 identical amino acids at the 3' extended region, which was considered a hallmark of the Solanaceae family. Northern blot analysis showed differences in mRNA band patterns between CMS and restorer lines, indicating that atp6 gene is one of the candidates for CMS in pepper.

Amino Acid Sequence↗

PubMed1997

The cox1 gene from Euglena gracilis: a protist mitochondrial gene without introns and genetic code modifications.

We present the nucleotide sequence of the cox 1 gene encoding subunit 1 of cytochrome c oxidase in Euglena gracilis, the first report on a mitochondrial gene from this protist. Its study reveals that the Euglena mitochondrial genome does not appear as a compact and homogeneous structure and that its A+T content is high (about 76%) whereas this value is less than 50% in nuclear DNA. The Euglena cox1 gene does not exhibit any intron, and an amino-acid alignment of Euglena COX1 with homologous proteins shows that the universal genetic code is used. Comparisons of the genomic and cDNA sequences of Euglena cox1 indicate that the transcript does not undergo RNA editing as found in trypanosomes and in higher plants. The phylogeny obtained with COX1 protein sequences is in agreement with that obtained with nuclear rRNA sequences and places Euglena and Trypanosoma far apart from other eukaryotes. This result strengthens the hypothesis that these protists represent the earliest mitochondrion-containing organisms.

Amino Acid Sequence↗

PubMed1997

The rapeseed mitochondrial gene for subunit 2 of the NADH dehydrogenase complex: a trans-spliced structure is conserved in one of the smallest plant mitochondrial genomes.

The single-copy gene encoding NADH dehydrogenase subunit 2 (nad2) has been identified in the mitochondrial genome of rapeseed (Brassica napus L.). The rapeseed nad2 gene has the same gene organization in Oenothera and wheat: it consists of five exons located in two loci encoding the two first exons and the last three exons respectively. All exons are separated by group-II introns. A trans-splicing event is required to join exons B and C. Putative splicing intermediates were identified by transcriptional analysis of the nad2 gene. The complexity of organization of the nad2 gene is completely conserved even in one of the smallest mitochondrial genomes of higher plants.

Amino Acid Sequence↗

PubMed1999

Photoperiod-sensitive cytoplasmic male sterility in wheat: nuclear-mitochondrial incompatibility results in differential processing of the mitochondrial orf25 gene.

An alloplasmic wheat line with the cytoplasm of Aegilops crassa expresses photoperiod-sensitive cytoplasmic male sterility (PCMS). Southern- and Northern-hybridization analyses showed that this line contains alterations in both the gene structure and transcription patterns of the mitochondrial gene orf25. In this study, the nucleotide sequence around the orf25 gene of Ae. crassa (CR-orf25) and common wheat (AE-orf25) was determined, and we found that the upstream region of CR-orf25 had been replaced by that of rps7 of common wheat (AE-rps7) through recombination. A novel open reading frame (orf48) is present upstream of CR-orf25. In these three genes, transcription was initiated from the consensus promoter motif of plant mitochondrial genes located in the upstream regions. Processing enzymes in Ae. crassa and common wheat cleave the respective precursor mRNAs, namely CR-orf25 and AE-rps7, at sites similar to that of the premature mitochondrial 26S rRNA. In contrast, the precursor mRNA is not effectively processed at the target sequence of CR-orf25 in the alloplasmic wheat line. Because major transcripts of the euplasmic CR-orf25 and AE-rps7 genes would result in a truncated orf48 product, one possibility is that the orf48 protein might disturb mitochondrial function at a specific stage and hence affect the expression of the PCMS trait.

Amino Acid Sequence↗

PubMed2002

Loss of the mitochondrial cox2 intron 1 in a family of monocotyledonous plants and utilization of mitochondrial intron sequences for the construction of a nuclear intron.

The intron content of plant organellar genes is a useful marker in molecular systematics and evolution. We have tested representatives of a wide range of monocotyledonous plant families for the presence of an intron (cox2 intron 1) in one of the most conservative mitochondrial genes, the cox2 locus. Almost all species analyzed were found to harbor a group II intron at a phylogenetically conserved position. The only exceptions were members of a single monocot family, the Ruscaceae: representatives of all genera in this family were found to lack cox2 intron 1, but instead harbor an intron in the 3' portion of the cox2 coding region (cox2 intron 2). The presence of cox2 intron 1 in families of monocotyledonous plants that are closely related to the Ruscaceae suggests that loss of the intron is specific to this family and may have accompanied the evolutionary appearance of the Ruscaceae. Interestingly, sequences that are highly homologous to cox2 intron 2 are found in a nuclear intron in a lineage of monocotyledonous plants, suggesting that the originally mitochondrial group II intron sequence was transferred to the nuclear genome and reused there to build a spliceosomal intron.

Amino Acid Sequence↗

PubMed2001

Mosses share mitochondrial group II introns with flowering plants, not with liverworts.

Extant bryophytes are regarded as the closest living relatives of the first land plants, but relationships among the bryophyte classes (mosses, liverworts and hornworts) and between them and other embryophytes have remained unclear. We have recently found that plant mitochondrial genes with positionally stable introns are well suited for addressing questions of plant phylogeny at a deep level. To explore further data sets we have chosen to investigate the mitochondrial genes nad4 and nad7, which are particularly rich in intron sequences. Surprisingly, we find that in these genes mosses share three group II introns with flowering plants, but none with the liverwort Marchantia polymorpha or other liverworts investigated here. In mitochondria of Marchantia, nad7 is a pseudogene containing stop codons, but nad7 appears as a functional mitochondrial gene in mosses, including the isolated genus Takakia. We observe the necessity for strikingly frequent C-to-U RNA editing to reconstitute conserved codons in Takakia when compared to other mosses. The findings underline the great evolutionary distances among the bryophytes as the presumptive oldest division of land plants. A scenario involving differential intron gains from fungal sources in what are perhaps the two earliest diverging land plant lineages, liverworts and other embryophytes, is discussed. With their positionally stable introns, nad4 and nad7 represent novel marker genes that may permit a detailed phylogenetic resolution of early clades of land plants.

Amino Acid Sequence↗