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Query: UNIPROT:P06889 (Mol)
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Trypanosomatids are causative agents of several devastating tropical diseases such as African sleeping sickness, Chagas' disease and leishmaniasis. There are no effective vaccines available to date for treatment of these protozoan diseases, while current drugs have limited efficacy, significant toxicity and suffer from increasing resistance. Trypanosomatids have several remarkable and unique metabolic and structural features that are of great interest for developing new anti-protozoan therapeutics. One such feature is "RNA editing", an essential process in these pathogenic protozoa. Transcripts for key trypanosomatid mitochondrial proteins undergo extensive post-transcriptional RNA editing by specifically inserting or deleting uridylates from pre-mature mRNA in order to create mature mRNAs that encode functional proteins. The RNA editing process is carried out in a approximately 1.6 MDa multi-protein complex, the editosome. In Trypanosoma brucei, one of the editosome's core enzymes, the RNA editing ligase 1 (TbREL1), has been shown to be essential for survival of both insect and bloodstream forms of the parasite. We report here the crystal structure of the catalytic domain of TbREL1 at 1.2 A resolution, in complex with ATP and magnesium. The magnesium ion interacts with the beta and gamma-phosphate groups and is almost perfectly octahedrally coordinated by six phosphate and water oxygen atoms. ATP makes extensive direct and indirect interactions with the ligase via essentially all its atoms while extending its base into a deep pocket. In addition, the ATP makes numerous interactions with residues that are conserved in the editing ligases only. Further away from the active site, TbREL1 contains a unique loop containing several hydrophobic residues that are highly conserved among trypanosomatid RNA editing ligases which may play a role in protein-protein interactions in the editosome. The distinct characteristics of the adenine-binding pocket, and the absence of any close homolog in the human genome, bode well for the design of selective inhibitors that will block the essential RNA ligase function in a number of major protozoan pathogens.
J Mol Biol 2004 Oct 22
PMID:High resolution crystal structure of a key editosome enzyme from Trypanosoma brucei: RNA editing ligase 1. 1546 48

T4 RNA ligase 2 (Rnl2) exemplifies a family of RNA-joining enzymes that includes protozoan RNA-editing ligases. Rnl2 efficiently seals 3'-OH/5'-PO4 RNA nicks in either a duplex RNA or an RNA:DNA hybrid but cannot seal DNA nicks. RNA specificity arises from a requirement for at least two ribonucleotides immediately flanking the 3'-OH of the nick; the rest of the nicked duplex can be replaced by DNA. The terminal 2'-OH at the nick is important for the attack of the 3'-OH on the 5'-adenylated strand to form a phosphodiester, but dispensable for nick recognition and adenylylation of the 5'-PO4 strand. The penultimate 2'-OH is important for nick recognition. Stable binding of Rnl2 at a nick depends on contacts to both the N-terminal adenylyltransferase domain and its signature C-terminal domain. Nick sensing also requires adenylylation of Rnl2. These results provide insights to the evolution of nucleic acid repair systems.
Mol Cell 2004 Oct 22
PMID:How an RNA ligase discriminates RNA versus DNA damage. 1549 8

2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNP), a member of the 2H phosphoesterase superfamily, is firmly bound to brain white matter and found mainly in the central nervous system of vertebrates, and it catalyzes the hydrolysis of 2',3'-cyclic nucleotide to produce 2'-nucleotide. Recent studies on CNP-knockout mice have revealed that the absence of CNP causes axonal swelling and neuronal degeneration. Here, the crystal structure of the catalytic fragment (CF) of human CNP (hCNP-CF) is solved at 1.8A resolution. It is an alpha+beta type structure consisting of three alpha-helices and nine beta-strands. The structural core of the molecule is comprised of two topologically equivalent three-stranded antiparallel beta-sheets that are related by a pseudo 2-fold symmetry. Each beta-sheet contains an H-X-T-X motif, which is strictly conserved among members of the 2H phosphoesterase superfamily. The phosphate ion is bound to the side-chains of His and Thr from each of the two motifs. Structural comparison of hCNP-CF with plant 1'',2''-cyclic nucleotide phosphodiesterase (CPDase) and bacterial 2'-5' RNA ligase reveals that the H-X-T-X motifs are structurally conserved among these enzymes, but the surface properties of the active site are quite different among the enzymes, reflecting the differences in their substrates. On the basis of the present crystal structure of the hCNP-CF/phosphate complex, the available structure of the CPDase/cyclic-nucleotide analogue complex, and the recent functional studies of rat CNP-CF, we propose a possible substrate-binding mode and catalytic mechanism of CNP, which employs the nucleophilic water molecule activated by His310. The proposed mechanism is basically equivalent to the second step of the well-accepted reaction mechanism of RNase A. Since the overall structure of hCNP-CF differs considerably from that of RNase A, it is likely that the similar active sites with two catalytic histidine residues in these enzymes arose through convergent evolution.
J Mol Biol 2005 Feb 25
PMID:Crystal structure of the catalytic fragment of human brain 2',3'-cyclic-nucleotide 3'-phosphodiesterase. 1571 63

Ants and other social insects forming large societies are generally characterized by marked reproductive division of labour. Queens largely monopolize reproduction whereas workers have little reproductive potential. In addition, some social insect species show tremendous lifespan differences between the queen and worker caste. Remarkably, queens and workers are usually genotypically identical, meaning that any phenotypic differences between the two castes arise from caste-specific gene expression. Using a combination of differential display, microarrays and reverse Northern blots, we found 16 genes that were differentially expressed between adult queens and workers in the ant Lasius niger, a species with highly pronounced reproductive division of labour and a several-fold lifespan difference between queens and workers. RNA ligase mediated rapid amplification of cDNA ends (RLM-RACE) and gene walking were used to further characterize these genes. On the basis of the molecular function of their nearest homologues, three genes appear to be involved in reproductive division of labour. Another three genes, which were exclusively overexpressed in queens, are possibly involved in the maintenance and repair of the soma, a candidate mechanism for lifespan determination. In-depth functional analyses of these genes are now needed to reveal their exact role.
Mol Ecol 2007 Feb
PMID:Differential gene expression between adult queens and workers in the ant Lasius niger. 1725 22

Mastitis is an inflammation of the mammary gland, most of the time caused by invading pathogens. Phagocytosis by neutrophils is a crucial defense of the mammary gland and the prompt recruitment of these phagocytes from blood to milk compartments is essential for the outcome of the infection. ELR+ CXC chemokines, ligands of the two interleukin-8 receptors (IL-8R), CXCR1 and CXCR2, are likely to be involved in the initiation of the inflammatory response and also in the migration of neutrophils. Recently, the polymorphism of bovine CXCR2 has been associated with resistance to mastitis. However, as the bovine IL-8R are not functionally defined, their contribution to the recruitment of neutrophils remains undetermined. In this study, the RNA ligase-mediated (RLM)-RACE method was used to clone a novel bovine interleukin-8 receptor (nIL-8R) of the bovine species. We showed that both bovine IL-8R (nIL-8R and the published CXCR2) are functional since bovine IL-8 induced migration of HEK-293 cells expressing either IL-8R. In addition, comparisons of full-length sequences suggested that the published CXCR2 sequence was improperly annotated and that the sequences of the nIL-8R and the published CXCR2 are homologous to human CXCR2 and CXCR1, respectively. This was confirmed by binding assays with labeled IL-8 and GRO-beta and calcium (Ca) flux responses of transfected cells. Moreover, the C-terminal of both bovine IL-8R showed 100% identity, whereas they differ in most other species, suggesting that the two bovine IL-8R initiate similar signal transduction. These results constitute a basis to improve our understanding of the molecular mechanisms implicated in the recruitment of bovine neutrophils.
Mol Immunol 2008 Feb
PMID:Identification and characterization of a new interleukin-8 receptor in bovine species. 1772 52

T4 RNA ligase, the product of the phage gene 63, is purified from phage-infected cells. It catalyzes the ATP-dependent covalent joining of single-stranded 5'-phosphoryl termini of DNA or RNA to single-stranded 3'-hydroxyl termini of DNA or RNA. This unit describes specific reaction conditions as well as applications such as radioactive labeling of 3' termini of RNA, circularizing deoxy- and ribo-oligonucleotides, ligating oligomers for oligonucleotide synthesis, and stimulating the blunt-end ligation activity of T4 DNA ligase.
Curr Protoc Mol Biol 2001 May
PMID:RNA ligases. 1826 24

Small RNAs that are derived from dsRNA precursors act as guide RNAs during sequence-specific epigenetic regulation of eukaryotic gene expression. These small regulatory RNAs are between 20 and 30 nucleotides in length, and fall into one or more of the following categories: small interfering RNAs (siRNAs), microRNAs (miRNAs), and heterochromatic siRNAs (hsiRNAs). Procedures to record the profile of small RNAs expressed in cultured cells or tissues are described. The small RNAs are directionally cloned after isolation from total RNA. The methods rely on T4 RNA ligase-based joining of adapter oligonucleotides to the 3' and 5' termini of the pool of small RNAs. The ligation products are reverse transcribed and PCR-amplified. It is recommended to directionally concatamerize the relatively short PCR products before cloning in order to increase the number of RNA sequences obtained per clone.
Curr Protoc Mol Biol 2005 Nov
PMID:Cloning of small RNA molecules. 1826 64

Transcription of the tricarboxylic acid cycle genes of Corynebacterium glutamicum was investigated. Northern hybridizations revealed that gltA-fkb, odhA-orfA, sucC-sucD, sdhC-sdhA-sdhB-orfB and mdh-orfC were transcribed as polycistronic mRNAs of size 1.9, 4.5, 2.5, 4.0 and 1.7 kb, respectively. The acn-acnR-gat gene cluster was transcribed as a mono-, bi- or tricistronic mRNA, depending on the carbon source. The 2.9-kb (acn) and 1.5-kb (acnR-gat) mRNAs, which were regulated by different promoters upstream of acn and acnR, were inversely expressed in acetate and glucose. The 4.5 kb (acn-acnR-gat) mRNA was constitutively expressed. The sizes of the mRNAs were 2.3, 2.1, 1.5, 1.3, 1.7, 1.5 and 2.9 kb for icd, sucB, fum, mdhB, mqo, aceA and aceB, respectively, indicating monocistronic transcription of these genes. RNA ligase-mediated rapid amplification of cDNA ends analysis of C. glutamicum RNA showed that the transcriptional start sites of gltA, acn, icd, odhA, sucB, sucC, sdhC, fum, mdh, mdhB, mqo, aceA and aceB were located 121, 107, 31, 99, 46, 83, 15, 25, 33, 23, 70, 111 and 183 bp upstream from the first nucleotide of the respective translation initiation codons. Alignment of these gene promoter regions provided evidence for highly conserved sequences that exhibited similarity to the sigma(A) consensus promoter sequences of Gram-positive bacteria.
J Mol Microbiol Biotechnol 2008
PMID:Transcription of Corynebacterium glutamicum genes involved in tricarboxylic acid cycle and glyoxylate cycle. 1828 91

The entire cDNA sequence of the growth hormone receptor (GHR) of the Chilean flounder (Paralichthys. adspersus) was cloned by RT-PCR and RNA ligase rapid amplification of 5' and 3'ends. The deduced amino acid sequence contains 641 residues and codes for the GHR1 form. The receptor includes all the structural domains and motifs responsible for its interaction with the growth hormone and growth signal transduction. Sequence comparison revealed 95 and 88% identity with other flat fish such as the Japanese flounder and Atlantic halibut respectively, but decreased to 41% with the GHR of other teleosts such as salmon. In addition we performed a phylogenetic analysis of this receptor in teleosts. RT-PCR experiments were performed to study the expression of GHR1 mRNA in different tissues of juvenile fish, detecting the transcripts in all tissues investigated with higher expressions in the liver, brain and gonads. Additionally, using whole-mount in situ hybridization in larvae stages, we observed an on and off GHR1 mRNA expression pattern. This novel finding evidences that during early development of a teleost, GHR1 is transiently expressed in somites, a source of muscle, bone and spinal chord precursors cells, suggesting a relevant role of GH in fish development. GHR1 was also temporally detected in the notochord, intestines, brain and retinal layers, before its ubiquitous establishment.
Comp Biochem Physiol B Biochem Mol Biol 2008 May
PMID:Dynamic expression pattern of the growth hormone receptor during early development of the Chilean flounder. 1831 61

Viroids, as a consequence of not encoding any protein, are extremely dependent on their hosts. Replication of these minimal genomes, composed exclusively by a circular RNA of 246-401 nt, occurs in the nucleus (family Pospiviroidae) or in the chloroplast (family Avsunviroidae) by an RNA-based rolling-circle mechanism with three steps: (1) synthesis of longer-than-unit strands catalyzed by host DNA-dependent RNA polymerases recruited and redirected to transcribe RNA templates, (2) cleavage to unit-length, which in family Avsunviroidae is mediated by hammerhead ribozymes, and (3) circularization through an RNA ligase or autocatalytically. This consistent but still fragmentary picture has emerged from a combination of studies with in vitro systems (analysis of RNA preparations from infected plants, transcription assays with nuclear and chloroplastic fractions, characterization of enzymes and ribozymes mediating cleavage and ligation of viroid strands, dissection of 5' terminal groups of viroid strands, and in situ hybridization and microscopy of subcellular fractions and tissues), and in vivo systems (tissue infiltration studies, protoplasts, studies in planta and use of transgenic plants expressing viroid RNAs).
Methods Mol Biol 2008
PMID:Analysis of viroid replication. 1837 Feb 55


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