Statistical Modelling and Phylogenetic Analysis of a Deaminase Domain

Mian, I. Saira; Moser, Michael J.; Holley, W.R.; Chatterjee, A.

doi:10.1089/cmb.1998.5.57

Cited by 24 publications

(21 citation statements)

References 66 publications

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“…The subdomain structure ␣2␤3␣3 (Fig. 1B) and signature sequence have been dubbed a zinc-dependent deaminase motif characteristic of C-to-U deaminases of pyrimidine metabolism, as well as C-to-U and A-to-I RNA-editing enzymes (21,34). Key structural differences exist between CDA and ScCD structures that affect substrate specificity.…”

Section: Resultsmentioning

confidence: 99%

The structure of a yeast RNA-editing deaminase provides insight into the fold and function of activation-induced deaminase and APOBEC-1

Xie

Sowden

Dance

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Activation-induced deaminase (AID) uses base deamination for class-switch recombination and somatic hypermutation and is related to the mammalian RNA-editing enzyme apolipoprotein B editing catalytic subunit 1 (APOBEC-1). CDD1 is a yeast ortholog of APOBEC-1 that exhibits cytidine deaminase and RNA-editing activity. Here, we present the crystal structure of CDD1 at 2.0-Å resolution and its use in comparative modeling of APOBEC-1 and AID. The models explain dimerization and the need for trans-acting loops that contribute to active site formation. Substrate selectivity appears to be regulated by a central active site ''flap'' whose size and flexibility accommodate large substrates in contrast to deaminases of pyrimidine metabolism that bind only small nucleosides or free bases. Most importantly, the results suggested both AID and APOBEC-1 are equally likely to bind single-stranded DNA or RNA, which has implications for the identification of natural AID targets.A ntibody diversity is generated during B cell development through class-switch recombination (CSR) and somatic hypermutation (SHM) (1), and in many vertebrates by gene conversion (2). Expression of activation-induced deaminase (AID) is critical for all three processes (3-5) and ectopic AID expression was sufficient to activate SHM in B cell lines, hybridomas, and fibroblasts (6-9), gene conversion in B cells (4, 5), as well as CSR in fibroblast cell lines (10). Mutations in the AID protein have been detected in humans with hyper-IgM type 2 syndrome (11). Expression of AID in Escherichia coli caused deoxycytidine-todeoxyuridine deamination in actively transcribed host genes that was enhanced in strains deficient in the deoxyuridine repair enzyme DNA uracil N-glycosylase (12). DNA uracil N-glycosylase deficiency in mammals resulted in altered patterns of CSR and SHM (13,14). In vitro studies revealed that AID catalyzed deamination on single-stranded DNA at WRCY hot spots, but not on doublestranded DNA, RNA-DNA hybrids, or single-stranded RNA (15,16). Cytidine deamination on single-stranded DNA within transcription bubbles (17, 18) and the observation that transcription rates influenced SHM activity (17)(18)(19) suggested that the biological substrate for AID is DNA.In contrast, the homology of AID to the mRNA-editing enzyme APOBEC-1 (3), suggested AID might edit RNA (3). This idea was intriguing because edited mRNAs either encode novel proteins or lose the ability to express proteins (20,21). Consistent with expression of a novel protein from edited mRNA, de novo protein synthesis was required for CSR subsequent to AID activation (22).APOBEC-1 and AID have proven difficult to purify at levels sufficient for structural studies. CDD1 from Saccharomyces cerevisiae (ScCDD1) can be purified readily, which is relevant due to its orthology with APOBEC-1 at the level of both cytidine deaminase (CDA) sequence similarity (27%) and mRNA-editing activity on apolipoprotein B (apoB) substrates (23). We determined the crystal structure of ScCDD1 to 2.0 Å resolution, which ...

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Section: Resultsmentioning

confidence: 99%

The structure of a yeast RNA-editing deaminase provides insight into the fold and function of activation-induced deaminase and APOBEC-1

Xie

Sowden

Dance

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…C-to-U editing is mediated by a minimal complex composed of apoB-editing catalytic subunit 1 (APOBEC1) and a complementing specificity factor (Chester et al 2003). The APOBEC1 subunit contains a zinc-dependent deaminase domain, which is conserved among cytidine deaminases (Mian et al 1998) and is essential for cytidine deamination. A gene, GL30624, encodes a deoxycytidylate deaminase containing an APOBEC domain, suggesting that this gene may function in RNA editing in G. lucidum.…”

Section: Discussionmentioning

confidence: 99%

Abundant and Selective RNA-Editing Events in the Medicinal Mushroom Ganoderma lucidum

et al. 2014

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RNA editing is a widespread, post-transcriptional molecular phenomenon that diversifies hereditary information across various organisms. However, little is known about genome-scale RNA editing in fungi. In this study, we screened for fungal RNA editing sites at the genomic level in Ganoderma lucidum, a valuable medicinal fungus. On the basis of our pipeline that predicted the editing sites from genomic and transcriptomic data, a total of 8906 possible RNA-editing sites were identified within the G. lucidum genome, including the exon and intron sequences and the 59-/39-untranslated regions of 2991 genes and the intergenic regions. The major editing types included C-to-U, A-to-G, G-to-A, and U-to-C conversions. Four putative RNA-editing enzymes were identified, including three adenosine deaminases acting on transfer RNA and a deoxycytidylate deaminase. The genes containing RNA-editing sites were functionally classified by the Kyoto Encyclopedia of Genes and Genomes enrichment and gene ontology analysis. The key functional groupings enriched for RNA-editing sites included laccase genes involved in lignin degradation, key enzymes involved in triterpenoid biosynthesis, and transcription factors. A total of 97 putative editing sites were randomly selected and validated by using PCR and Sanger sequencing. We presented an accurate and large-scale identification of RNA-editing events in G. lucidum, providing global and quantitative cataloging of RNA editing in the fungal genome. This study will shed light on the role of transcriptional plasticity in the growth and development of G. lucidum, as well as its adaptation to the environment and the regulation of valuable secondary metabolite pathways. RNA editing is a post-transcriptional process that can enhance the diversity of gene products by altering RNA sequences. This can involve site-specific nucleotide modifications, nucleotide insertions/deletions, and nucleotide substitutions (Gott and Emeson 2000;Bass 2002;Farajollahi and Maas 2010). RNA editing can affect messenger RNAs (mRNAs), transfer RNAs (tRNAs), ribosomal RNAs, and small regulatory RNAs present in all cellular compartments and has been described in a wide range of organisms from viruses to fungi, mammals, and plants ( Gott and Emeson 2000;Gott 2003;Kawahara et al. 2007). The prevalent RNA-editing pathways in higher eukaryotes involves the deamination of cytidine (C) to create uridine (U) and deamination of adenosine (A) to create inosine (I) (Bass 2002;Gott 2003). The editing process generally involves a specificity factor (RNA or protein) that recognizes the editing site, as well as an enzyme, occasionally with other accessory factors, that catalyzes the reaction (Bass 2002). The functions of RNA editing include regulation of gene expression, increasing protein diversity and reversion of the effect of mutations in the genome (Gott and Emeson 2000;Gott 2003). In many cases, RNA editing is essential for correcting protein production (Young 1990) or for modulating the functional properties of proteins...

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“…Recent studies on mammalian CDDs have revealed the existence of a family of related proteins [6], and in the C. elegans genome there is at least one other predicted protein that could potentially compensate for any phenotype obtained by RNAi with Ce-cdd-1 and -2. This gene, Ce-cdd-3, is located on chromosome II (cosmid position C29F5.3), and was detected initially by scanning ACeDB with a PROSITE CDD signature motif [13]. In addition, there are three other predicted proteins in Worm Pep that share the active site motif of CDDs and deoxycytidylate deaminases.…”

Section: Discussionmentioning

confidence: 99%

“…Because genes that are triggered by the transition from vector to mammal might have important roles in the establishment of the infection, Bp-cdd has been the focus of extensive characterization [11,12]. Although phylogenetic analysis grouped the Brugia CDD with the cytosine nucleoside deaminases of prokaryotes [11,13] that neither bind nor edit RNA, the temporal expression pattern of the Brugia molecule was not consistent with a role in the salvage pathway. In addition, the recombinant Brugia CDD was shown to possess RNA-binding activity with an affinity for AU-rich RNA templates [11], in contrast with the Escherichia coli and Bacillus subtilis molecules, which fail to bind RNA.…”

Section: Introductionmentioning

confidence: 99%

Biochemical and molecular characterization of two cytidine deaminases in the nematode Caenorhabditis elegans

Thompson

Britton

Wheatley

et al. 2002

Biochemical Journal

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Two cytidine deaminases (CDDs) from the free-living nematode Caenorhabditis elegans have been cloned and characterized. Both Ce-CDD-1 and Ce-CDD-2 are authentic deaminases and both exhibit RNA-binding activity towards AU-rich templates. In order to study their temporal and spatial expression patterns in the worm, reporter gene constructs were made using approx. 2kb of upstream sequence. Transfection of C. elegans revealed that both genes localized to the cells of the intestine, although their temporal expression patterns were different. Expression of Ce-cdd-1 peaked in the early larval stages, whereas Ce-cdd-2 was expressed in all life cycle stages examined. RNA-interference (RNAi) assays were performed for both genes, either alone or in combination, but only cdd-2 RNAi produced a consistent visible phenotype. A proportion of eggs laid from these worms were swollen and distorted in shape.

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Statistical Modelling and Phylogenetic Analysis of a Deaminase Domain

Cited by 24 publications

References 66 publications

The structure of a yeast RNA-editing deaminase provides insight into the fold and function of activation-induced deaminase and APOBEC-1

The structure of a yeast RNA-editing deaminase provides insight into the fold and function of activation-induced deaminase and APOBEC-1

Abundant and Selective RNA-Editing Events in the Medicinal Mushroom Ganoderma lucidum

Biochemical and molecular characterization of two cytidine deaminases in the nematode Caenorhabditis elegans

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