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PubMed2003

Crystal structure of the conserved protein TT1542 from Thermus thermophilus HB8.

The TT1542 protein from Thermus thermophilus HB8 is annotated as a conserved hypothetical protein, and belongs to the DUF158 family in the Pfam database. A BLAST search revealed that homologs of TT1542 are present in a wide range of organisms. The TT1542 homologs in eukaryotes, PIG-L in mammals, and GPI12 in yeast and protozoa, have N-acetylglucosaminylphosphatidylinositol (GlcNAc-PI) de-N-acetylase activity. Although most of the homologs in prokaryotes are hypothetical and have no known function, Rv1082 and Rv1170 from Mycobacterium tuberculosis are enzymes involved in the mycothiol detoxification pathway. Here we report the crystal structure of the TT1542 protein at 2.0 A resolution, which represents the first structure for this superfamily of proteins. The structure of the TT1542 monomer consists of a twisted beta-sheet composed of six parallel beta-strands and one antiparallel beta-strand (with the strand order 3-2-1-4-5-7-6) sandwiched between six alpha-helices. The N-terminal five beta-strands and four alpha-helices form an incomplete Rossmann fold-like structure. The structure shares some similarity to the sugar-processing enzymes with Rossmann fold-like domains, especially those of the GPGTF (glycogen phosphorylase/glycosyl transferase) superfamily, and also to the NAD(P)-binding Rossmann fold domains. TT1542 is a homohexamer in the crystal and in solution, the six monomers forming a cylindrical structure. Putative active sites are suggested by the structure and conserved amino acid residues.

Amino Acid Sequence↗
PubMed2005

Evolution of distinct EGF domains with specific functions.

EGF domains are extracellular protein modules cross-linked by three intradomain disulfides. Past studies suggest the existence of two types of EGF domain with three-disulfides, human EGF-like (hEGF) domains and complement C1r-like (cEGF) domains, but to date no functional information has been related to the two different types, and they are not differentiated in sequence or structure databases. We have developed new sequence patterns based on the different C-termini to search specifically for the two types of EGF domains in sequence databases. The exhibited sensitivity and specificity of the new pattern-based method represents a significant advancement over the currently available sequence detection techniques. We re-annotated EGF sequences in the latest release of Swiss-Prot looking for functional relationships that might correlate with EGF type. We show that important post-translational modifications of three-disulfide EGFs, including unusual forms of glycosylation and post-translational proteolytic processing, are dependent on EGF subtype. For example, EGF domains that are shed from the cell surface and mediate intercellular signaling are all hEGFs, as are all human EGF receptor family ligands. Additional experimental data suggest that functional specialization has accompanied subtype divergence. Based on our structural analysis of EGF domains with three-disulfide bonds and comparison to laminin and integrin-like EGF domains with an additional inter-domain disulfide, we propose that these hEGF and cEGF domains may have arisen from a four-disulfide ancestor by selective loss of different cysteine residues.

Amino Acid Sequence↗
PubMed2006

Analysis of Pseudomonas aeruginosa diguanylate cyclases and phosphodiesterases reveals a role for bis-(3'-5')-cyclic-GMP in virulence.

The opportunistic pathogen Pseudomonas aeruginosa is responsible for systemic infections in immunocompromised individuals and chronic respiratory disease in patients with cystic fibrosis. Cyclic nucleotides are known to play a variety of roles in the regulation of virulence-related factors in pathogenic bacteria. A set of P. aeruginosa genes, encoding proteins that contain putative domains characteristic of diguanylate cyclases (DGCs) and phosphodiesterases (PDEs) that are responsible for the maintenance of cellular levels of the second messenger bis-(3'-5')-cyclic dimeric GMP (c-di-GMP) was identified in the annotated genomes of P. aeruginosa strains PAO1 and PA14. Although the majority of these genes are components of the P. aeruginosa core genome, several are located on presumptive horizontally acquired genomic islands. A comprehensive analysis of P. aeruginosa genes encoding the enzymes of c-di-GMP metabolism (DGC- and PDE-encoding genes) was carried out to analyze the function of c-di-GMP in two disease-related phenomena, cytotoxicity and biofilm formation. Analysis of the phenotypes of DGC and PDE mutants and overexpressing clones revealed that certain virulence-associated traits are controlled by multiple DGCs and PDEs through alterations in c-di-GMP levels. A set of mutants in selected DGC- and PDE-encoding genes exhibited attenuated virulence in a mouse infection model. Given that insertions in different DGC and PDE genes result in distinct phenotypes, it seems likely that the formation or degradation of c-di-GMP by these enzymes is in highly localized and intimately linked to particular targets of c-di-GMP action.

Bacterial Proteins↗
PubMed2006

Identification and evolutionary analysis of novel exons and alternative splicing events using cross-species EST-to-genome comparisons in human, mouse and rat.

BACKGROUND: Alternative splicing (AS) is important for evolution and major biological functions in complex organisms. However, the extent of AS in mammals other than human and mouse is largely unknown, making it difficult to study AS evolution in mammals and its biomedical implications. RESULTS: Here we describe a cross-species EST-to-genome comparison algorithm (ENACE) that can identify novel exons for EST-scanty species and distinguish conserved and lineage-specific exons. The identified exons represent not only novel exons but also evolutionarily meaningful AS events that are not previously annotated. A genome-wide AS analysis in human, mouse and rat using ENACE reveals a total of 758 novel cassette-on exons and 167 novel retained introns that have no EST evidence from the same species. RT-PCR-sequencing experiments validated approximately 50 approximately 80% of the tested exons, indicating high presence of exons predicted by ENACE. ENACE is particularly powerful when applied to closely related species. In addition, our analysis shows that the ENACE-identified AS exons tend not to pass the nonsynonymous-to-synonymous substitution ratio test and not to contain protein domain, implying that such exons may be under positive selection or relaxed negative selection. These AS exons may contribute to considerable inter-species functional divergence. Our analysis further indicates that a large number of exons may have been gained or lost during mammalian evolution. Moreover, a functional analysis shows that inter-species divergence of AS events may be substantial in protein carriers and receptor proteins in mammals. These exons may be of interest to studies of AS evolution. The ENACE programs and sequences of the ENACE-identified AS events are available for download. CONCLUSION: ENACE can identify potential novel cassette exons and retained introns between closely related species using a comparative approach. It can also provide information regarding lineage- or species-specificity in transcript isoforms, which are important for evolutionary and functional studies.

Algorithms↗
PubMed2002

Annotated expressed sequence tags and cDNA microarrays for studies of brain and behavior in the honey bee.

To accelerate the molecular analysis of behavior in the honey bee (Apis mellifera), we created expressed sequence tag (EST) and cDNA microarray resources for the bee brain. Over 20,000 cDNA clones were partially sequenced from a normalized (and subsequently subtracted) library generated from adult A. mellifera brains. These sequences were processed to identify 15,311 high-quality ESTs representing 8912 putative transcripts. Putative transcripts were functionally annotated (using the Gene Ontology classification system) based on matching gene sequences in Drosophila melanogaster. The brain ESTs represent a broad range of molecular functions and biological processes, with neurobiological classifications particularly well represented. Roughly half of Drosophila genes currently implicated in synaptic transmission and/or behavior are represented in the Apis EST set. Of Apis sequences with open reading frames of at least 450 bp, 24% are highly diverged with no matches to known protein sequences. Additionally, over 100 Apis transcript sequences conserved with other organisms appear to have been lost from the Drosophila genome. DNA microarrays were fabricated with over 7000 EST cDNA clones putatively representing different transcripts. Using probe derived from single bee brain mRNA, microarrays detected gene expression for 90% of Apis cDNAs two standard deviations greater than exogenous control cDNAs. [The sequence data described in this paper have been submitted to Genbank data library under accession nos. BI502708-BI517278. The sequences are also available at http://titan.biotec.uiuc.edu/bee/honeybee_project.htm.]

Animals↗
PubMed2006

AGRIS and AtRegNet. a platform to link cis-regulatory elements and transcription factors into regulatory networks.

Gene regulatory pathways converge at the level of transcription, where interactions among regulatory genes and between regulators and target genes result in the establishment of spatiotemporal patterns of gene expression. The growing identification of direct target genes for key transcription factors (TFs) through traditional and high-throughput experimental approaches has facilitated the elucidation of regulatory networks at the genome level. To integrate this information into a Web-based knowledgebase, we have developed the Arabidopsis Gene Regulatory Information Server (AGRIS). AGRIS, which contains all Arabidopsis (Arabidopsis thaliana) promoter sequences, TFs, and their target genes and functions, provides the scientific community with a platform to establish regulatory networks. AGRIS currently houses three linked databases: AtcisDB (Arabidopsis thaliana cis-regulatory database), AtTFDB (Arabidopsis thaliana transcription factor database), and AtRegNet (Arabidopsis thaliana regulatory network). AtTFDB contains 1,690 Arabidopsis TFs and their sequences (protein and DNA) grouped into 50 (October 2005) families with information on available mutants in the corresponding genes. AtcisDB consists of 25,806 (September 2005) promoter sequences of annotated Arabidopsis genes with a description of putative cis-regulatory elements. AtRegNet links, in direct interactions, several hundred genes with the TFs that control their expression. The current release of AtRegNet contains a total of 187 (September 2005) direct targets for 66 TFs. AGRIS can be accessed at http://Arabidopsis.med.ohio-state.edu.

Arabidopsis↗
PubMed2025

Origin and Evolution of Bacterial Periplasmic Force Transducers.

In double-membraned bacteria, non-equilibrium processes that occur at the outer membrane are typically coupled to the chemiosmotically energized inner membrane. TolA and TonB are homologous proteins which energetically couple inner membrane motor proteins to the essential processes of outer membrane stabilization and substrate import, respectively. The evolutionary trajectories of these proteins have been difficult to elucidate due to low-sequence conservation, yet they are thought to transduce force similarly. Here, this problem was addressed using structural prediction approaches to identify and annotate force transduction operons to trace their distribution and evolutionary origins. In the process, we identify a novel outer membrane-tethering system and a previously unknown family of monomeric force transducers. This approach revealed putative tolA genes, and thus the core organizational principles of the tol-pal operon throughout diverse bacterial taxa. We discovered that the α-helical structure of the periplasm-spanning domain II of TolA previously thought its hallmark, is anomalous amongst most Tol-Pal systems. This structure is mainly prevalent in γ-proteobacteria, likely in adaptation to their lifestyle. Comparison of Tol-Pal and Ton system distribution suggests that TolA emerged from a TonB paralogue and co-emerged with Pal, the outer membrane-tethering lipoprotein that functionalizes the Tol-Pal system. We also determined that TolB, the Pal-mobilizing protein, likely emerged from a family of outer membrane proteins; and CpoB, a periplasmic factor that coordinates peptidoglycan remodeling with cell division, was originally a lipoprotein present in the ancestral Tol-Pal system. The extensive conservation of the Tol-Pal system throughout Gracilicutes highlights its significance in bacterial cell biology.

Evolution, Molecular↗
PubMed2006

Complex functionality of gene groups identified from high-throughput data.

Relating experimental data to biological knowledge is necessary to cope with the avalanches of new data emerging from recent developments in high-throughput technologies. Automatic functional profiling becomes the de facto standard approach for the secondary analysis of high-throughput data. A number of tools employing available gene functional annotations have been developed for this purpose. However, current annotations are derived mostly from traditional analysis of the individual gene function. The complex biological phenomena carried out by the concerted activity of many genes often requires the definition of new complex functionality (related to a group of genes), which is, in many cases, not available in current annotation vocabularies. Functional profiling with annotation terms related to the description of individual biological functions of a gene may fail to provide reasonable interpretation of biological relationships in a set of genes involved in complex biological phenomena. We introduce a novel procedure to profile a complex functionality of a gene set. Complex functionality is constructed as a combination of available annotation terms. By profiling ChIP-chip data from Saccharomyces cerevisiae we demonstrate that this technique produces deeper insights into the results of high-throughput experiments that are beyond the known facts described in the functional classifications.

Animals↗
PubMed2003

Identification of stop codon readthrough genes in Saccharomyces cerevisiae.

We specifically sought genes within the yeast genome controlled by a non-conventional translation mechanism involving the stop codon. For this reason, we designed a computer program using the yeast database genomic regions, and seeking two adjacent open reading frames separated only by a unique stop codon (called SORFs). Among the 58 SORFs identified, eight displayed a stop codon bypass level ranging from 3 to 25%. For each of the eight sequences, we demonstrated the presence of a poly(A) mRNA. Using isogenic [PSI(+)] and [psi(-)] yeast strains, we showed that for two of the sequences the mechanism used is a bona fide readthrough. However, the six remaining sequences were not sensitive to the PSI state, indicating either a translation termination process independent of eRF3 or a new stop codon bypass mechanism. Our results demonstrate that the presence of a stop codon in a large ORF may not always correspond to a sequencing error, or a pseudogene, but can be a recoding signal in a functional gene. This emphasizes that genome annotation should take into account the fact that recoding signals could be more frequently used than previously expected.

Base Sequence↗
PubMed2026

Evidence for the prognostic value of TP53 mutations in circulating tumor DNA across solid malignancies: a systematic review and meta-analysis.

BACKGROUND: The purpose of this meta-analysis study is to provide evidence for the clinical utility of TP53 mutations in circulating tumor DNA (ctDNA) as a prognostic biomarker. METHODS: We searched the PubMed, Embase, Cochrane, and Web of Science databases (last update May 2025) for studies on TP53 mutations in ctDNA or cfDNA as prognosis overall survival and in solid tumors. A total of 21 studies that met the criteria were utilized and data was collected regarding the authors, year of publication, study design, site of the study, number of patients, detection, mutation sample size and outcome measures were collected. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the study, and meta-analysis was done by using STATA 16.0. Effect sizes were in the form of hazard ratios (HR) that had 95% confidence intervals (CI). The models used were fixed-effects and random-effects based on heterogeneity. Funnel plots, and Egger's test was used to measure publication bias, and sensitivity analysis conducted through a leave-one-out method. RESULTS: A total of 21 studies (2,685 TP53-mutated patients, one unreported) showed: Mutated patients had worse progression-free survival (PFS) (HR=2.10, p=0.000; 12 studies, heterogeneity resolved after excluding Yoshida 2023), shorter OS (HR=1.74, p=0.014; 9 studies), and reduced DFS (HR=1.73, p=0.007; 3 studies), but RFS (2 items) showed no statistically significant differences. Subgroup analyses revealed: Prospective studies showed stronger PFS (HR=2.14 vs retrospective 1.90) with Japanese subgroup HR=4.90; Lung/liver cancers had higher HRs than breast. Prospective OS HR=2.25 (lung 3.14, endometrial 0.75). Retrospective DFS HR=1.89 vs Japanese breast RFS HR=4.00. Heterogeneity originated from study design, region, and cancer type variations, with no significant publication bias (Egger's test p>0.05). CONCLUSION: Current evidence suggests that TP53 mutations detected in ctDNA are significantly associated with poor prognosis in various solid tumors, particularly lung cancer. The association is robust for PFS and OS, though high heterogeneity and biological complexity warrant cautious interpretation. These findings support the potential incorporation of ctDNA-based TP53 mutation status into clinical prognostic assessment systems as an adjunctive parameter; however, further standardization of detection protocols, functional annotation of mutation types (e.g., LOF vs. GOF), incorporation of VAF and clonality analysis, and validation in large prospective multicenter cohorts are needed before routine clinical implementation. PROSPERO REGISTRATION NUMBER: CRD420251021095.

Humans↗
PubMed2002

Genome-wide analysis of core cell cycle genes in Arabidopsis.

Cyclin-dependent kinases and cyclins regulate with the help of different interacting proteins the progression through the eukaryotic cell cycle. A high-quality, homology-based annotation protocol was applied to determine the core cell cycle genes in the recently completed Arabidopsis genome sequence. In total, 61 genes were identified belonging to seven selected families of cell cycle regulators, for which 30 are new or corrections of the existing annotation. A new class of putative cell cycle regulators was found that probably are competitors of E2F/DP transcription factors, which mediate the G1-to-S progression. In addition, the existing nomenclature for cell cycle genes of Arabidopsis was updated, and the physical positions of all genes were compared with segmentally duplicated blocks in the genome, showing that 22 core cell cycle genes emerged through block duplications. This genome-wide analysis illustrates the complexity of the plant cell cycle machinery and provides a tool for elucidating the function of new family members in the future.

Amino Acid Sequence↗
PubMed2026

Genome sequence data of the chitinase-producing bacterium Paenibacillus mucilaginosus YWY-5.1.

Paenibacillus mucilaginosus is a beneficial bacterium widely applied as a biofertilizer in agriculture. To date, genomic information on this species remains limited; however, no genome assemblies from Vietnam have been reported. This work presented the draft genome of P. mucilaginosus YWY-5.1, a promising strain with strong chitin-degrading capability and agricultural potential, isolated from Yok Don National Park, Vietnam, using Illumina technology. Results showed that the assembled genome comprised 48 contigs with 4,076,146 bp and 73.8% GC-content. Genome annotation identified 3,611 protein-coding genes, 2 rRNA genes, and 53 tRNA genes. A total of 150 carbohydrate-active enzyme-related genes were predicted from the genome; among them, seven putative chitinolytic genes were identified, including 4 genes related to family 18 chitinase, 2 genes to family 20 β-N-acetylglucosaminidase, and one gene to auxiliary activity family 10. In addition, at least 32 genes related to plant growth-promoting functions were identified, including those associated with indole-3-acetic acid production, phosphate and potassium solubilization, siderophore biosynthesis, iron uptake, ACC metabolism, and nitrate transport and reduction. Furthermore, genome mining identified 4 biosynthetic gene clusters probably involved in secondary metabolite production, of which 3 displayed no similarity to previously reported clusters, indicating potential for novel bioactive compounds. These genomic data improved our understanding of the biodegradation capacity and agricultural potential of P. mucilaginosus YWY-5.1 isolated from Vietnam, and provided a valuable genomic resource for future functional and biotechnological investigations toward crop production and related fields.

Chitinases↗
PubMed2004

Some microsatellites may act as novel polymorphic cis-regulatory elements through transcription factor binding.

Although microsatellites with functional effects have been described, generally, these repeats are considered as "junk" DNA in the same way as other repetitive sequences. Our aim was to investigate if certain microsatellites can have a functional role as cis-regulatory elements. A database was created of all short tandem repeats, from 2 to 10 bases, located in the first 10-kb 5' of the transcription start sites of all annotated genes of the human genome. Of 114 microsatellites selected based on their size and location in the promoter, 51 were found to be polymorphic. Using electrophoretic mobility shift assay (EMSA), we studied five repetitive motifs and three displayed specific protein binding which were found in 12 of the polymorphic microsatellites. An interesting microsatellite is the CTC/GAG repeat which, as double-stranded (DS) DNA, bound specificity protein 1 (SP1) with high affinity, formed triplexes in vitro and displayed differences in SP1 binding and triplex formation capacity for repeats with distinct numbers of repeat units. Interestingly, the polypyrimidine strand of the repeat (CTC) bound other proteins such as polypyrimidine tract-binding protein 1 (PTBP1) as single-stranded (SS) DNA, and a model with two alternative DNA conformations is proposed for these repeats. Distinct protein binding to DS DNA was also observed for different numbers of AAACA and AAAAT repeats. Our results suggest that certain microsatellites may act as cis-regulatory elements, controlling gene expression through transcription factor binding and/or secondary DNA structure formation. Due to their high polymorphism and abundance, they might represent an important source of quantitative genetic variation.

Base Sequence↗
PubMed2004

The major form of MeCP2 has a novel N-terminus generated by alternative splicing.

MeCP2 is a methyl-CpG binding protein that can repress transcription of nearby genes. In humans, mutations in the MECP2 gene are the major cause of Rett syndrome. By searching expressed sequence tag (EST) databases we have found a novel MeCP2 splice isoform (MeCP2alpha) which encodes a distinct N-terminus. We demonstrate that the MeCP2alpha mRNA splice variant is more abundant than the previously annotated MeCP2 mRNA (MeCP2beta) in mouse tissues and human brain. Furthermore, MeCP2beta mRNA has an upstream open reading frame that inhibits its translation. As a result of these differences, >90% of MeCP2 in mouse brain is MeCP2alpha. Both protein isoforms are nuclear and colocalize with densely methylated heterochromatic foci in mouse cells. The presence of a previously unknown MeCP2 isoform has implications for the genetic screening of Rett syndrome patients and for studies of the functional significance of MeCP2.

Alternative Splicing↗
PubMed1996

Perspectives: sequence data base searching in the era of large-scale genomic sequencing.

Large-scale sequencing of human and model organism genomes will have a profound impact on our ability to use sequence data base searching to predict the biochemical functions of sequences of interest. Despite the great value of more sequences in the data bases, a huge increase in data base size will also have adverse effects on data base searches. Upcoming problems will include (1) greatly increased search times, (2) an increase in background noise of high-scoring but biologically irrelevant matches, (3) inaccurate coding region prediction, leading to problems in protein data base searching, and (4) limited first-pass sequence annotation, making it difficult to determine the biological relevance of data base hits. Improved data base annotation tools and construction of smaller data bases of representative and highly-annotated sequences for first-pass analyses will be essential to deal with the impending flood of new genomic sequence.

Animals↗
PubMed2006

Analysis of bacteria-challenged wild silkmoth, Antheraea mylitta (lepidoptera) transcriptome reveals potential immune genes.

BACKGROUND: In the recent years a strong resemblance has been observed between the insect immune system and the mammalian innate immune mechanisms suggesting their common origin. Among the insects, only the dipterans (Drosophila and various mosquito species) have been widely investigated for their immune responses towards diverse pathogens. In the present study we constructed and analysed the immune transcriptome of the lepidopteran Antheraea mylitta, an economically important Indian tasar silkmoth with a view to unravel the potential immune-related genes and pathways. RESULTS: An expressed sequence tag (EST) library was constructed from mRNA obtained from fat bodies of A. mylitta larvae that had been challenged by infection with Escherichia coli cells. We identified 719 unique ESTs from a total of 1412 sequences so generated. A third of the transcriptome showed similarity with previously characterized immune-related genes that included both the known and putative immune genes. Of the four putative novel defence proteins (DFPs) annotated by PSI-BLAST three showed similarity to extracellular matrix proteins from vertebrates implicated in innate immunity, while the fourth was similar to, yet distinct from, the anti-microbial protein cecropin. Finally, we analysed the expression profiles of 15 potential immune-related genes, and the majority of them were induced more prominently with E. coli compared to Micrococcus luteus. We also identified several unknown proteins, some of which could have probable immune-related functions based on the results of the ProDom analysis. CONCLUSION: The present study has identified many potential immune-related genes in A. mylitta some of which are vertebrate homologues and others are hitherto unreported putative defence proteins. Several genes were present as members of gene families, as has also been observed in other insect species.

Amino Acid Sequence↗
PubMed2025

Synaptic protein CSF levels relate to memory scores in individuals without dementia.

BACKGROUND: We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), and investigated the effect of amyloid positivity on these associations. METHODS: We included 242 CN (105(43%) abnormal amyloid), and 278 MCI individuals (183(66%) abnormal amyloid) from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). For 181 (EMIF-AD MBD) and 36 (ADNI) proteins with a synaptic annotation in SynGO, associations with word learning recall were analysed with linear models. RESULTS: Subsets of synaptic proteins showed lower levels with worse recall in preclinical AD (EMIF-AD MBD: 7, ADNI: 5 proteins, none overlapping), prodromal AD (EMIF-AD MBD only, 27 proteins) and non-AD MCI (EMIF-AD MBD: 1, ADNI: 7 proteins). The majority of these associations were specific to these clinical groups. CONCLUSIONS: Synaptic disturbance-related memory impairment occurred very early in AD, indicating it may be relevant to develop therapies targeting the synapse early in the disease.

Humans↗
PubMed2002

Visualization techniques for genomic data.

In order to take full advantage of the newly available public human genome sequence data and associated annotations, biologists require visualization tools that can accommodate the high frequency of alternative splicing in human genes and other complexities. In this article, we describe techniques for presenting human genomic sequence data and annotations in an interactive, graphical format, with the aim of providing developers with a guide to what features are most likely to meet biologists' needs. These techniques include: one-dimensional semantic zooming to show sequence data alongside gene structures; moveable, adjustable tiers; visual encoding of translation frame to show how alternative transcript structure affects encoded proteins; and display of protein domains in the context of genomic sequence to show how alternative splicing impacts protein structure and function.

Algorithms↗