Biomedical subjects

Tobias Doerks

Publications and source records attributed to Tobias Doerks.

15 recordsLinked to original sources

PubMed2006

STRING 7--recent developments in the integration and prediction of protein interactions.

Information on protein-protein interactions is still mostly limited to a small number of model organisms, and originates from a wide variety of experimental and computational techniques. The database and online resource STRING generalizes access to protein interaction data, by integrating known and predicted interactions from a variety of sources. The underlying infrastructure includes a consistent body of completely sequenced genomes and exhaustive orthology classifications, based on which interaction evidence is transferred between organisms. Although primarily developed for protein interaction analysis, the resource has also been successfully applied to comparative genomics, phylogenetics and network studies, which are all facilitated by programmatic access to the database backend and the availability of compact download files. As of release 7, STRING has almost doubled to 373 distinct organisms, and contains more than 1.5 million proteins for which associations have been pre-computed. Novel features include AJAX-based web-navigation, inclusion of additional resources such as BioGRID, and detailed protein domain annotation. STRING is available at http://string.embl.de/

Databases, Protein↗

PubMed2006

Computational characterization of multiple Gag-like human proteins.

In a genome-wide analysis, we have identified 85 human genes encoding 103 protein isoforms that resemble retroviral Gag proteins. These genes were domesticated from retrotransposons in at least five independent events during vertebrate evolution and were subsequently duplicated further in mammals. Structural insights into the mammalian proteins can be inferred by homology to Gag from viruses such as HIV; in turn, the cellular roles of the mammalian Gag homologs, such as apoptosis-related functions and binding to ubiquitin ligases, might hint at further functionality of viral Gag itself.

Animals↗

PubMed2006

mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes.

MicroRNAs (miRNAs) silence the expression of target genes post-transcriptionally. Their function is mediated by the Argonaute proteins (AGOs), which colocalize to P-bodies with mRNA degradation enzymes. Mammalian P-bodies are also marked by the GW182 protein, which interacts with the AGOs and is required for miRNA function. We show that depletion of GW182 leads to changes in mRNA expression profiles strikingly similar to those observed in cells depleted of the essential Drosophila miRNA effector AGO1, indicating that GW182 functions in the miRNA pathway. When GW182 is bound to a reporter transcript, it silences its expression, bypassing the requirement for AGO1. Silencing by GW182 is effected by changes in protein expression and mRNA stability. Similarly, miRNAs silence gene expression by repressing protein expression and/or by promoting mRNA decay, and both mechanisms require GW182. mRNA degradation, but not translational repression, by GW182 or miRNAs is inhibited in cells depleted of CAF1, NOT1, or the decapping DCP1:DCP2 complex. We further show that the N-terminal GW repeats of GW182 interact with the PIWI domain of AGO1. Our findings indicate that GW182 links the miRNA pathway to mRNA degradation by interacting with AGO1 and promoting decay of at least a subset of miRNA targets.

Amino Acid Sequence↗

PubMed2006

Toward automatic reconstruction of a highly resolved tree of life.

We have developed an automatable procedure for reconstructing the tree of life with branch lengths comparable across all three domains. The tree has its basis in a concatenation of 31 orthologs occurring in 191 species with sequenced genomes. It revealed interdomain discrepancies in taxonomic classification. Systematic detection and subsequent exclusion of products of horizontal gene transfer increased phylogenetic resolution, allowing us to confirm accepted relationships and resolve disputed and preliminary classifications. For example, we place the phylum Acidobacteria as a sister group of delta-Proteobacteria, support a Gram-positive origin of Bacteria, and suggest a thermophilic last universal common ancestor.

Amino Acyl-tRNA Synthetases↗

PubMed2005

DCD - a novel plant specific domain in proteins involved in development and programmed cell death.

BACKGROUND: Recognition of microbial pathogens by plants triggers the hypersensitive reaction, a common form of programmed cell death in plants. These dying cells generate signals that activate the plant immune system and alarm the neighboring cells as well as the whole plant to activate defense responses to limit the spread of the pathogen. The molecular mechanisms behind the hypersensitive reaction are largely unknown except for the recognition process of pathogens. We delineate the NRP-gene in soybean, which is specifically induced during this programmed cell death and contains a novel protein domain, which is commonly found in different plant proteins. RESULTS: The sequence analysis of the protein, encoded by the NRP-gene from soybean, led to the identification of a novel domain, which we named DCD, because it is found in plant proteins involved in development and cell death. The domain is shared by several proteins in the Arabidopsis and the rice genomes, which otherwise show a different protein architecture. Biological studies indicate a role of these proteins in phytohormone response, embryo development and programmed cell by pathogens or ozone. CONCLUSION: It is tempting to speculate, that the DCD domain mediates signaling in plant development and programmed cell death and could thus be used to identify interacting proteins to gain further molecular insights into these processes.

Amino Acid Motifs↗

PubMed2005

Systematic association of genes to phenotypes by genome and literature mining.

One of the major challenges of functional genomics is to unravel the connection between genotype and phenotype. So far no global analysis has attempted to explore those connections in the light of the large phenotypic variability seen in nature. Here, we use an unsupervised, systematic approach for associating genes and phenotypic characteristics that combines literature mining with comparative genome analysis. We first mine the MEDLINE literature database for terms that reflect phenotypic similarities of species. Subsequently we predict the likely genomic determinants: genes specifically present in the respective genomes. In a global analysis involving 92 prokaryotic genomes we retrieve 323 clusters containing a total of 2,700 significant gene-phenotype associations. Some clusters contain mostly known relationships, such as genes involved in motility or plant degradation, often with additional hypothetical proteins associated with those phenotypes. Other clusters comprise unexpected associations; for example, a group of terms related to food and spoilage is linked to genes predicted to be involved in bacterial food poisoning. Among the clusters, we observe an enrichment of pathogenicity-related associations, suggesting that the approach reveals many novel genes likely to play a role in infectious diseases.

Bacteria↗

PubMed2004

Functional clues for hypothetical proteins based on genomic context analysis in prokaryotes.

Three integrated genomic context methods were used to annotate uncharacterized proteins in 102 bacterial genomes. Of 7853 orthologous groups with unknown function containing 45,110 proteins, 1738 groups could be linked to functionally associated partners. In many cases, those partners are uncharacterized themselves (hinting at newly identified modules) or have been described in general terms only. However, we were able to assign pathways, cellular processes or physical complexes for 273 groups (encompassing 3624 previously functionally uncharacterized proteins).

Bacterial Proteins↗

PubMed2004

SMART 4.0: towards genomic data integration.

SMART (Simple Modular Architecture Research Tool) is a web tool (http://smart.embl.de/) for the identification and annotation of protein domains, and provides a platform for the comparative study of complex domain architectures in genes and proteins. The January 2004 release of SMART contains 685 protein domains. New developments in SMART are centred on the integration of data from completed metazoan genomes. SMART now uses predicted proteins from complete genomes in its source sequence databases, and integrates these with predictions of orthology. New visualization tools have been developed to allow analysis of gene intron-exon structure within the context of protein domain structure, and to align these displays to provide schematic comparisons of orthologous genes, or multiple transcripts from the same gene. Other improvements include the ability to query SMART by Gene Ontology terms, improved structure database searching and batch retrieval of multiple entries.

Algorithms↗

PubMed2004

Global analysis of bacterial transcription factors to predict cellular target processes.

Whole-genome sequences are now available for >100 bacterial species, giving unprecedented power to comparative genomics approaches. We have applied genome-context methods to predict target processes that are regulated by transcription factors (TFs). Of 128 orthologous groups of proteins annotated as TFs, to date, 36 are functionally uncharacterized; in our analysis we predict a probable cellular target process or biochemical pathway for half of these functionally uncharacterized TFs.

Bacteria↗

PubMed2002

Protein domain analysis in the era of complete genomes.

Domains present one of the most useful levels at which to understand protein function, and domain family-based analysis has had a profound impact on the study of individual proteins. Protein domain discovery has been progressing steadily over the past 30 years. What are the realistically achievable goals of sequence-based domain analysis, and how far off are they for the sequences encoded in eukaryotic genomes? Here we address some of the issues involved in better coverage of sequence-based domain annotation, and the integration of these results within the wider context of genomes, structures and function.

Amino Acid Sequence↗

PubMed2002

Recent improvements to the SMART domain-based sequence annotation resource.

SMART (Simple Modular Architecture Research Tool, http://smart.embl-heidelberg.de) is a web-based resource used for the annotation of protein domains and the analysis of domain architectures, with particular emphasis on mobile eukaryotic domains. Extensive annotation for each domain family is available, providing information relating to function, subcellular localization, phyletic distribution and tertiary structure. The January 2002 release has added more than 200 hand-curated domain models. This brings the total to over 600 domain families that are widely represented among nuclear, signalling and extracellular proteins. Annotation now includes links to the Online Mendelian Inheritance in Man (OMIM) database in cases where a human disease is associated with one or more mutations in a particular domain. We have implemented new analysis methods and updated others. New advanced queries provide direct access to the SMART relational database using SQL. This database now contains information on intrinsic sequence features such as transmembrane regions, coiled-coils, signal peptides and internal repeats. SMART output can now be easily included in users' documents. A SMART mirror has been created at http://smart.ox.ac.uk.

Animals↗

PubMed2002

BSD: a novel domain in transcription factors and synapse-associated proteins.

This article describes a novel domain, BSD, that is present in basal transcription factors, synapse-associated proteins and several hypothetical proteins. It occurs in a variety of species ranging from primal protozoan to human. The BSD domain is characterized by three predicted alpha helices, which probably form a three-helical bundle, as well as by conserved tryptophan and phenylalanine residues, located at the C terminus of the domain.

Amino Acid Motifs↗

PubMed2002

CASH--a beta-helix domain widespread among carbohydrate-binding proteins.

In this article, we describe a novel, widespread domain (CASH) that is shared by many carbohydrate-binding proteins and sugar hydrolases. This domain occurs in more than 1000 proteins distributed among all three kingdoms of life. The CASH domain is characterized by internal repetitions of glycines and hydrophobic residues that correspond to the repetitive units of a predicted or observed right-handed beta-helix structure of the pectate lyase superfamily.

Amino Acid Motifs↗

PubMed2002

AMOP, a protein module alternatively spliced in cancer cells.

This article describes a new extracellular domain--AMOP, for adhesion-associated domain in MUC4 and other proteins. This domain occurs in putative cell adhesion molecules and in some splice variants of MUC4. MUC4 splice variants are overexpressed in several tumours; in particular, they are highly expressed in pancreatic carcinomas but not in normal pancreas. The presence of AMOP in cell adhesion molecules could be indicative of a role for this domain in adhesion.

Alternative Splicing↗

PubMed2002

Systematic identification of novel protein domain families associated with nuclear functions.

A systematic computational analysis of protein sequences containing known nuclear domains led to the identification of 28 novel domain families. This represents a 26% increase in the starting set of 107 known nuclear domain families used for the analysis. Most of the novel domains are present in all major eukaryotic lineages, but 3 are species specific. For about 500 of the 1200 proteins that contain these new domains, nuclear localization could be inferred, and for 700, additional features could be predicted. For example, we identified a new domain, likely to have a role downstream of the unfolded protein response; a nematode-specific signalling domain; and a widespread domain, likely to be a noncatalytic homolog of ubiquitin-conjugating enzymes.

Amidohydrolases↗