Biomedical subjects

Johannes Söding

Publications and source records attributed to Johannes Söding.

12 recordsLinked to original sources

PubMed2007

TPRpred: a tool for prediction of TPR-, PPR- and SEL1-like repeats from protein sequences.

BACKGROUND: Solenoid repeat proteins of the Tetratrico Peptide Repeat (TPR) family are involved as scaffolds in a broad range of protein-protein interactions. Several resources are available for the prediction of TPRs, however, they often fail to detect divergent repeat units. RESULTS: We have developed TPRpred, a profile-based method which uses a P-value-dependent score offset to include divergent repeat units and which exploits the tendency of repeats to occur in tandem. TPRpred detects not only TPR-like repeats, but also the related Pentatrico Peptide Repeats (PPRs) and SEL1-like repeats. The corresponding profiles were generated through iterative searches, by varying the threshold parameters for inclusion of repeat units into the profiles, and the best profiles were selected based on their performance on proteins of known structure. We benchmarked the performance of TPRpred in detecting TPR-containing proteins and in delineating the individual repeats therein, against currently available resources. CONCLUSION: TPRpred performs significantly better in detecting divergent repeats in TPR-containing proteins, and finds more individual repeats than the existing methods. The web server is available at http://tprpred.tuebingen.mpg.de, and the C++ and Perl sources of TPRpred along with the profiles can be downloaded from ftp://ftp.tuebingen.mpg.de/ebio/protevo/TPRpred/.

Algorithms↗

PubMed2006

HHrep: de novo protein repeat detection and the origin of TIM barrels.

HHrep is a web server for the de novo identification of repeats in protein sequences, which is based on the pairwise comparison of profile hidden Markov models (HMMs). Its main strength is its sensitivity, allowing it to detect highly divergent repeat units in protein sequences whose repeats could as yet only be detected from their structures. Examples include sequences with beta-propellor fold, ferredoxin-like fold, double psi barrels or (betaalpha)8 (TIM) barrels. We illustrate this with proteins from four superfamilies of TIM barrels by revealing a clear 4- and 8-fold symmetry, which we detect solely from their sequences. This symmetry might be the trace of an ancient origin through duplication of a betaalphabetaalpha or betaalpha unit. HHrep can be accessed at http://hhrep.tuebingen.mpg.de.

Internet↗

PubMed2006

HHsenser: exhaustive transitive profile search using HMM-HMM comparison.

HHsenser is the first server to offer exhaustive intermediate profile searches, which it combines with pairwise comparison of hidden Markov models. Starting from a single protein sequence or a multiple alignment, it can iteratively explore whole superfamilies, producing few or no false positives. The output is a multiple alignment of all detected homologs. HHsenser's sensitivity should make it a useful tool for evolutionary studies. It may also aid applications that rely on diverse multiple sequence alignments as input, such as homology-based structure and function prediction, or the determination of functional residues by conservation scoring and functional subtyping.HHsenser can be accessed at http://hhsenser.tuebingen.mpg.de/. It has also been integrated into our structure and function prediction server HHpred (http://hhpred.tuebingen.mpg.de/) to improve predictions for near-singleton sequences.

Internet↗

PubMed2006

The MPI Bioinformatics Toolkit for protein sequence analysis.

The MPI Bioinformatics Toolkit is an interactive web service which offers access to a great variety of public and in-house bioinformatics tools. They are grouped into different sections that support sequence searches, multiple alignment, secondary and tertiary structure prediction and classification. Several public tools are offered in customized versions that extend their functionality. For example, PSI-BLAST can be run against regularly updated standard databases, customized user databases or selectable sets of genomes. Another tool, Quick2D, integrates the results of various secondary structure, transmembrane and disorder prediction programs into one view. The Toolkit provides a friendly and intuitive user interface with an online help facility. As a key feature, various tools are interconnected so that the results of one tool can be forwarded to other tools. One could run PSI-BLAST, parse out a multiple alignment of selected hits and send the results to a cluster analysis tool. The Toolkit framework and the tools developed in-house will be packaged and freely available under the GNU Lesser General Public Licence (LGPL). The Toolkit can be accessed at http://toolkit.tuebingen.mpg.de.

Computational Biology↗

PubMed2006

Comparative analysis of coiled-coil prediction methods.

In this study we compare commonly used coiled-coil prediction methods against a database derived from proteins of known structure. We find that the two older programs COILS and PairCoil/MultiCoil are significantly outperformed by two recent developments: Marcoil, a program built on hidden Markov models, and PCOILS, a new COILS version that uses profiles as inputs; and to a lesser extent by a PairCoil update, PairCoil2. Overall Marcoil provides a slightly better performance over the reference database than PCOILS and is considerably faster, but it is sensitive to highly charged false positives, whereas the weighting option of PCOILS allows the identification of such sequences.

Amino Acid Sequence↗

PubMed2006

Expression, crystallization and preliminary X-ray crystallographic studies of the outer membrane protein OmpW from Escherichia coli.

OmpW is an eight-stranded 21 kDa molecular-weight beta-barrel protein from the outer membrane of Gram-negative bacteria. It is a major antigen in bacterial infections and has implications in antibiotic resistance and in the oxidative degradation of organic compounds. OmpW from Escherichia coli was cloned and the protein was expressed in inclusion bodies. A method for refolding and purification was developed which yields properly folded protein according to circular-dichroism measurements. The protein has been crystallized and crystals were obtained that diffracted to a resolution limit of 3.5 angstroms. The crystals belong to space group P422, with unit-cell parameters a = 122.5, c = 105.7 angstroms. A homology model of OmpW is presented based on known structures of eight-stranded beta-barrels, intended for use in molecular-replacement trials.

Bacterial Outer Membrane Proteins↗

PubMed2005

REPPER--repeats and their periodicities in fibrous proteins.

REPPER (REPeats and their PERiodicities) is an integrated server that detects and analyzes regions with short gapless repeats in protein sequences or alignments. It finds periodicities by Fourier Transform (FTwin) and internal similarity analysis (REPwin). FTwin assigns numerical values to amino acids that reflect certain properties, for instance hydrophobicity, and gives information on corresponding periodicities. REPwin uses self-alignments and displays repeats that reveal significant internal similarities. Both programs use a sliding window to ensure that different periodic regions within the same protein are detected independently. FTwin and REPwin are complemented by secondary structure prediction (PSIPRED) and coiled coil prediction (COILS), making the server a versatile analysis tool for sequences of fibrous proteins. REPPER is available at http://protevo.eb.tuebingen.mpg.de/repper.

Adhesins, Bacterial↗

PubMed2005

The HHpred interactive server for protein homology detection and structure prediction.

HHpred is a fast server for remote protein homology detection and structure prediction and is the first to implement pairwise comparison of profile hidden Markov models (HMMs). It allows to search a wide choice of databases, such as the PDB, SCOP, Pfam, SMART, COGs and CDD. It accepts a single query sequence or a multiple alignment as input. Within only a few minutes it returns the search results in a user-friendly format similar to that of PSI-BLAST. Search options include local or global alignment and scoring secondary structure similarity. HHpred can produce pairwise query-template alignments, multiple alignments of the query with a set of templates selected from the search results, as well as 3D structural models that are calculated by the MODELLER software from these alignments. A detailed help facility is available. As a demonstration, we analyze the sequence of SpoVT, a transcriptional regulator from Bacillus subtilis. HHpred can be accessed at http://protevo.eb.tuebingen.mpg.de/hhpred.

Bacterial Proteins↗

PubMed2005

Retroactive, a membrane-anchored extracellular protein related to vertebrate snake neurotoxin-like proteins, is required for cuticle organization in the larva of Drosophila melanogaster.

Mutations in the rtv gene cause disarrangement of chitin fibers in the cuticle of the Drosophila larva, and occasionally the cuticle detaches from the epidermis. We have identified the rtv gene, and using the new HHpred homology detection method, we show that the Rtv protein defines a new family of disulfide-rich proteins in insects that are related to vertebrate snake neurotoxin-like proteins, including CD59 and transforming growth factor-beta type II receptors. Rtv is an extracellular membrane-anchored protein exposing six aromatic residues that may mediate binding to chitin. We propose that this binding function of Rtv may assist the organization of chitin fibers at the epidermal cell surface during cuticle assembly.

Amino Acid Sequence↗

PubMed2005

AbrB-like transcription factors assume a swapped hairpin fold that is evolutionarily related to double-psi beta barrels.

AbrB is a key transition-state regulator of Bacillus subtilis. Based on the conservation of a betaalphabeta structural unit, we proposed a beta barrel fold for its DNA binding domain, similar to, but topologically distinct from, double-psi beta barrels. However, the NMR structure revealed a novel fold, the "looped-hinge helix." To understand this discrepancy, we undertook a bioinformatics study of AbrB and its homologs; these form a large superfamily, which includes SpoVT, PrlF, MraZ, addiction module antidotes (PemI, MazE), plasmid maintenance proteins (VagC, VapB), and archaeal PhoU homologs. MazE and MraZ form swapped-hairpin beta barrels. We therefore reexamined the fold of AbrB by NMR spectroscopy and found that it also forms a swapped-hairpin barrel. The conservation of the core betaalphabeta element supports a common evolutionary origin for swapped-hairpin and double-psi barrels, which we group into a higher-order class, the cradle-loop barrels, based on the peculiar shape of their ligand binding site.

Amino Acid Sequence↗

PubMed2004

Protein homology detection by HMM-HMM comparison.

MOTIVATION: Protein homology detection and sequence alignment are at the basis of protein structure prediction, function prediction and evolution. RESULTS: We have generalized the alignment of protein sequences with a profile hidden Markov model (HMM) to the case of pairwise alignment of profile HMMs. We present a method for detecting distant homologous relationships between proteins based on this approach. The method (HHsearch) is benchmarked together with BLAST, PSI-BLAST, HMMER and the profile-profile comparison tools PROF_SIM and COMPASS, in an all-against-all comparison of a database of 3691 protein domains from SCOP 1.63 with pairwise sequence identities below 20%.Sensitivity: When the predicted secondary structure is included in the HMMs, HHsearch is able to detect between 2.7 and 4.2 times more homologs than PSI-BLAST or HMMER and between 1.44 and 1.9 times more than COMPASS or PROF_SIM for a rate of false positives of 10%. Approximately half of the improvement over the profile-profile comparison methods is attributable to the use of profile HMMs in place of simple profiles. Alignment quality: Higher sensitivity is mirrored by an increased alignment quality. HHsearch produced 1.2, 1.7 and 3.3 times more good alignments ('balanced' score >0.3) than the next best method (COMPASS), and 1.6, 2.9 and 9.4 times more than PSI-BLAST, at the family, superfamily and fold level, respectively.Speed: HHsearch scans a query of 200 residues against 3691 domains in 33 s on an AMD64 2GHz PC. This is 10 times faster than PROF_SIM and 17 times faster than COMPASS.

Algorithms↗

PubMed2003

More than the sum of their parts: on the evolution of proteins from peptides.

Despite their seemingly endless diversity, proteins adopt a limited number of structural forms. It has been estimated that 80% of proteins will be found to adopt one of only about 400 folds, most of which are already known. These folds are largely formed by a limited 'vocabulary' of recurring supersecondary structure elements, often by repetition of the same element and, increasingly, elements similar in both structure and sequence are discovered. This suggests that modern proteins evolved by fusion and recombination from a more ancient peptide world and that many of the core folds observed today may contain homologous building blocks. The peptides forming these building blocks would not in themselves have had the ability to fold, but would have emerged as cofactors supporting RNA-based replication and catalysis (the 'RNA world'). Their association into larger structures and eventual fusion into polypeptide chains would have allowed them to become independent of their RNA scaffold, leading to the evolution of a novel type of macromolecule: the folded protein.

Animals↗