IWS: Integrated web server for protein sequence and structure analysis

Rapid increase in protein sequence information from genome sequencing projects demand the intervention of bioinformatics tools to recognize interesting gene-products and associated function. Often, multiple algorithms need to be employed to improve accuracy in predictions and several structure prediction algorithms are on the public domain. Here, we report the availability of an Integrated Web-server as a bioinformatics online package dedicated for in-silico analysis of protein sequence and structure data (IWS). IWS provides web interface to both in-house and widely accepted programs from major bioinformatics groups, organized as 10 different modules. IWS also provides interactive images for Analysis Work Flow, which will provide transparency to the user to carry out analysis by moving across modules seamlessly and to perform their predictions in a rapid manner

A census of actin-associated proteins in humans

Actin filaments help in maintaining the cell structure and coordinating cellular movements and cargo transport within the cell. Actin participates in the interaction with several proteins and also with itself to form the helical filamentous actin (F-actin). Actin-binding proteins (ABPs) and actin-associated proteins (AAPs) coordinate the actin filament assembly and processing, regulate the flux between globular G-actin and F-actin in the cell, and help maintain the cellular structure and integrity. We have used protein–protein interaction data available through multiple sources (STRING, BioGRID, mentha, and a few others), functional annotation, and classical actin-binding domains to identify actin-binding and actin-associated proteins in the human proteome. Here, we report 2482 AAPs and present an analysis of their structural and sequential domains, functions, evolutionary conservation, cellular localization, abundance, and tissue-specific expression patterns. This analysis provides a base for the characterization of proteins involved in actin dynamics and turnover in the cell

GenDiS: Genomic Distribution of protein structural domain Superfamilies

Several proteins that have substantially diverged during evolution retain similar three-dimensional structures and biological function inspite of poor sequence identity. The database on Genomic Distribution of protein structural domain Superfamilies (GenDiS) provides record for the distribution of 4001 protein domains organized as 1194 structural superfamilies across 18 997 genomes at various levels of hierarchy in taxonomy. GenDiS database provides a survey of protein domains enlisted in sequence databases employing a 3-fold sequence search approach. Lineage-specific literature is obtained from the taxonomy database for individual protein members to provide a platform for performing genomic and phyletic studies across organisms. The database documents residual properties and provides alignments for the various superfamily members in genomes, offering insights into the rational design of experiments and for the better understanding of a superfamily. GenDiS database can be accessed at http://www.ncbs.res.in/~faculty/mini/gendis/home.html

PASS2: an automated database of protein alignments organised as structural superfamilies

BACKGROUND: The functional selection and three-dimensional structural constraints of proteins in nature often relates to the retention of significant sequence similarity between proteins of similar fold and function despite poor sequence identity. Organization of structure-based sequence alignments for distantly related proteins, provides a map of the conserved and critical regions of the protein universe that is useful for the analysis of folding principles, for the evolutionary unification of protein families and for maximizing the information return from experimental structure determination. The Protein Alignment organised as Structural Superfamily (PASS2) database represents continuously updated, structural alignments for evolutionary related, sequentially distant proteins. DESCRIPTION: An automated and updated version of PASS2 is, in direct correspondence with SCOP 1.63, consisting of sequences having identity below 40% among themselves. Protein domains have been grouped into 628 multi-member superfamilies and 566 single member superfamilies. Structure-based sequence alignments for the superfamilies have been obtained using COMPARER, while initial equivalencies have been derived from a preliminary superposition using LSQMAN or STAMP 4.0. The final sequence alignments have been annotated for structural features using JOY4.0. The database is supplemented with sequence relatives belonging to different genomes, conserved spatially interacting and structural motifs, probabilistic hidden markov models of superfamilies based on the alignments and useful links to other databases. Probabilistic models and sensitive position specific profiles obtained from reliable superfamily alignments aid annotation of remote homologues and are useful tools in structural and functional genomics. PASS2 presents the phylogeny of its members both based on sequence and structural dissimilarities. Clustering of members allows us to understand diversification of the family members. The search engine has been improved for simpler browsing of the database. CONCLUSIONS: The database resolves alignments among the structural domains consisting of evolutionarily diverged set of sequences. Availability of reliable sequence alignments of distantly related proteins despite poor sequence identity and single-member superfamilies permit better sampling of structures in libraries for fold recognition of new sequences and for the understanding of protein structure-function relationships of individual superfamilies. PASS2 is accessible a

Analysis of the impact of ERK5, JNK, and P38 kinase cascades on each other: A systems approach

The classical concept of linear pathways is being increasingly challenged by network representations, which emphasize the importance of interactions between components of a biological system, and motivates for adopting a system‐level approach in biology. We have developed a dynamical system that integrates quantitative, dynamic and topological representation of network of ERK5 (Extracellular signal‐regulated kinases 5), JNK(c‐Jun N‐terminal kinases) and P38 kinase cascades. We have observered that, the transient activation of ERK5, JNK1 and P38β kinase, and the persistent activation of JNK2, JNK3 and P38 δ kinase does not get affected due to the cross‐talks between ERK5, JNK and P38 kinase cascades. But it is due to the cross ‐ talks, the transiently activated P38α kinase become inactivated, and the transiently activated P38γ kinase become persistently activated. The impacts of one‐way cross‐talks between the cascades are insignificant and differ from the impact of two‐way cross‐talks. We generate a hypothesis that, signaling pathways should be studied as a system by considering the cross‐talks between the two adjacent cascades

Computational prediction and analysis of impact of the cross‐talks between JNK and P38 kinase cascades

Signal transduction is a complex protein signaling process with a rich network of multifunctional interactions that occur in a non‐linear fashion. Mitogen‐activated protein kinase (MAPK) signal transduction pathways regulate diverse cellular processes ranging from proliferation and differentiation to apoptosis. In mammals, out of five, there are three well characterized subfamilies of MAPKs ‐ ERKs (Extracellular signal‐regulated kinases), JNKs (c‐Jun N‐terminal kinases), and P38 kinases, and their activators, are implicated in human diseases and are targets for drug development. Kinase cascades in MAPK pathways mediate the sensing and processing of stimuli. To understand how cells makes decisions, the dynamic interactions of components of signaling cascades are important rather than just creating static maps. Based on enzyme kinetic reactions, we have developed a mathematical model to analyze the impact of the cross‐talks between JNK and P38 kinase cascades. Cross‐talks between JNK and P38 kinase cascades influence the activities of P38 kinases. Responses of the signals should be studied for network of kinase cascades by considering cross‐talks

Cross genome phylogenetic analysis of human and Drosophila G protein-coupled receptors: application to functional annotation of orphan receptors

BACKGROUND: The cell-membrane G-protein coupled receptors (GPCRs) are one of the largest known superfamilies and are the main focus of intense pharmaceutical research due to their key role in cell physiology and disease. A large number of putative GPCRs are 'orphans' with no identified natural ligands. The first step in understanding the function of orphan GPCRs is to identify their ligands. Phylogenetic clustering methods were used to elucidate the chemical nature of receptor ligands, which led to the identification of natural ligands for many orphan receptors. We have clustered human and Drosophila receptors with known ligands and orphans through cross genome phylogenetic analysis and hypothesized higher relationship of co-clustered members that would ease ligand identification, as related receptors share ligands with similar structure or class. RESULTS: Cross-genome phylogenetic analyses were performed to identify eight major groups of GPCRs dividing them into 32 clusters of 371 human and 113 Drosophila proteins (excluding olfactory, taste and gustatory receptors) and reveal unexpected levels of evolutionary conservation across human and Drosophila GPCRs. We also observe that members of human chemokine receptors, involved in immune response, and most of nucleotide-lipid receptors (except opsins) do not have counterparts in Drosophila. Similarly, a group of Drosophila GPCRs (methuselah receptors), associated in aging, is not present in humans. CONCLUSION: Our analysis suggests ligand class association to 52 unknown Drosophila receptors and 95 unknown human GPCRs. A higher level of phylogenetic organization was revealed in which clusters with common domain architecture or cellular localization or ligand structure or chemistry or a shared function are evident across human and Drosophila genomes. Such analyses will prove valuable for identifying the natural ligands of Drosophila and human orphan receptors that can lead to a better understanding of physiological and pathological roles of these receptors

DIAL: a web-based server for the automatic identification of structural domains in proteins

DIAL is a web server for the automatic identification of structural domains given the 3D coordinates of a protein. Delineation of the structural domains and their exact boundaries are the starting points for the better realization of distantly related members of the domain families, for the rational design of the experiments and for clearer understanding of the biological function. The current server can examine crystallographic multiple chains and provide structural domain solutions that can also describe domain swapping events. The server can be accessed from . The Supplementary data can be accessed from

Genome wide survey of G protein-coupled receptors in Tetraodon nigroviridis

BACKGROUND: The G-protein-coupled receptors (GPCRs) constitute one of the largest and most ancient superfamilies of membrane proteins. They play a central role in physiological processes affecting almost all aspects of the life cycle of an organism. Availability of the complete sets of putative members of a family from diverse species provides the basis for cross genome comparative studies. RESULTS: We have defined the repertoire of GPCR superfamily of Tetraodon complement with the availability of complete sequence of the freshwater puffer fish Tetraodon nigroviridis. Almost all 466 Tetraodon GPCRs (Tnig-GPCRs) identified had a clear human homologue. 189 putative human and Tetraodon GPCR orthologous pairs could be identified. Tetraodon GPCRs are classified into five GRAFS families, by phylogenetic analysis, concurrent with human GPCR classification. CONCLUSION: Direct comparison of GPCRs in Tetraodon and human genomes displays a high level of orthology and supports large-scale gene duplications in Tetraodon. Examples of lineage specific gene expansions were also observed in opsin and odorant receptors. The human and Tetraodon GPCR sequences are analogous in terms of GPCR subfamilies but display disproportionate numbers of receptors at the subfamily level. The teleost genome with its expanded set of GPCRs provides additional and interesting comparators to study both evolution and function of these receptors

Genome-wide survey and phylogeny of S-Ribosylhomocysteinase (LuxS) enzyme in bacterial genomes

Background: The study of survival and communication of pathogenic bacteria is important to combat diseases caused by such micro-organisms. Bacterial cells communicate with each other using a density-dependent cell-cell communication process called Quorum Sensing (QS). LuxS protein is an important member of interspecies quorumsensing system, involved in the biosynthesis of Autoinducer-2 (AI-2), and has been identified as a drug target. Despite the above mentioned significance, their evolution has not been fully studied, particularly from a structural perspective. Results: Search for LuxS in the non-redundant database of protein sequences yielded 3106 sequences. Phylogenetic analysis of these sequences revealed grouping of sequences into five distinct clusters belonging to different phyla and according to their habitat. A majority of the neighbouring genes of LuxS have been found to be hypothetical proteins. However, gene synteny analyses in different bacterial genomes reveal the presence of few interesting gene neighbours. Moreover, LuxS gene was found to be a component of an operon in only six out of 36 genomes. Analysis of conserved motifs in representative LuxS sequences of different clusters revealed the presence of conserved motifs common to sequences of all the clusters as well as motifs unique to each cluster. Homology modelling of LuxS protein sequences of each cluster revealed few structural features unique to protein of each cluster. Analyses of surface electrostatic potentials of the homology models of each cluster showed the interactions that are common to all the clusters, as well as cluster-specific potentials and therefore interacting partners, which may be unique to each cluster. Conclusions: LuxS protein evolved early during the course of bacterial evolution, but has diverged into five subtypes. Analysis of sequence motifs and homology models of representative members reveal cluster-specific structural properties of LuxS. Further, it is also shown that LuxS protein may be involved in various protein-protein or proteinRNA interactions, which may regulate the activity of LuxS proteins in bacteria