SA-Mot: a web server for the identification of motifs of interest extracted from protein loops

The detection of functional motifs is an important step for the determination of protein functions. We present here a new web server SA-Mot (Structural Alphabet Motif) for the extraction and location of structural motifs of interest from protein loops. Contrary to other methods, SA-Mot does not focus only on functional motifs, but it extracts recurrent and conserved structural motifs involved in structural redundancy of loops. SA-Mot uses the structural word notion to extract all structural motifs from uni-dimensional sequences corresponding to loop structures. Then, SA-Mot provides a description of these structural motifs using statistics computed in the loop data set and in SCOP superfamily, sequence and structural parameters. SA-Mot results correspond to an interactive table listing all structural motifs extracted from a target structure and their associated descriptors. Using this information, the users can easily locate loop regions that are important for the protein folding and function. The SA-Mot web server is available at http://sa-mot.mti.univ-paris-diderot.fr

Assembly of an interactive correlation network for the Arabidopsis genome using a novel heuristic clustering algorithm

Peer reviewedPublisher PD

Inter-residue interactions in membrane proteins

Knowing the precise 3D-structure of a protein is crucial to understand its functional mechanism at the molecular level and to develop new pharmacological agents to targeting it. Nowadays only a few hundred integral membrane protein structures have been solved at high resolution due to the associated technical difficulties. In the present study we aim to characterize the main interactions in alpha and beta membrane proteins that are responsible of the maintenance of the overall structure. With this purpose, two nonredundant databases of alpha and beta transmembrane segments were constructed and analysed. The interactions that stabilize the structure of alpha and beta membrane proteins were quantified. The results reveal important differences in inter-residues interactions between alpha and beta membrane proteins. This novel structural information may be useful in predicting 3D models of proteins lacking structural information or in refining initial models of alpha and beta membrane proteins

Motif Discovery in Protein Sequences

Biology has become a data‐intensive research field. Coping with the flood of data from the new genome sequencing technologies is a major area of research. The exponential increase in the size of the datasets produced by “next‐generation sequencing” (NGS) poses unique computational challenges. In this context, motif discovery tools are widely used to identify important patterns in the sequences produced. Biological sequence motifs are defined as short, usually fixed length, sequence patterns that may represent important structural or functional features in nucleic acid and protein sequences such as transcription binding sites, splice junctions, active sites, or interaction interfaces. They can occur in an exact or approximate form within a family or a subfamily of sequences. Motif discovery is therefore an important field in bioinformatics, and numerous methods have been developed for the identification of motifs shared by a set of functionally related sequences. This chapter will review the existing motif discovery methods for protein sequences and their ability to discover biologically important features as well as their limitations for the discovery of new motifs. Finally, we will propose new horizons for motif discovery in order to address the short comings of the existent methods

Integration and mining of malaria molecular, functional and pharmacological data: how far are we from a chemogenomic knowledge space?

The organization and mining of malaria genomic and post-genomic data is highly motivated by the necessity to predict and characterize new biological targets and new drugs. Biological targets are sought in a biological space designed from the genomic data from Plasmodium falciparum, but using also the millions of genomic data from other species. Drug candidates are sought in a chemical space containing the millions of small molecules stored in public and private chemolibraries. Data management should therefore be as reliable and versatile as possible. In this context, we examined five aspects of the organization and mining of malaria genomic and post-genomic data: 1) the comparison of protein sequences including compositionally atypical malaria sequences, 2) the high throughput reconstruction of molecular phylogenies, 3) the representation of biological processes particularly metabolic pathways, 4) the versatile methods to integrate genomic data, biological representations and functional profiling obtained from X-omic experiments after drug treatments and 5) the determination and prediction of protein structures and their molecular docking with drug candidate structures. Progresses toward a grid-enabled chemogenomic knowledge space are discussed.Comment: 43 pages, 4 figures, to appear in Malaria Journa

A Comprehensive Analysis of the Structure-Function Relationship in Proteins Based on Local Structure Similarity

BACKGROUND:Sequence similarity to characterized proteins provides testable functional hypotheses for less than 50% of the proteins identified by genome sequencing projects. With structural genomics it is believed that structural similarities may give functional hypotheses for many of the remaining proteins. METHODOLOGY/PRINCIPAL FINDINGS:We provide a systematic analysis of the structure-function relationship in proteins using the novel concept of local descriptors of protein structure. A local descriptor is a small substructure of a protein which includes both short- and long-range interactions. We employ a library of commonly reoccurring local descriptors general enough to assemble most existing protein structures. We then model the relationship between these local shapes and Gene Ontology using rule-based learning. Our IF-THEN rule model offers legible, high resolution descriptions that combine local substructures and is able to discriminate functions even for functionally versatile folds such as the frequently occurring TIM barrel and Rossmann fold. By evaluating the predictive performance of the model, we provide a comprehensive quantification of the structure-function relationship based only on local structure similarity. Our findings are, among others, that conserved structure is a stronger prerequisite for enzymatic activity than for binding specificity, and that structure-based predictions complement sequence-based predictions. The model is capable of generating correct hypotheses, as confirmed by a literature study, even when no significant sequence similarity to characterized proteins exists. CONCLUSIONS/SIGNIFICANCE:Our approach offers a new and complete description and quantification of the structure-function relationship in proteins. By demonstrating how our predictions offer higher sensitivity than using global structure, and complement the use of sequence, we show that the presented ideas could advance the development of meta-servers in function prediction

Systems analysis of endothelial cell plasma membrane proteome of rat lung microvasculature

<p>Abstract</p> <p>Background</p> <p>Endothelial cells line all blood vessels to form the blood-tissue interface which is critical for maintaining organ homeostasis and facilitates molecular exchange. We recently used tissue subcellular fractionation combined with several multi-dimensional mass spectrometry-based techniques to enhance identification of lipid-embedded proteins for large-scale proteomic mapping of luminal endothelial cell plasma membranes isolated directly from rat lungs <it>in vivo</it>. The biological processes and functions of the proteins expressed at this important blood-tissue interface remain unexplored at a large scale.</p> <p>Results</p> <p>We performed an unbiased systems analysis of the endothelial cell surface proteome containing over 1800 proteins to unravel the major functions and pathways apparent at this interface. As expected, many key functions of plasma membranes in general (i.e., cell surface signaling pathways, cytoskeletal organization, adhesion, membrane trafficking, metabolism, mechanotransduction, membrane fusion, and vesicle-mediated transport) and endothelial cells in particular (i.e., blood vessel development and maturation, angiogenesis, regulation of endothelial cell proliferation, protease activity, and endocytosis) were significantly overrepresented in this proteome. We found that endothelial cells express multiple proteins that mediate processes previously reported to be restricted to neuronal cells, such as neuronal survival and plasticity, axon growth and regeneration, synaptic vesicle trafficking and neurotransmitter metabolic process. Surprisingly, molecular machinery for protein synthesis was also detected as overrepresented, suggesting that endothelial cells, like neurons, can synthesize proteins locally at the cell surface.</p> <p>Conclusion</p> <p>Our unbiased systems analysis has led to the potential discovery of unexpected functions in normal endothelium. The discovery of the existence of protein synthesis at the plasma membrane in endothelial cells provides new insight into the blood-tissue interface and endothelial cell surface biology.</p

The evolutionary differentiation of two histone H2A.Z variants in chordates (H2A.Z-1 and H2A.Z-2) is mediated by a stepwise mutation process that affects three amino acid residues

<p>Abstract</p> <p>Background</p> <p>The histone H2A family encompasses the greatest number of core histone variants of which the replacement variant H2A.Z is currently one of the most heavily studied. No clear mechanism for the functional variability that H2A.Z imparts to chromatin has yet been proposed. While most of the past studies have referred to H2A.Z generically as a single protein, in vertebrates it is a mixture of two protein forms H2A.Z-1 (previously H2A.Z) and H2A.Z-2 (previously H2A.F/Z or H2A.V) that differ by three amino acids.</p> <p>Results</p> <p>We have performed an extensive study on the long-term evolution of H2A.Z across metazoans with special emphasis on the possible selective mechanisms responsible for the differentiation between H2A.Z-1 and H2A.Z-2. Our results reveal a common origin of both forms early in chordate evolution. The evolutionary process responsible for the differentiation involves refined stepwise mutation change within the codons of the three differential residues. This eventually led to differences in the intensity of the selective constraints acting upon the different H2A.Z forms in vertebrates.</p> <p>Conclusion</p> <p>The results presented in this work definitively reveal that the existence of H2A.Z-1 and H2A.Z-2 is not a whim of random genetic drift. Our analyses demonstrate that H2A.Z-2 is not only subject to a strong purifying selection but it is significantly more evolutionarily constrained than H2A.Z-1. Whether or not the evolutionary drift between H2A.Z-1 and H2A.Z-2 has resulted in a functional diversification of these proteins awaits further research. Nevertheless, the present work suggests that in the process of their differently constrained evolutionary pathways, these two forms may have acquired new or complementary functions.</p