A Completely Reimplemented MPI Bioinformatics Toolkit with a New HHpred Server at its Core

ExPASy (http://www.expasy.org) has worldwide reputation as one of the main bioinformatics resources for proteomics. It has now evolved, becoming an extensible and integrative portal accessing many scientific resources, databases and software tools in different areas of life sciences. Scientists can henceforth access seamlessly a wide range of resources in many different domains, such as proteomics, genomics, phylogeny/evolution, systems biology, population genetics, transcriptomics, etc. The individual resources (databases, web-based and downloadable software tools) are hosted in a 'decentralized' way by different groups of the SIB Swiss Institute of Bioinformatics and partner institutions. Specifically, a single web portal provides a common entry point to a wide range of resources developed and operated by different SIB groups and external institutions. The portal features a search function across 'selected' resources. Additionally, the availability and usage of resources are monitored. The portal is aimed for both expert users and people who are not familiar with a specific domain in life sciences. The new web interface provides, in particular, visual guidance for newcomers to ExPASy.

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ExPASy: SIB bioinformatics resource portal.

Cavities on a proteins surface as well as specific amino acid positioning within it create the physicochemical properties needed for a protein to perform its function. CASTp (http://cast.engr.uic.edu) is an online tool that locates and measures pockets and voids on 3D protein structures. This new version of CASTp includes annotated functional information of specific residues on the protein structure. The annotations are derived from the Protein Data Bank (PDB), Swiss-Prot, as well as Online Mendelian Inheritance in Man (OMIM), the latter contains information on the variant single nucleotide polymorphisms (SNPs) that are known to cause disease. These annotated residues are mapped to surface pockets, interior voids or other regions of the PDB structures. We use a semi-global pair-wise sequence alignment method to obtain sequence mapping between entries in Swiss-Prot, OMIM and entries in PDB. The updated CASTp web server can be used to study surface features, functional regions and specific roles of key residues of proteins.

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CASTp: computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated residues.

ScanProsite--http://www.expasy.org/tools/scanprosite/--is a new and improved version of the web-based tool for detecting PROSITE signature matches in protein sequences. For a number of PROSITE profiles, the tool now makes use of ProRules--context-dependent annotation templates--to detect functional and structural intra-domain residues. The detection of those features enhances the power of function prediction based on profiles. Both user-defined sequences and sequences from the UniProt Knowledgebase can be matched against custom patterns, or against PROSITE signatures. To improve response times, matches of sequences from UniProtKB against PROSITE signatures are now retrieved from a pre-computed match database. Several output modes are available including simple text views and a rich mode providing an interactive match and feature viewer with a graphical representation of results.

ScanProsite: detection of PROSITE signature matches and ProRule-associated functional and structural residues in proteins

HP1a can nucleate into foci that display liquid properties during the early stages of heterochromatin domain formation in Drosophila embryos, suggesting that the repressive action of heterochromatin may be mediated in part by emergent properties of phase separation. The gene-silencing action of heterochromatin is thought to arise from the spread of proteins such as HP1 that compact the underlying chromatin and recruit repressors. Two papers in this issue demonstrate that HP1α has the ability to form phase-separated droplets. Gary Karpen and colleagues show that HP1α can nucleate into foci that display liquid properties during the early stages of heterochromatin domain formation in Drosophila embryos. Geeta Narlikar and colleagues demonstrate that human HP1α protein also forms phase-separated droplets. Phosphorylation or DNA binding promotes the physical partitioning of HP1α out of the soluble aqueous phase into droplets. These related findings suggest that the repressive action of heterochromatin may be in part mediated by the phase separation of HP1, with the droplets being initiated or dissolved by various ligands depending on nuclear context. Constitutive heterochromatin is an important component of eukaryotic genomes that has essential roles in nuclear architecture, DNA repair and genome stability1, and silencing of transposon and gene expression2. Heterochromatin is highly enriched for repetitive sequences, and is defined epigenetically by methylation of histone H3 at lysine 9 and recruitment of its binding partner heterochromatin protein 1 (HP1). A prevalent view of heterochromatic silencing is that these and associated factors lead to chromatin compaction, resulting in steric exclusion of regulatory proteins such as RNA polymerase from the underlying DNA3. However, compaction alone does not account for the formation of distinct, multi-chromosomal, membrane-less heterochromatin domains within the nucleus, fast diffusion of proteins inside the domain, and other dynamic features of heterochromatin. Here we present data that support an alternative hypothesis: that the formation of heterochromatin domains is mediated by phase separation, a phenomenon that gives rise to diverse non-membrane-bound nuclear, cytoplasmic and extracellular compartments4. We show that Drosophila HP1a protein undergoes liquid–liquid demixing in vitro, and nucleates into foci that display liquid properties during the first stages of heterochromatin domain formation in early Drosophila embryos. Furthermore, in both Drosophila and mammalian cells, heterochromatin domains exhibit dynamics that are characteristic of liquid phase-separation, including sensitivity to the disruption of weak hydrophobic interactions, and reduced diffusion, increased coordinated movement and inert probe exclusion at the domain boundary. We conclude that heterochromatic domains form via phase separation, and mature into a structure that includes liquid and stable compartments. We propose that emergent biophysical properties associated with phase-separated systems are critical to understanding the unusual behaviours of heterochromatin, and how chromatin domains in general regulate essential nuclear functions.

Phase separation drives heterochromatin domain formation

The ExPASy (the Expert Protein Analysis System) World Wide Web server (http://www.expasy.org), is provided as a service to the life science community by a multidisciplinary team at the Swiss Institute of Bioinformatics (SIB). It provides access to a variety of databases and analytical tools dedicated to proteins and proteomics. ExPASy databases include SWISS-PROT and TrEMBL, SWISS-2DPAGE, PROSITE, ENZYME and the SWISS-MODEL repository. Analysis tools are available for specific tasks relevant to proteomics, similarity searches, pattern and profile searches, post-translational modification prediction, topology prediction, primary, secondary and tertiary structure analysis and sequence alignment. These databases and tools are tightly interlinked: a special emphasis is placed on integration of database entries with related resources developed at the SIB and elsewhere, and the proteomics tools have been designed to read the annotations in SWISS-PROT in order to enhance their predictions. ExPASy started to operate in 1993, as the first WWW server in the field of life sciences. In addition to the main site in Switzerland, seven mirror sites in different continents currently serve the user community.

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ExPASy: The proteomics server for in-depth protein knowledge and analysis.

ExPASy [1,2] (the Expert Protein Analysis System) is a World Wide Web server (http://www.expasy.org) which is provided as a service to the Life Sciences community. Its main focus is on proteins. It provides access to a variety of databases and analytical tools dedicated to what is now known as proteomics. It is developed at the Swiss Institute of Bioinformatics (SIB) (http://www.isb-sib.ch) by a multidisciplinary team. It first started to operate in August 1993 and has been running without interruption since that date. It seems to have been the first WWW server to be established in the field of life sciences. In December 2002 it had been accessed 242 million times by a total of more than 3 million computer hosts from 185 countries. We describe here what are the information resources and tools available on ExPASy.

The ExPASy proteome WWW server in 2003

ExPASy es un servidor de biologia molecular que provee acceso a informacion en proteomica a traves de un conjunto de herramientas de analisis y bases de datos dedicadas. Este servidor, desarrollado por el Instituto Suizo de Bioinformatica (SIB), es pionero en su clase y actualmente se ha convertido en una de las refe-rencias mas consultadas por centros de investigacion e industrias de biotecnologia a nivel mundial. Sitios mirrors han sido implementados alrededor del mundo, en instituciones academicas y de investigacion, para ofrecer un acceso eficiente a los centros de investigacion y desarrollo en biologia molecular geograficamente distri-buidos. La Universidad Catolica Boliviana, mediante el Instituto de Investigacion en Informatica Aplicada (IIIA), en colaboracion con el SIB, ha implementado un nuevo servidor mirror http://bo.expasy.org para la region latinoamericana que ha sido puesto a disposicion de la comunidad cientifica a principios de noviembre 2002. Este articulo tiene por objetivo presentar el contenido del sitio mirror y sus posibles aplicaciones para la investigacion y la industria.

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Ivan Ivanyi

Papers

ExPASy: The proteomics server for in-depth protein knowledge and analysis.

The ExPASy proteome WWW server in 2003

El nuevo servidor Latinoamericano de biologia molecular de la UCB: bo.expasy.org