Eric Martz

ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids.

It is informative to detect highly conserved positions in proteins and nucleic acid sequence/structure since they are often indicative of structural and/or functional importance. ConSurf (http://consurf.tau.ac.il) and ConSeq (http://conseq.tau.ac.il) are two well-established web servers for calculating the evolutionary conservation of amino acid positions in proteins using an empirical Bayesian inference, starting from protein structure and sequence, respectively. Here, we present the new version of the ConSurf web server that combines the two independent servers, providing an easier and more intuitive step-by-step interface, while offering the user more flexibility during the process. In addition, the new version of ConSurf calculates the evolutionary rates for nucleic acid sequences. The new version is freely available at: http://consurf.tau.ac.il/.

ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures

Key amino acid positions that are important for maintaining the 3D structure of a protein and/or its function(s), e.g. catalytic activity, binding to ligand, DNA or other proteins, are often under strong evolutionary constraints. Thus, the biological importance of a residue often correlates with its level of evolutionary conservation within the protein family. ConSurf () is a web-based tool that automatically calculates evolutionary conservation scores and maps them on protein structures via a user-friendly interface. Structurally and functionally important regions in the protein typically appear as patches of evolutionarily conserved residues that are spatially close to each other. We present here version 3.0 of ConSurf. This new version includes an empirical Bayesian method for scoring conservation, which is more accurate than the maximum-likelihood method that was used in the earlier release. Various additional steps in the calculation can now be controlled by a number of advanced options, thus further improving the accuracy of the calculation. Moreover, ConSurf version 3.0 also includes a measure of confidence for the inferred amino acid conservation scores.

ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules

The degree of evolutionary conservation of an amino acid in a protein or a nucleic acid in DNA/RNA reflects a balance between its natural tendency to mutate and the overall need to retain the structural integrity and function of the macromolecule. The ConSurf web server (http://consurf.tau.ac.il), established over 15 years ago, analyses the evolutionary pattern of the amino/nucleic acids of the macromolecule to reveal regions that are important for structure and/or function. Starting from a query sequence or structure, the server automatically collects homologues, infers their multiple sequence alignment and reconstructs a phylogenetic tree that reflects their evolutionary relations. These data are then used, within a probabilistic framework, to estimate the evolutionary rates of each sequence position. Here we introduce several new features into ConSurf, including automatic selection of the best evolutionary model used to infer the rates, the ability to homology-model query proteins, prediction of the secondary structure of query RNA molecules from sequence, the ability to view the biological assembly of a query (in addition to the single chain), mapping of the conservation grades onto 2D RNA models and an advanced view of the phylogenetic tree that enables interactively rerunning ConSurf with the taxa of a sub-tree.

Selecton 2007: advanced models for detecting positive and purifying selection using a Bayesian inference approach

Biologically significant sites in a protein may be identified by contrasting the rates of synonymous (Ks) and non-synonymous (Ka) substitutions. This enables the inference of site-specific positive Darwinian selection and purifying selection. We present here Selecton version 2.2 (http://selecton.bioinfo.tau.ac.il), a web server which automatically calculates the ratio between Ka and Ks (ω) at each site of the protein. This ratio is graphically displayed on each site using a color-coding scheme, indicating either positive selection, purifying selection or lack of selection. Selecton implements an assembly of different evolutionary models, which allow for statistical testing of the hypothesis that a protein has undergone positive selection. Specifically, the recently developed mechanistic-empirical model is introduced, which takes into account the physicochemical properties of amino acids. Advanced options were introduced to allow maximal fine tuning of the server to the users specific needs, including calculation of statistical support of the ω values, an advanced graphic display of the proteins 3-dimensional structure, use of different genetic codes and inputting of a pre-built phylogenetic tree. Selecton version 2.2 is an effective, user-friendly and freely available web server which implements up-to-date methods for computing site-specific selection forces, and the visualization of these forces on the proteins sequence and structure.

Mechanism of Specific Tumor-Cell Lysis by Alloimmune T Lymphocytes: Resolution and Characterization of Discrete Steps in the Cellular Interaction

A cytolytic thymus-derived lymphocyte (CTL)* is a specialized cell the recognized function of which is immune killing. CTLs are generated by a process of antigen-induced clonal selection, proliferation, and differentiation. Each CTL apparently recognizes a single H-2 alloantigen. CTL targets are eukaryotic tissue cells bearing specific membrane-associated antigen, such as virus-infected autologous cells, grafted cells of genetically different origin, tumor cells, or autologous cells made more immunogenic by chemical modification. CTLs are believed to play a uniquely important role in physiological immune tissue destruction (for which serum immunoglobulins are usually insufficient), probably utilizing mononuclear phagocytes as an amplifying mechanism.

LFA‐1 and Lyt‐2,3, Molecules Associated with T Lymphocyte‐Mediated Killing; and Mac‐1, an LFA‐1 Homologue Associated with Complement Receptor Function1

Killer cells are an important component in the immune response to cells with altered or foreign cell surface antigens. Antigen-specific killing is mediated by a subset of Thy-T thymus-derived (T) lymphocytes which have been termed cytolytic T lymphocytes (CTL). CTL can be elicited in response to allogeneic or xenogeneic cells bearing foreign histocompatibility antigens, or in response to syngeneic cells bearing foreign antigenic determinants introduced by chemical haptenation or viral infection (reviewed in Engers & MacDonald 1976, Golstein 1976, Martz 1977, Henney 1977, Berke 1980, Burakoff et al. 1980). Inductionof maximal cytolyticactivity requires 5 to 10 days for a primary response. Cytolytic activity displays all the hallmarks of specific immunity, i.e. it is highly specific for antigens on the eliciting cells, and it shows accelerated development and reaches

CTL: virus control cells first and cytolytic cells second? DNA fragmentation, apoptosis and the prelytic halt hypothesis

It is usually presumed that cytotoxic T lymphocytes (CTL) stop viral replication by lysing infected cells before a full virus yield has been assembled. Unlike complement-mediated lysis, however, CTL induce apoptosis, including fragmentation of target cell DNA. Why should CTL do this? Here, Eric Martz and Donna Howell suggest that since the major function of CTL appears to be control of viruses, CTL may be able to halt viral replication without inducing rapid lysis. It may be more useful to think of CTL as virus control cells rather than as cytolytic cells.

Epitopia: a web-server for predicting B-cell epitopes

BackgroundDetecting candidate B-cell epitopes in a protein is a basic and fundamental step in many immunological applications. Due to the impracticality of experimental approaches to systematically scan the entire protein, a computational tool that predicts the most probable epitope regions is desirable.ResultsThe Epitopia server is a web-based tool that aims to predict immunogenic regions in either a protein three-dimensional structure or a linear sequence. Epitopia implements a machine-learning algorithm that was trained to discern antigenic features within a given protein. The Epitopia algorithm has been compared to other available epitope prediction tools and was found to have higher predictive power. A special emphasis was put on the development of a user-friendly graphical interface for displaying the results.ConclusionEpitopia is a user-friendly web-server that predicts immunogenic regions for both a protein structure and a protein sequence. Its accuracy and functionality make it a highly useful tool. Epitopia is available at http://epitopia.tau.ac.il and includes extensive explanations and example predictions.

Antigens involved in mouse cytolytic t-lymphocyte (ctl)- -mediated killing: functional screening and topographic relationship.

Abstract To investigate the repertoire of molecules which are associated with cytolytic T-lymphocyte (CTL)-mediated killing, function-blocking monoclonal antibodies (MAb) have been selected and characterized. Spleen cells from rats immunized with secondary mouse CTL were fused with mouse myeloma cells. Antibodies secreted by 2400 hybrid cultures were selected solely by their ability to block CTL-mediated killing in a mouse anti-rat xenogeneic system. Fifteen cultures with antibodies which blocked CTL-mediated killing were chosen for cloning and further characterized by immunoprecipitation and immunofluorescence flow cytometry. One group of five monoclonal antibodies recognized the Lyt-2,3 molecule of 35,000 M r . The second group of six MAb recognized the LFA-1 antigen containing two subunits of 180,000 and 95,000 M r . One MAb giving only partial inhibition of killing was an IgM anti-Thy-1. It strongly agglutinated CTL. The target antigens defined by three other MAb were not definitively identified. Competition in cell binding between anti-Lyt-2,3 and anti-LFA-1 MAb suggested that their blocking effect in cytolysis is due to binding to distinct and spatially separate molecules on effector cells. The results of direct screening for functional blockade support the important role of Lyt-2,3 and LFA-1 molecules in T-cell-mediated cytolysis.

Proteopedia - a scientific 'wiki' bridging the rift between three-dimensional structure and function of biomacromolecules

Many scientists lack the background to fully utilize the wealth of solved three-dimensional biomacromolecule structures. Thus, a resource is needed to present structure/function information in a user-friendly manner to a broad scientific audience. Proteopediahttp://www.proteopedia.org is an interactive, wiki web-resource whose pages have embedded three-dimensional structures surrounded by descriptive text containing hyperlinks that change the appearance (view, representations, colors, labels) of the adjacent three-dimensional structure to reflect the concept explained in the text.