The molecular chaperone Hsp90 regulates the folding of diverse signal transducers in all eukaryotes, profoundly affecting cellular circuitry. In fungi, Hsp90 influences development, drug resistance, ...and evolution. Hsp90 interacts with -10% of the proteome in the model yeast Saccharomyces cerevisiae, while only two interactions have been identified in Candida albicans, the leading fungal pathogen of humans. Utilizing a chemical genomic approach, we mapped the C. albicans Hsp90 interaction network under diverse stress conditions. The chaperone network is environmentally contingent, and most of the 226 genetic interactors are important for growth only under specific conditions, suggesting that they operate downstream of Hsp90, as with the MAPK Hog1. Few interactors are important for growth in many environments, and these are poised to operate upstream of Hsp90, as with the protein kinase CK2 and the transcription factor Ahr1. We establish environmental contingency in the first chaperone network of a fungal pathogen, novel effectors upstream and downstream of Hsp90, and network rewiring over evolutionary time.
A travel guide to Cytoscape plugins Saito, Rintaro; Smoot, Michael E; Ono, Keiichiro ...
Nature methods,
11/2012, Letnik:
9, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Cytoscape is open-source software for integration, visualization and analysis of biological networks. It can be extended through Cytoscape plugins, enabling a broad community of scientists to ...contribute useful features. This growth has occurred organically through the independent efforts of diverse authors, yielding a powerful but heterogeneous set of tools. We present a travel guide to the world of plugins, covering the 152 publicly available plugins for Cytoscape 2.5-2.8. We also describe ongoing efforts to distribute, organize and maintain the quality of the collection.
SH3 domains are protein modules that mediate protein-protein interactions in many eukaryotic signal transduction pathways. The majority of SH3 domains studied thus far act by binding to proline-rich ...sequences in partner proteins, but a growing number of studies have revealed alternative recognition mechanisms. We have comprehensively surveyed the specificity landscape of human SH3 domains in an unbiased manner using peptide-phage display and deep sequencing. Based on ∼70,000 unique binding peptides, we obtained 154 specificity profiles for 115 SH3 domains, which reveal that roughly half of the SH3 domains exhibit non-canonical specificities and collectively recognize a wide variety of peptide motifs, most of which were previously unknown. Crystal structures of SH3 domains with two distinct non-canonical specificities revealed novel peptide-binding modes through an extended surface outside of the canonical proline-binding site. Our results constitute a significant contribution toward a complete understanding of the mechanisms underlying SH3-mediated cellular responses.
•We obtained a map of 154 specificity profiles for 115 human SH3 domains•Half of the SH3 domains exhibit a variety of non-canonical specificities•Crystal structures reveal novel peptide-binding modes for SH3 domains•The specificity map can guide further structural and biological studies
The 154 specificity profiles obtained for 115 SH3 domains reveal that roughly half of the domains exhibit non-canonical specificities. The wide variety of atypical specificities suggests diverse strategies for recognizing peptide ligands, and crystal structures show the details for two novel SH3-peptide-binding modes.
Pathway Commons (http://www.pathwaycommons.org) is a collection of publicly available pathway data from multiple organisms. Pathway Commons provides a web-based interface that enables biologists to ...browse and search a comprehensive collection of pathways from multiple sources represented in a common language, a download site that provides integrated bulk sets of pathway information in standard or convenient formats and a web service that software developers can use to conveniently query and access all data. Database providers can share their pathway data via a common repository. Pathways include biochemical reactions, complex assembly, transport and catalysis events and physical interactions involving proteins, DNA, RNA, small molecules and complexes. Pathway Commons aims to collect and integrate all public pathway data available in standard formats. Pathway Commons currently contains data from nine databases with over 1400 pathways and 687,000 interactions and will be continually expanded and updated.
The mammalian brain is complex, with multiple cell types performing a variety of diverse functions, but exactly how each cell type is affected in aging remains largely unknown. Here we performed a ...single-cell transcriptomic analysis of young and old mouse brains. We provide comprehensive datasets of aging-related genes, pathways and ligand-receptor interactions in nearly all brain cell types. Our analysis identified gene signatures that vary in a coordinated manner across cell types and gene sets that are regulated in a cell-type specific manner, even at times in opposite directions. These data reveal that aging, rather than inducing a universal program, drives a distinct transcriptional course in each cell population, and they highlight key molecular processes, including ribosome biogenesis, underlying brain aging. Overall, these large-scale datasets (accessible online at https://portals.broadinstitute.org/single_cell/study/aging-mouse-brain ) provide a resource for the neuroscience community that will facilitate additional discoveries directed towards understanding and modifying the aging process.
From an shRNA screen, we identified ClpP as a member of the mitochondrial proteome whose knockdown reduced the viability of K562 leukemic cells. Expression of this mitochondrial protease that has ...structural similarity to the cytoplasmic proteosome is increased in leukemic cells from approximately half of all patients with AML. Genetic or chemical inhibition of ClpP killed cells from both human AML cell lines and primary samples in which the cells showed elevated ClpP expression but did not affect their normal counterparts. Importantly, Clpp knockout mice were viable with normal hematopoiesis. Mechanistically, we found that ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes, and knockdown of ClpP in leukemic cells inhibited oxidative phosphorylation and mitochondrial metabolism.
•ClpP is a mitochondrial protease overexpressed in a subset of AML and stem cells•Inhibition of ClpP decreases the viability of AML cells with high ClpP expression•ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes•Genetic knockdown of ClpP impairs oxidative phosphorylation and complex II
Cole et al. show that ClpP, a mitochondrial protease, is overexpressed in a large fraction of human acute myeloid leukemias (AMLs) and that inactivation of ClpP selectively kills these AML cells via inhibition of oxidative phosphorylation and mitochondrial metabolism.
Patient classification has widespread biomedical and clinical applications, including diagnosis, prognosis, and treatment response prediction. A clinically useful prediction algorithm should be ...accurate, generalizable, be able to integrate diverse data types, and handle sparse data. A clinical predictor based on genomic data needs to be interpretable to drive hypothesis‐driven research into new treatments. We describe netDx, a novel supervised patient classification framework based on patient similarity networks, which meets these criteria. In a cancer survival benchmark dataset integrating up to six data types in four cancer types, netDx significantly outperforms most other machine‐learning approaches across most cancer types. Compared to traditional machine‐learning‐based patient classifiers, netDx results are more interpretable, visualizing the decision boundary in the context of patient similarity space. When patient similarity is defined by pathway‐level gene expression, netDx identifies biological pathways important for outcome prediction, as demonstrated in breast cancer and asthma. netDx can serve as a patient classifier and as a tool for discovery of biological features characteristic of disease. We provide a free software implementation of netDx with automation workflows.
Synopsis
netDx is a supervised patient classification algorithm based on the paradigm of patient similarity networks. It integrates multi‐omic data and uses biological pathway information to help with model interpretability.
In a cancer survival prediction benchmark, netDx performs competitively or better than a diverse panel of machine‐learning algorithms.
When patient similarity is defined by pathway‐level gene expression, netDx identifies biological pathways predictive of outcome, as demonstrated in diverse data sets (breast cancer and asthma).
netDx is freely available as an R package and as a Docker image. Code, tutorials and worked examples are available at: http://netdx.org.
netDx is a supervised patient classification algorithm based on the paradigm of patient similarity networks. It integrates multi‐omic data and uses biological pathway information to help with model interpretability.
The Biomolecular Interaction Network Database (BIND: http://bind.ca) archives biomolecular interaction, complex and pathway information. A web-based system is available to query, view and submit ...records. BIND continues to grow with the addition of individual submissions as well as interaction data from the PDB and a number of large-scale interaction and complex mapping experiments using yeast two hybrid, mass spectrometry, genetic interactions and phage display. We have developed a new graphical analysis tool that provides users with a view of the domain composition of proteins in interaction and complex records to help relate functional domains to protein interactions. An interaction network clustering tool has also been developed to help focus on regions of interest. Continued input from users has helped further mature the BIND data specification, which now includes the ability to store detailed information about genetic interactions. The BIND data specification is available as ASN.1 and XML DTD.
Meningiomas are the most common primary intracranial tumour in adults
. Patients with symptoms are generally treated with surgery as there are no effective medical therapies. The World Health ...Organization histopathological grade of the tumour and the extent of resection at surgery (Simpson grade) are associated with the recurrence of disease; however, they do not accurately reflect the clinical behaviour of all meningiomas
. Molecular classifications of meningioma that reliably reflect tumour behaviour and inform on therapies are required. Here we introduce four consensus molecular groups of meningioma by combining DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation and messenger RNA abundance in a unified analysis. These molecular groups more accurately predicted clinical outcomes compared with existing classification schemes. Each molecular group showed distinctive and prototypical biology (immunogenic, benign NF2 wild-type, hypermetabolic and proliferative) that informed therapeutic options. Proteogenomic characterization reinforced the robustness of the newly defined molecular groups and uncovered highly abundant and group-specific protein targets that we validated using immunohistochemistry. Single-cell RNA sequencing revealed inter-individual variations in meningioma as well as variations in intrinsic expression programs in neoplastic cells that mirrored the biology of the molecular groups identified.
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