Missense variant interaction scanning reveals a critical role of the FERM domain for tumor suppressor protein NF2 conformation and function.

NF2 (moesin-ezrin-radixin-like [MERLIN] tumor suppressor) is frequently inactivated in cancer, where its NF2 tumor suppressor functionality is tightly coupled to protein conformation. How NF2 conformation is regulated and how NF2 conformation influences tumor suppressor activity is a largely open question. Here, we systematically characterized three NF2 conformation-dependent protein interactions utilizing deep mutational scanning interaction perturbation analyses.

A human kinase yeast array for the identification of kinases modulating phosphorylation-dependent protein-protein interactions.

Protein kinases play an important role in cellular signaling pathways and their dysregulation leads to multiple diseases, making kinases prime drug targets. While more than 500 human protein kinases are known to collectively mediate phosphorylation of over 290,000 S/T/Y sites, the activities have been characterized only for a minor, intensively studied subset. To systematically address this discrepancy, we developed a human kinase array in Saccharomyces cerevisiae as a simple readout tool to systematically assess kinase activities.

Horizon Scanning: Rise of Planetary Health Genomics and Digital Twins for Pandemic Preparedness.

The Covid-19 pandemic accelerated research and development not only in infectious diseases but also in digital technologies to improve monitoring, forecasting, and intervening on planetary and ecological risks. In the European Commission, the Destination Earth (DestinE) is a current major initiative to develop a digital model of the Earth (a "digital twin") with high precision. Moreover, omics systems science is undergoing digital transformation impacting nearly all dimensions of the field, including real-time phenotype capture to data analytics using machine learning and artificial intelligence, to name but a few emerging frontiers.

A modular synthetic route to size-defined immunogenic b antigens is key to the identification of an octasaccharide lead vaccine candidate.

The first glycoconjugate vaccine using isolated glycans was licensed to protect children from serotype b (Hib) infections. Subsequently, the first semisynthetic glycoconjugate vaccine using a mixture of antigens derived by polymerization targeted the same pathogen. Still, a detailed understanding concerning the correlation between oligosaccharide chain length and the immune response towards the polyribosyl-ribitol-phosphate (PRP) capsular polysaccharide that surrounds Hib remains elusive.

Multi-Omics Research Trends in Sepsis: A Bibliometric, Comparative Analysis Between the United States, the European Union 28 Member States, and China.

"-Omics" research is in transition with the recent rise of multi-omics technology platforms. Integration of "-omics" and multi-omics research is of high priority in sepsis, a heterogeneous syndrome that is widely recognized as a global health burden and a priority biomedical funding field. We report here an original study on bibliometric trends in the use of "-omics" technologies, and multi-omics approaches in particular, in sepsis research in three (supra)national settings, the United States, the European Union 28 Member States (EU-28), and China.

Protein interaction perturbation profiling at amino-acid resolution.

The identification of genomic variants in healthy and diseased individuals continues to rapidly outpace our ability to functionally annotate these variants. Techniques that both systematically assay the functional consequences of nucleotide-resolution variation and can scale to hundreds of genes are urgently required. We designed a sensitive yeast two-hybrid-based 'off switch' for positive selection of interaction-disruptive variants from complex genetic libraries.

Defining Human Tyrosine Kinase Phosphorylation Networks Using Yeast as an In Vivo Model Substrate.

Systematic assessment of tyrosine kinase-substrate relationships is fundamental to a better understanding of cellular signaling and its profound alterations in human diseases such as cancer. In human cells, such assessments are confounded by complex signaling networks, feedback loops, conditional activity, and intra-kinase redundancy. Here we address this challenge by exploiting the yeast proteome as an in vivo model substrate.

Bioinformatics Analysis of PTM-Modified Protein Interaction Networks and Complexes.

Normal cellular functioning is maintained by macromolecular machines that control both core and specialized molecular tasks. These machines are in large part multi-subunit protein complexes that undergo regulation at multiple levels, from expression of requisite components to a vast array of post-translational modifications (PTMs). PTMs such as phosphorylation, ubiquitination, and acetylation currently number more than 200,000 in the human proteome and function within all molecular pathways.

Omics approaches to individual variation: modeling networks and the virtual patient.

Every human is unique. We differ in our genomes, environment, behavior, disease history, and past and current medical treatment-a complex catalog of differences that often leads to variations in the way each of us responds to a particular therapy. We argue here that true personalization of drug therapies will rely on "virtual patient" models based on a detailed characterization of the individual patient by molecular, imaging, and sensor techniques.

Systematic Protein-Protein Interaction Analysis Reveals Intersubcomplex Contacts in the Nuclear Pore Complex.

The nuclear pore complex (NPC) enables transport across the nuclear envelope. It is one of the largest multiprotein assemblies in the cell, built from about 30 proteins called nucleoporins (Nups), organized into distinct subcomplexes. Structure determination of the NPC is a major research goal.

Virtual Clinical Trials, an Essential Step in Increasing the Effectiveness of the Drug Development Process.

Every patient is different--his/her genomes, environment, disease history and exposure to drugs. Tumours, in particular, are often heterogeneous in their genetic make-up and their response to drugs, both within and between samples. Classic clinical trials basically ignore this complexity or, as in stratified medicine, attempt to reduce it to an analysis of a small number of still enormously heterogeneous patient groups.

Phospho-tyrosine dependent protein-protein interaction network.

Post-translational protein modifications, such as tyrosine phosphorylation, regulate protein-protein interactions (PPIs) critical for signal processing and cellular phenotypes. We extended an established yeast two-hybrid system employing human protein kinases for the analyses of phospho-tyrosine (pY)-dependent PPIs in a direct experimental, large-scale approach. We identified 292 mostly novel pY-dependent PPIs which showed high specificity with respect to kinases and interacting proteins and validated a large fraction in co-immunoprecipitation experiments from mammalian cells.

Studying post-translational modifications with protein interaction networks.

At least 46 interactome studies, broad at proteome scale or biologically more focused, have together mapped about 75,000 human protein-protein interactions (PPIs). Many of the studies addressed local interactome data paucity analyzing specific homeostatic and regulatory systems, with recent focus demonstrating the involvement of post-translational protein modification (PTM) enzyme families in a wide range of cellular functions. These datasets provided insight into binding mechanisms, the dynamic modularity of complexes or delineated combinatorial enzymatic cascades.

Molecular interaction networks in the analyses of sequence variation and proteomics data.

Protein-protein interaction networks are typically generated in standard cell lines or model organisms as it is prohibitively difficult to record large interaction datasets from specific tissues or disease models at a reasonable pace. Although the interaction data are of high confidence, they thus do not reflect in vivo relationships as such. A wealth of physiologically relevant protein information, obtained under different conditions and from different systems, is available including information on genetic variation, protein levels, and PTMs.

Dual coordination of post translational modifications in human protein networks.

Post-translational modifications (PTMs) regulate protein activity, stability and interaction profiles and are critical for cellular functioning. Further regulation is gained through PTM interplay whereby modifications modulate the occurrence of other PTMs or act in combination. Integration of global acetylation, ubiquitination and tyrosine or serine/threonine phosphorylation datasets with protein interaction data identified hundreds of protein complexes that selectively accumulate each PTM, indicating coordinated targeting of specific molecular functions.

A Y2H-seq approach defines the human protein methyltransferase interactome.

To accelerate high-density interactome mapping, we developed a yeast two-hybrid interaction screening approach involving short-read second-generation sequencing (Y2H-seq) with improved sensitivity and a quantitative scoring readout allowing rapid interaction validation. We applied Y2H-seq to investigate enzymes involved in protein methylation, a largely unexplored post-translational modification. The reported network of 523 interactions involving 22 methyltransferases or demethylases is comprehensively annotated and validated through coimmunoprecipitation experiments and defines previously undiscovered cellular roles of nonhistone protein methylation.

Expression analysis of proline rich 15 (Prr15) in mouse and human gastrointestinal tumors.

Proline rich 15 (Prr15), which encodes a protein of unknown function, is expressed almost exclusively in postmitotic cells both during fetal development and in adult tissues, such as the intestinal epithelium and the testis. To determine if this specific expression is lost in intestinal neoplasias, we examined Prr15 expression by in situ hybridization (ISH) on mouse intestinal tumors caused by different gene mutations, and on human colorectal cancer (CRC) samples. Prr15/PRR15 expression was consistently observed in mouse gastrointestinal (GI) tumors caused by mutations in the Apc gene, as well as in several advanced stage human CRCs.