The signaling adaptor p62 is a critical mediator of important cellular functions, owing to its ability to establish interactions with various signaling intermediaries. Here, we identify raptor as an ...interacting partner of p62. Thus, p62 is an integral part of the mTORC1 complex and is necessary to mediate amino acid signaling for the activation of S6K1 and 4EBP1. p62 interacts in an amino acid-dependent manner with mTOR and raptor. In addition, p62 binds the Rags proteins and favors formation of the active Rag heterodimer that is further stabilized by raptor. Interestingly, p62 colocalizes with Rags at the lysosomal compartment and is required for the interaction of mTOR with Rag GTPases in vivo and for translocation of the mTORC1 complex to the lysosome, a crucial step for mTOR activation.
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► p62 is a component of mTORC1 complex and not mTORC2 via interaction with raptor ► p62 is required for mTORC1 activation in response to amino acids ► p62 interacts with the Rag GTPases and induces the formation of the active Rag dimer ► p62 mediates mTORC1 recruitment to lysosomes
Survey of Protein Sequence Embedding Models Tran, Chau; Khadkikar, Siddharth; Porollo, Aleksey
International journal of molecular sciences,
02/2023, Letnik:
24, Številka:
4
Journal Article
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Derived from the natural language processing (NLP) algorithms, protein language models enable the encoding of protein sequences, which are widely diverse in length and amino acid composition, in ...fixed-size numerical vectors (embeddings). We surveyed representative embedding models such as Esm, Esm1b, ProtT5, and SeqVec, along with their derivatives (GoPredSim and PLAST), to conduct the following tasks in computational biology: embedding the
proteome, gene ontology (GO) annotation of the uncharacterized proteins of this organism, relating variants of human proteins to disease status, correlating mutants of beta-lactamase TEM-1 from
with experimentally measured antimicrobial resistance, and analyzing diverse fungal mating factors. We discuss the advances and shortcomings, differences, and concordance of the models. Of note, all of the models revealed that the uncharacterized proteins in yeast tend to be less than 200 amino acids long, contain fewer aspartates and glutamates, and are enriched for cysteine. Less than half of these proteins can be annotated with GO terms with high confidence. The distribution of the cosine similarity scores of benign and pathogenic mutations to the reference human proteins shows a statistically significant difference. The differences in embeddings of the reference TEM-1 and mutants have low to no correlation with minimal inhibitory concentrations (MIC).
Environmental allergens, including fungi, insects and mites, trigger type 2 immunity; however, the innate sensing mechanisms and initial signaling events remain unclear. Herein, we demonstrate that ...allergens trigger RIPK1-caspase 8 ripoptosome activation in epithelial cells. The active caspase 8 subsequently engages caspases 3 and 7, which directly mediate intracellular maturation and release of IL-33, a pro-atopy, innate immunity, alarmin cytokine. Mature IL-33 maintained functional interaction with the cognate ST2 receptor and elicited potent pro-atopy inflammatory activity in vitro and in vivo. Inhibiting caspase 8 pharmacologically and deleting murine Il33 and Casp8 each attenuated allergic inflammation in vivo. Clinical data substantiated ripoptosome activation and IL-33 maturation as likely contributors to human allergic inflammation. Our findings reveal an epithelial barrier, allergen-sensing mechanism that converges on the ripoptosome as an intracellular molecular signaling platform, triggering type 2 innate immune responses. These findings have significant implications for understanding and treating human allergic diseases.
Antimicrobial resistance (AMR) is a major health concern worldwide. A better understanding of the underlying molecular mechanisms is needed. Advances in whole genome sequencing and other ...high-throughput unbiased instrumental technologies to study the molecular pathogenicity of infectious diseases enable the accumulation of large amounts of data that are amenable to bioinformatic analysis and the discovery of new signatures of AMR. In this work, we review representative methods published in the past five years to define major approaches developed to-date in the understanding of AMR mechanisms. Advantages and limitations for applications of these methods in clinical laboratory testing and basic research are discussed.
Early detection of antimicrobial resistance in pathogens and prescription of more effective antibiotics is a fast-emerging need in clinical practice. High-throughput sequencing technology, such as ...whole genome sequencing (WGS), may have the capacity to rapidly guide the clinical decision-making process. The prediction of antimicrobial resistance in Gram-negative bacteria, often the cause of serious systemic infections, is more challenging as genotype-to-phenotype (drug resistance) relationship is more complex than for most Gram-positive organisms.
We have used NCBI BioSample database to train and cross-validate eight XGBoost-based machine learning models to predict drug resistance to cefepime, cefotaxime, ceftriaxone, ciprofloxacin, gentamicin, levofloxacin, meropenem, and tobramycin tested in
,
,
,
, and
. The input is the WGS data in terms of the coverage of known antibiotic resistance genes by shotgun sequencing reads. Models demonstrate high performance and robustness to class imbalanced datasets.
Whole genome sequencing enables the prediction of antimicrobial resistance in Gram-negative bacteria. We present a tool that provides an
antibiogram for eight drugs. Predictions are accompanied with a reliability index that may further facilitate the decision making process. The demo version of the tool with pre-processed samples is available at https://vancampn.shinyapps.io/wgs2amr/. The stand-alone version of the predictor is available at https://github.com/pieterjanvc/wgs2amr/.
Macromolecular visualization as well as automated structural and functional annotation tools play an increasingly important role in the post-genomic era, contributing significantly towards the ...understanding of molecular systems and processes. For example, three dimensional (3D) models help in exploring protein active sites and functional hot spots that can be targeted in drug design. Automated annotation and visualization pipelines can also reveal other functionally important attributes of macromolecules. These goals are dependent on the availability of advanced tools that integrate better the existing databases, annotation servers and other resources with state-of-the-art rendering programs.
We present a new tool for protein structure analysis, with the focus on annotation and visualization of protein complexes, which is an extension of our previously developed POLYVIEW web server. By integrating the web technology with state-of-the-art software for macromolecular visualization, such as the PyMol program, POLYVIEW-3D enables combining versatile structural and functional annotations with a simple web-based interface for creating publication quality structure rendering, as well as animated images for Powerpoint, web sites and other electronic resources. The service is platform independent and no plug-ins are required. Several examples of how POLYVIEW-3D can be used for structural and functional analysis in the context of protein-protein interactions are presented to illustrate the available annotation options.
POLYVIEW-3D server features the PyMol image rendering that provides detailed and high quality presentation of macromolecular structures, with an easy to use web-based interface. POLYVIEW-3D also provides a wide array of options for automated structural and functional analysis of proteins and their complexes. Thus, the POLYVIEW-3D server may become an important resource for researches and educators in the fields of protein science and structural bioinformatics. The new server is available at http://polyview.cchmc.org/polyview3d.html.
Calpains are a family of intracellular, calcium-dependent cysteine proteases involved in a variety of regulatory processes, including cytoskeletal dynamics, cell-cycle progression, signal ...transduction, gene expression, and apoptosis. These enzymes have been implicated in a number of disease processes, notably for this review involving eosinophilic tissue inflammation, such as eosinophilic esophagitis (EoE), a chronic inflammatory disorder triggered by allergic hypersensitivity to food and associated with genetic variants in calpain 14 (CAPN14) . Herein we review the genetic, structural, and biochemical properties of CAPN14 and its gene product CAPN14, and its emerging role in patients with EoE. The CAPN14 gene is localized at chromosome 2p23.1-p21 and is most homologous to CAPN13 (36% sequence identity), which is located 365 kb downstream of CAPN14 . Structurally, CAPN14 has classical calpain motifs, including a cysteine protease core. In comparison with other human calpains, CAPN14 has a unique expression pattern, with the highest levels in the upper gastrointestinal tract, particularly in the squamous epithelium of the esophagus. The CAPN14 gene is positioned in an epigenetic hotspot regulated by IL-13, a TH 2 cytokine with increased levels in patients with EoE that has been shown to be a mediator of the disease. CAPN14 induces disruptive effects on the esophageal epithelium by impairing epithelial barrier function in association with loss of desmoglein-1 expression and has a regulatory role in repairing epithelial changes induced by IL-13. Thus CAPN14 is a unique protease with distinct tissue-specific expression and function in patients with EoE and is a potential therapeutic target for EoE and related eosinophilic and allergic diseases.
Macrophages possess numerous mechanisms to combat microbial invasion, including sequestration of essential nutrients, like zinc (Zn). The pleiotropic cytokine granulocyte macrophage-colony ...stimulating factor (GM-CSF) enhances antimicrobial defenses against intracellular pathogens such as Histoplasma capsulatum, but its mode of action remains elusive. We have found that GM-CSF-activated infected macrophages sequestered labile Zn by inducing binding to metallothioneins (MTs) in a STAT3 and STAT5 transcription-factor-dependent manner. GM-CSF upregulated expression of Zn exporters, Slc30a4 and Slc30a7; the metal was shuttled away from phagosomes and into the Golgi apparatus. This distinctive Zn sequestration strategy elevated phagosomal H+ channel function and triggered reactive oxygen species generation by NADPH oxidase. Consequently, H. capsulatum was selectively deprived of Zn, thereby halting replication and fostering fungal clearance. GM-CSF mediated Zn sequestration via MTs in vitro and in vivo in mice and in human macrophages. These findings illuminate a GM-CSF-induced Zn-sequestration network that drives phagocyte antimicrobial effector function.
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•Metallothioneins, or Zn-sequestering proteins, drive GM-CSF effector function•Zn sequestration augments production of reactive oxygen species via HV1•GM-CSF triggers Zn deprivation and enhances ROS to kill fungi in macrophages•GM-CSF drives Zn sequestration in vivo and in human macrophages
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