RESUMEN
Almost twenty years after its initial release, the Eukaryotic Linear Motif (ELM) resource remains an invaluable source of information for the study of motif-mediated protein-protein interactions. ELM provides a comprehensive, regularly updated and well-organised repository of manually curated, experimentally validated short linear motifs (SLiMs). An increasing number of SLiM-mediated interactions are discovered each year and keeping the resource up-to-date continues to be a great challenge. In the current update, 30 novel motif classes have been added and five existing classes have undergone major revisions. The update includes 411 new motif instances mostly focused on cell-cycle regulation, control of the actin cytoskeleton, membrane remodelling and vesicle trafficking pathways, liquid-liquid phase separation and integrin signalling. Many of the newly annotated motif-mediated interactions are targets of pathogenic motif mimicry by viral, bacterial or eukaryotic pathogens, providing invaluable insights into the molecular mechanisms underlying infectious diseases. The current ELM release includes 317 motif classes incorporating 3934 individual motif instances manually curated from 3867 scientific publications. ELM is available at: http://elm.eu.org.
Asunto(s)
Enfermedades Transmisibles/genética , Bases de Datos de Proteínas , Interacciones Huésped-Patógeno/genética , Dominios y Motivos de Interacción de Proteínas , Programas Informáticos , Citoesqueleto de Actina/química , Citoesqueleto de Actina/metabolismo , Animales , Sitios de Unión , Ciclo Celular/genética , Membrana Celular/química , Membrana Celular/metabolismo , Enfermedades Transmisibles/metabolismo , Enfermedades Transmisibles/virología , Ciclinas/química , Ciclinas/genética , Ciclinas/metabolismo , Células Eucariotas/citología , Células Eucariotas/metabolismo , Células Eucariotas/virología , Regulación de la Expresión Génica , Humanos , Integrinas/química , Integrinas/genética , Integrinas/metabolismo , Ratones , Anotación de Secuencia Molecular , Unión Proteica , Ratas , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Transducción de Señal , Vesículas Transportadoras/química , Vesículas Transportadoras/metabolismo , Virus/genética , Virus/metabolismoRESUMEN
The risk of zoonotic coronavirus spillover into the human population, as highlighted by the SARS-CoV-2 pandemic, demands the development of pan-coronavirus antivirals. The efficacy of existing antiviral ribonucleoside/ribonucleotide analogs, such as remdesivir, is decreased by the viral proofreading exonuclease NSP14-NSP10 complex. Here, using a novel assay and in silico modeling and screening, we identified NSP14-NSP10 inhibitors that increase remdesivir's potency. A model compound, sofalcone, both inhibits the exonuclease activity of SARS-CoV-2, SARS-CoV, and MERS-CoV in vitro, and synergistically enhances the antiviral effect of remdesivir, suppressing the replication of SARS-CoV-2 and the related human coronavirus OC43. The validation of top hits from our primary screenings using cellular systems provides proof-of-concept for the NSP14 complex as a therapeutic target.
Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Exorribonucleasas/metabolismo , SARS-CoV-2/efectos de los fármacos , Proteínas no Estructurales Virales/metabolismo , Proteínas Reguladoras y Accesorias Virales/metabolismo , Células A549 , Adenosina Monofosfato/farmacología , Alanina/farmacología , Antivirales/farmacología , Humanos , SARS-CoV-2/enzimología , Replicación Viral/efectos de los fármacosRESUMEN
MOTIVATION: Cell polarity refers to the asymmetric organization of cellular components in various cells. Epithelial cells are the best-known examples of polarized cells, featuring apical and basolateral membrane domains. Mounting evidence suggests that short linear motifs play a major role in protein trafficking to these domains, although the exact rules governing them are still elusive. RESULTS: In this study we prepared neural networks that capture recurrent patterns to classify transmembrane proteins localizing into apical and basolateral membranes. Asymmetric expression of drug transporters results in vectorial drug transport, governing the pharmacokinetics of numerous substances, yet the data on how proteins are sorted in epithelial cells is very scattered. The provided method may offer help to experimentalists to identify or better characterize molecular networks regulating the distribution of transporters or surface receptors (including viral entry receptors like that of COVID-19). AVAILABILITY: The prediction server PolarProtPred is available at http://polarprotpred.ttk.hu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
RESUMEN
Most cells in multicellular organisms are somehow asymmetric, polarized: maintaining separate membrane domains. Typical examples are the epithelial cells (apical-basal polarization), neurons (dendritic-axonal domains), or migratory cells (with a leading and a trailing edge). Here we present the most comprehensive database containing experimentally verified mammalian proteins that display polarized sorting or secretion, focusing on epithelial polarity. In addition to the source cells or tissues, homology-based inferences and transmembrane topology (if applicable) are all provided. PolarProtDb also offers a detailed interface displaying all information that may be relevant for trafficking: including post-translational modifications (glycosylations and phosphorylations), known or predicted short linear motifs conserved across orthologs, as well as potential interaction partners. Data on polarized sorting has so far been scattered across myriads of publications, hence difficult to access. This information can help researchers in several areas, such as scanning for potential entry points of viral agents like COVID-19. PolarProtDb shall be a useful resource to design future experiments as well as for comparative analyses. The database is available at http://polarprotdb.enzim.hu.