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Mutations in a Plasmodium de-ubiquitinase UBP1 have been linked to antimalarial drug resistance. However, the UBP1-mediated drug-resistant mechanism remains unknown. Through drug selection, genetic mapping, allelic exchange, and functional characterization, here we show that simultaneous mutations of two amino acids (I1560N and P2874T) in the Plasmodium yoelii UBP1 can mediate high-level resistance to mefloquine, lumefantrine, and piperaquine. Mechanistically, the double mutations are shown to impair UBP1 cytoplasmic aggregation and de-ubiquitinating activity, leading to increased ubiquitination levels and altered protein localization, from the parasite digestive vacuole to the plasma membrane, of the P. yoelii multidrug resistance transporter 1 (MDR1). The MDR1 on the plasma membrane enhances the efflux of substrates/drugs out of the parasite cytoplasm to confer multidrug resistance, which can be reversed by inhibition of MDR1 transport. This study reveals a previously unknown drug-resistant mechanism mediated by UBP1 through altered MDR1 localization and substrate transport direction in a mouse model, providing a new malaria treatment strategy.
Pubmed ID: 38413566 RIS Download
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Original SAMTOOLS package has been split into three separate repositories including Samtools, BCFtools and HTSlib. Samtools for manipulating next generation sequencing data used for reading, writing, editing, indexing,viewing nucleotide alignments in SAM,BAM,CRAM format. BCFtools used for reading, writing BCF2,VCF, gVCF files and calling, filtering, summarising SNP and short indel sequence variants. HTSlib used for reading, writing high throughput sequencing data.
View all literature mentionsAmerican company incorporated that develops, manufactures and markets integrated systems for the analysis of genetic variation and biological function. Provides a line of products and services that serve the sequencing, genotyping and gene expression and proteomics markets. Its headquarters are located in San Diego, California.
View all literature mentionsFunctional genomic database for malaria parasites. Database for Plasmodium spp. Provides resource for data analysis and visualization in gene-by-gene or genome-wide scale. PlasmoDB 5.5 contains annotated genomes, evidence of transcription, proteomics evidence, protein function evidence, population biology and evolution data. Data can be queried by selecting from query grid or drop down menus. Results can be combined with each other on query history page. Search results can be downloaded with associated functional data and registered users can store their query history for future retrieval or analysis.Key community database for malaria researchers, intersecting many types of laboratory and computational data, aggregated by gene.
View all literature mentionsSoftware tool as fully automated protein structure homology modeling server, accessible via ExPASy web server, or from program DeepView Swiss Pdb-Viewer. Structural bioinformatics web-server dedicated to homology modeling of 3D protein structures. Used to make protein modelling accessible to all biochemists and molecular biologists.
View all literature mentionsWeb tool to predict order and disorder from amino acid sequence. Used to predict of natural disordered regions in proteins.
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