A5042128774- Parasites and Host Interactions
- Sphingolipid Metabolism and Signaling
- Parasitic Infections and Diagnostics
- Toxoplasma gondii Research Studies
- Drug Transport and Resistance Mechanisms
- Erythrocyte Function and Pathophysiology
- Cellular transport and secretion
- Parasite Biology and Host Interactions
- Escherichia coli research studies
- Helminth infection and control
- RNA and protein synthesis mechanisms
- Viral Infections and Vectors
- DNA and Nucleic Acid Chemistry
- Metal complexes synthesis and properties
- Lipid Membrane Structure and Behavior
- Receptor Mechanisms and Signaling
- Vector-borne infectious diseases
- Parasitic Diseases Research and Treatment
- Pneumocystis jirovecii pneumonia detection and treatment
- Research on Leishmaniasis Studies
- Bacterial Genetics and Biotechnology
- Pancreatic and Hepatic Oncology Research
- Peptidase Inhibition and Analysis
- Parasitic infections in humans and animals
- Tuberculosis Research and Epidemiology
University of Zurich
2015-2025
University of California, San Francisco
2009-2010
QB3
2010
Swiss Tropical and Public Health Institute
2009
Institute of Parasitology
2009
Abstract ABC exporters harness the energy of ATP to pump substrates across membranes. Extracellular gate opening and closure are key steps transport cycle, but underlying mechanism is poorly understood. Here, we generated a synthetic single domain antibody (sybody) that recognizes heterodimeric exporter TM287/288 exclusively in presence ATP, which was essential solve 3.2 Å crystal structure outward-facing transporter. The sybody binds an extracellular wing strongly inhibits ATPase activity...
Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count hearing defects. also exports S1P-mimicking FTY720-P (Fingolimod) thereby central pharmacokinetics of this drug when treating multiple sclerosis. Here, we use combination cryo-electron microscopy, immunofluorescence, vitro binding vivo export assays, molecular dynamics simulations probe...
Background The possible emergence of resistance to the only available drug for schistosomiasis spurs discovery that has been recently incentivized by availability improved transcriptome and genome sequence information. Transient RNAi emerged as a straightforward important technique interrogate information through decreased or loss gene function identify potential targets. To date, studies in schistosome stages infecting humans have focused on single (or up 3) genes interest. Therefore,...
ABSTRACT The dynamic evolution of organelle compartmentalization in eukaryotes and how strictly is maintained are matters ongoing debate. While the endoplasmic reticulum (ER) classically envisioned as site protein cotranslational translocation, it has recently been proposed to have pluripotent functions. Using transfected reporter constructs, organelle-specific markers, functional enzyme assays, we now show that an early-diverging protozoan, Giardia lamblia , endocytosis subsequent...
Lectins are carbohydrate-binding proteins that involved in fundamental intra- and extracellular biological processes. They occur ubiquitously nature especially abundant plants fungi. It has been well established certain higher fungi produce lectins their fruiting bodies and/or sclerotia as a part of natural resistance against free-living fungivorous nematodes other pests. Despite relatively high diversity the glycan structures nature, many glycans targeted by fungal conserved among organisms...
The uptake of glutamate by synaptic vesicles is mediated vesicular transporters (VGLUTs). central role these in excitatory neurotransmission underpins their importance as pharmacological targets. Although several compounds inhibit VGLUTs, highly specific inhibitors were so far unavailable, thus limiting applications to vitro experiments. Besides potential pharmacology, would also be beneficial for the elucidation transport mechanisms. To overcome this shortage, we generated nanobodies (Nbs)...
Ceramides are bioactive sphingolipids crucial for regulating cellular metabolism. and dihydroceramides synthesized by six ceramide synthase (CerS) enzymes, each with specificity different acyl-CoA substrates. Ceramide a 16-carbon acyl chain (C16 ceramide) has been implicated in obesity, insulin resistance liver disease the C16 ceramide-synthesizing CerS6 is regarded as an attractive drug target obesity-associated disease. Despite their importance, molecular mechanism underlying synthesis...
The highly reduced protozoan parasite Giardia lamblia has minimal machinery for cellular processes such as protein trafficking. trophozoites maintain diverse and regulated secretory pathways but lack an identifiable Golgi complex. During differentiation to cysts, however, they produce specialized compartments termed encystation-specific vesicles (ESVs). ESVs are hypothesized be unique developmentally Golgi-like organelles dedicated maturation export of pre-sorted cyst wall proteins. Here we...
The canine heartworm (Dirofilaria immitis) is a mosquito-borne parasitic nematode whose range extending due to climate change. In four-dimensional analysis involving HPLC, MALDI-TOF-MS and MS/MS in combination with chemical enzymatic digestions, we here reveal an N-glycome of unprecedented complexity. We detect N-glycans up 7000 Da, which contain long fucosylated HexNAc-based repeats, as well glucuronylated structures. While some modifications including LacdiNAc, chitobiose, α1,3-fucose...
Background Blood flukes of the genus Schistosoma cause schistosomiasis, a parasitic disease that infects over 240 million people worldwide, and for which there is need to identify new targets chemotherapeutic interventions. Our research focused on mansoni prolyl oligopeptidase (SmPOP) from serine peptidase family S9, has not been investigated in detail trematodes. Methodology/Principal Findings We demonstrate SmPOP expressed adult worms schistosomula an enzymatically active form. By...
Membrane-bound styrene oxide isomerase (SOI) catalyses the Meinwald rearrangement-a Lewis-acid-catalysed isomerization of an epoxide to a carbonyl compound-and has been used in single and cascade reactions. However, structural information that explains its reaction mechanism remained elusive. Here we determine cryo-electron microscopy (cryo-EM) structures SOI bound single-domain antibody with without competitive inhibitor benzylamine, elucidate catalytic using electron paramagnetic resonance...
Synthesis of glucosylceramide via synthase (GCS) is a crucial event in higher eukaryotes, both for the production complex glycosphingolipids and regulating cellular levels ceramide, potent antiproliferative second messenger. In this study, we explored dependence early branching eukaryote Giardia lamblia on GCS activity. Biochemical analyses revealed that parasite has located endoplasmic reticulum (ER) membranes active proliferating encysting trophozoites. Pharmacological inhibition induced...
Mycobacterium tuberculosis adenylyl cyclase (AC) Rv1625c/Cya is an evolutionary ancestor of the mammalian membrane ACs and a model system for studies their structure function. Although vital role in cellular signalling well established, function transmembrane (TM) regions remains unknown. Here, we describe cryo-EM Cya bound to stabilizing nanobody at 3.6 Å resolution. The TM helices 1-5 form structurally conserved domain that facilitates assembly helical catalytic domains. region contains...
P-glycoprotein (P-gp) is a membrane-bound efflux pump that actively exports wide range of compounds from the cell and associated with phenomenon multidrug resistance. However, role P-gp in normal physiological processes remains elusive. Using P-gp-deficient fibroblasts, we showed was critical for replication intracellular parasite <i>Toxoplasma gondii</i> but not involved invasion host cells by parasite. Importantly, found protein participated transport host-derived cholesterol to <i>T. only...
Abstract Ceramides are bioactive sphingolipids that play pivotal roles in regulating cellular metabolism. and dihydroceramides synthesized by a family of six ceramide synthase enzymes (CerS), each with distinct specificity for the acyl-CoA substrate. Importantly, acyl chain length plays key role determining physiological function ceramides, as well their metabolic disease. Ceramide an 16 carbons (C16 ceramide) has been implicated obesity, insulin resistance liver disease, C16...
ABSTRACT Sphingolipid biosynthesis pathways have recently emerged as a promising target for therapeutic intervention against pathogens, including parasites. A key step in the synthesis of complex sphingolipids is glucosylation ceramide, mediated by glucosylceramide (GlcCer) synthase, whose activity can be inhibited PPMP (1-phenyl-2-palmitoylamino-3-morpholino-1-propanol). In this study, we investigated whether inhibits proliferation and differentiation pathogenic parasite Giardia lamblia ,...
Blood-fed insects can be used to analyse the host blood for circulating vertebrate pathogens or antibodies directed against them. We tested whether naturally acquired in different species detected by host-specific and pan-specific ELISAs mosquito meals. Cat- alpaca-specific could detect Toxoplasma gondii SARS-CoV-2 meals of Aedes japonicus 48 at least 24 h, respectively. In ELISA, a conjugated protein A/G anti-IgY were mammalian bird hosts. Thus, mosquitoes fed on from humans, chicken, pig,...
Abstract Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count hearing defects. also exports S1P-mimicking FTY720-P (Fingolimod) thereby central pharmacokinetics of this drug when treating multiple sclerosis. Here, we use combination cryo-electron microscopy, immunofluorescence, vitro binding vivo export assays, molecular dynamic simulations...
ABSTRACT ABC exporters harness the energy of ATP to pump substrates across membranes. Extracellular gate opening and closure are key steps transport cycle, but underlying mechanism is poorly understood. Here, we generated a synthetic single domain antibody (sybody) that recognizes heterodimeric exporter TM287/288 exclusively in presence ATP, which was essential solve 3.2 Å crystal structure outward-facing transporter. The sybody binds an extracellular wing strongly inhibits ATPase activity...