A5061323368- Glycosylation and Glycoproteins Research
- Ubiquitin and proteasome pathways
- SARS-CoV-2 and COVID-19 Research
- Cancer, Hypoxia, and Metabolism
- HIV Research and Treatment
- Bacteriophages and microbial interactions
- RNA and protein synthesis mechanisms
- Protein Degradation and Inhibitors
- Cellular transport and secretion
- Amino Acid Enzymes and Metabolism
- Cytomegalovirus and herpesvirus research
- Caveolin-1 and cellular processes
- Peptidase Inhibition and Analysis
- Virus-based gene therapy research
- RNA modifications and cancer
- interferon and immune responses
- Erythrocyte Function and Pathophysiology
- RNA Research and Splicing
- Metabolism and Genetic Disorders
- ATP Synthase and ATPases Research
- HIV/AIDS drug development and treatment
- Monoclonal and Polyclonal Antibodies Research
- Genetics and Neurodevelopmental Disorders
- Sphingolipid Metabolism and Signaling
- Cancer-related Molecular Pathways
Technische Universität Berlin
2023-2024
Max Delbrück Center
2010-2024
Humboldt-Universität zu Berlin
2020-2023
Charité - Universitätsmedizin Berlin
2019-2023
Freie Universität Berlin
2010-2023
The Francis Crick Institute
2013-2015
University of Konstanz
2010
Targeted protein degradation induced by heterobifunctional compounds and molecular glues presents an exciting avenue for chemical probe drug discovery. To date, small-molecule ligands have been discovered only a limited number of E3 ligases, which is important limiting factor realizing the full potential targeted degradation. We report herein discovery proteomics azetidine acrylamides that stereoselectively site-specifically react with cysteine (C1113) in ligase substrate receptor DCAF1....
The inhibition of carbohydrate−protein interactions by tailored multivalent ligands is a powerful strategy for the treatment many human diseases. Crucial success this approach an understanding molecular mechanisms as to how binding enhancement ligand achieved. We have synthesized series N-acetylglucosamine (GlcNAc) derivatives and studied their interaction with plant lectin wheat germ agglutinin (WGA) enzyme-linked assay (ELLA) X-ray crystallography. solution conformation one was determined...
SAMHD1 restricts HIV-1 infection of myeloid-lineage and resting CD4+ T-cells. Most likely this occurs through deoxynucleoside triphosphate triphosphohydrolase activity that reduces cellular dNTP to a level where reverse transcriptase cannot function, although alternative mechanisms have been proposed recently. Here, we present combined structural virological data demonstrating in addition allosteric activation activity, restriction correlates with the capacity form "long-lived" enzymatically...
Despite unprecedented global efforts to rapidly develop SARS-CoV-2 treatments, in order reduce the burden placed on health systems, situation remains critical. Effective diagnosis, treatment, and prophylactic measures are urgently required meet demand: recombinant antibodies fulfill these requirements have marked clinical potential. Here, we describe fast-tracked development of an alpaca Nanobody specific for receptor-binding-domain (RBD) Spike protein with potential therapeutic...
The SAMHD1 triphosphohydrolase inhibits HIV-1 infection of myeloid and resting T cells by depleting dNTPs. To overcome SAMHD1, HIV-2 some SIVs encode either two lineages the accessory protein Vpx that bind N or C terminus redirect host cullin-4 ubiquitin ligase to target for proteasomal degradation. We present ternary complex from SIV infects mandrills (SIVmnd-2) with substrate receptor, DCAF1, N-terminal SAM domains mandrill SAMHD1. structure reveals details lineage-specific targeting...
GTPases of immunity-associated proteins (GIMAPs) are a distinctive family GTPases, which control apoptosis in lymphocytes and play central role lymphocyte maturation lymphocyte-associated diseases. To explore their function mechanism, we determined crystal structures representative member, GIMAP2, different nucleotide-loading oligomerization states. Nucleotide-free GDP-bound GIMAP2 were monomeric revealed guanine nucleotide-binding domain the TRAFAC (translation factor associated) class with...
SummaryGTPases of immunity-associated proteins (GIMAPs) are regulators lymphocyte survival and homeostasis. We previously determined the structural basis GTP-dependent GIMAP2 scaffold formation on lipid droplets. To understand how its GTP hydrolysis is activated, we screened for other GIMAPs droplets identified GIMAP7. In contrast to GIMAP2, GIMAP7 displayed dimerization-stimulated hydrolysis. The crystal structure GTP-bound showed a homodimer that assembled via G domains, with helical...
Abstract The biological role of RNA-binding proteins in the secretory pathway is not well established. Here, we describe that human HDLBP/Vigilin directly interacts with more than 80% ER-localized mRNAs. PAR-CLIP analysis reveals these transcripts represent high affinity HDLBP substrates and are specifically bound their coding sequences (CDS), contrast to CDS/3’UTR-bound cytosolic crosslinks strongly long CU-rich motifs, which frequently reside CDS mRNAs result multivalent interactions. In...
Neurological conditions are the leading cause of ill health worldwide. Here, we show that neurodevelopmental disorder-associated ubiquitin ligase UBE3C regulates cellular composition murine cerebral cortex and human brain organoids, with its loss favoring neurogenesis suppressing glial fate. Using genetic complementation, demonstrate disease-associated mutations alter autoubiquitination activity disrupt cortical lamination. Proteomic profiling UBE3C-deficient forebrains organoids identifies...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) Omicron variant sub-lineages spread rapidly worldwide, mostly due to their immune-evasive properties. This has put a significant part of the population at risk for disease and underscores need effective anti-SARS-CoV-2 agents against emergent strains in vulnerable patients. Camelid nanobodies are attractive therapeutic candidates high stability, ease large-scale production, potential delivery via inhalation. Here, we...
Abstract Human cytomegalovirus (CMV) is a ubiquitously distributed pathogen whose rodent counterparts such as mouse and rat CMV serve common infection models. Here, we conducted global proteome profiling of CMV‐infected cells uncovered pronounced loss the transcription factor STAT2, which crucial for antiviral interferon signalling. Via deletion mutagenesis, found that viral protein E27 required CMV‐induced STAT2 depletion. Cellular in vitro analyses showed exploits host‐cell Cullin4‐RING...
Viruses have evolved means to manipulate the host's ubiquitin-proteasome system, in order down-regulate antiviral host factors. The Vpx/Vpr family of lentiviral accessory proteins usurp substrate receptor DCAF1 Cullin4-RING ligases (CRL4), a modular ubiquitin involved DNA replication, repair and cell cycle regulation. CRL4DCAF1 specificity modulation by Vpx Vpr from certain simian immunodeficiency viruses (SIV) leads recruitment, poly-ubiquitylation subsequent proteasomal degradation...
Mutations in SAMHD1 cause Aicardi-Goutières syndrome (AGS), a Mendelian inflammatory disease which displays remarkable clinical and biochemical overlap with congenital viral infection. (SAM domain HD domain-containing protein 1) has also been defined as an HIV-1 restriction-factor that, through novel triphosphohydrolase activity, inhibits early stage replication myeloid-derived dendritic cells (MDDCs), macrophages resting CD4+ T-cells. The potent activity of is likely to be the subject...
Abstract Despite unprecedented global efforts to rapidly develop SARS-CoV-2 treatments, in order reduce the burden placed on health systems, situation remains critical. Effective diagnosis, treatment, and prophylactic measures are urgently required meet demand: recombinant antibodies fulfill these requirements have marked clinical potential. Here, we describe fast-tracked development of an alpaca Nanobody specific for receptor-binding-domain (RBD) Spike protein with therapeutic potential...
GTP ases of Immunity-Associated Proteins (GIMAPs) are a family guanine nucleotide binding (G) proteins which implicated in the regulation apoptosis lymphocytes. GIMAPs composed an amino-terminal G domain and carboxy-terminal extensions varying size. Our recent biochemical structural analysis representative GIMAP member, GIMAP2, revealed molecular basis GTP-dependent oligomerization involves two interfaces domain. Whereas amphipathic helix α7 C-terminal extension closely folds against...
Abstract Peripheral nerves contain sensory and motor neuron axons coated by glial cells whose interplay ensures function, but molecular details are lacking. SNARE‐proteins mediate the exchange secretion of cargo fusing vesicles with target organelles, how SNAREs contribute to peripheral nerve function is largely unknown. We, here, identify non‐neuronal Synaptobrevin (Syb) as essential vesicular SNARE in Drosophila glia insulate metabolically supply neurons. We show that tetanus neurotoxin...
GTPases of immunity-associated proteins (GIMAPs) are important regulators T-cell death and survival. Here, the crystallization data collection three GIMAP2 constructs in various nucleotide-loaded states is described. Selenomethionine-substituted carboxy-terminally truncated (amino-acid residues 1–260; GIMAP21–260) nucleotide-free form crystallized space group P212121 crystals diffracted X-rays to 1.5 Å resolution. The phase problem was solved using single anomalous dispersion (SAD) protocol....