A5077066530- Complement system in diseases
- RNA and protein synthesis mechanisms
- Erythrocyte Function and Pathophysiology
- Streptococcal Infections and Treatments
- Lipid Membrane Structure and Behavior
- Bacteriophages and microbial interactions
- Enzyme Structure and Function
- Viral Infections and Immunology Research
- Cytokine Signaling Pathways and Interactions
- RNA Interference and Gene Delivery
- Burkholderia infections and melioidosis
- Toxin Mechanisms and Immunotoxins
- Mosquito-borne diseases and control
- RNA modifications and cancer
- Virus-based gene therapy research
- RNA Research and Splicing
- Plant Virus Research Studies
- Magnetic and Electromagnetic Effects
- Advanced Electron Microscopy Techniques and Applications
- interferon and immune responses
- Viral gastroenteritis research and epidemiology
- Plant Pathogenic Bacteria Studies
- Plant-Microbe Interactions and Immunity
- Systemic Lupus Erythematosus Research
- Galectins and Cancer Biology
Imperial College London
2015-2024
Contipro (Czechia)
2023
Wadsworth Center
1997-2018
New York State Department of Health
1997-2018
Centre for Human Genetics
2007-2012
University of Oxford
2007-2012
Harvard University
2005-2007
European Molecular Biology Laboratory
2006
University at Albany, State University of New York
1997
Rockefeller University
1997
Abstract In response to complement activation, the membrane attack complex (MAC) assembles from fluid-phase proteins form pores in lipid bilayers. MAC directly lyses pathogens by a ‘multi-hit’ mechanism; however, sublytic on host cells activate signalling pathways. Previous studies have described structures of individual components and subcomplexes; molecular details its assembly mechanism action remain unresolved. Here we report electron cryo-microscopy structure human at subnanometre...
Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in genes encoding genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder shares features with autoimmune disease systemic lupus erythematosus (SLE). Here we determined heterozygous parents of AGS patients exhibit an intermediate phenotype and demonstrated genetic association between rare RNASEH2 sequence...
An oligomer of the Sec61 trimeric complex is thought to form protein-conducting channel for protein transport across endoplasmic reticulum. A purified yeast bound monomeric ribosomes as an in a saturable fashion. Cryo–electron microscopy ribosome-Sec61 and three-dimensional reconstruction showed that attached large ribosomal subunit by single connection. Moreover, funnel-shaped pore aligned with exit tunnel traversing subunit, strongly suggesting both structures function together...
ABSTRACT Poliovirus provides a well-characterized system for understanding how nonenveloped viruses enter and infect cells. Upon binding its receptor, poliovirus undergoes an irreversible conformational change to the 135S cell entry intermediate. This transition involves shifts of capsid protein β barrels, accompanied by externalization VP4 N terminus VP1. Both polypeptides associate with membranes are postulated facilitate forming translocation pore viral RNA. We have calculated...
Ribonuclease H2 is the major nuclear enzyme degrading cellular RNA/DNA hybrids in eukaryotes and sole nuclease known to be able hydrolyze ribonucleotides misincorporated during genomic replication. Mutation RNASEH2 causes Aicardi–Goutières syndrome, an auto-inflammatory disorder that may arise from nucleic acid byproducts generated DNA Here, we report crystal structures of Archaeoglobus fulgidus RNase HII complex with PCNA, human PCNA bound a C-terminal peptide RNASEH2B. In archaeal...
Abstract The membrane attack complex (MAC) is one of the immune system’s first responders. Complement proteins assemble on target membranes to form pores that lyse pathogens and impact tissue homeostasis self-cells. How MAC disrupts barrier remains unclear. Here we use electron cryo-microscopy flicker spectroscopy show interacts with lipid bilayers in two distinct ways. Whereas C6 C7 associate outer leaflet reduce energy for bending, C8 C9 traverse bilayer increasing rigidity. CryoEM...
Abstract The membrane attack complex (MAC) is a hetero-oligomeric protein assembly that kills pathogens by perforating their cell envelopes. MAC formed sequential of soluble complement proteins C5b, C6, C7, C8 and C9, but little known about the rate-limiting steps in this process. Here, we use rapid atomic force microscopy (AFM) imaging to show oligomerize within membrane, unlike structurally homologous bacterial pore-forming toxins. C5b-7 interacts with lipid bilayer prior recruiting C8. We...
Plants, algae, and cyanobacteria fix carbon dioxide to organic with the Calvin–Benson (CB) cycle. Phosphoribulokinase (PRK) glyceraldehyde 3-phosphate dehydrogenase (GAPDH) are essential CB-cycle enzymes that control substrate availability for carboxylation enzyme Rubisco. PRK consumes ATP produce Rubisco ribulose bisphosphate (RuBP). GAPDH catalyzes reduction step of CB cycle NADPH sugar (GAP), which is used regeneration RuBP main exit point coregulated by redox state a conditionally...
Macroautophagy/autophagy is an intracellular degradation process central to cellular homeostasis and defense against pathogens in eukaryotic cells. Regulation of autophagy relies on hierarchical binding cargo receptors adaptors ATG8/LC3 protein family members. Interactions with are typically facilitated by a conserved, short linear sequence, referred as the interacting motif/region (AIM/LIR), present well pathogen virulence factors targeting host machinery. Since canonical AIM/LIR sequence...
Abstract CD59 is an abundant immuno-regulatory receptor that protects human cells from damage during complement activation. Here we show how the binds proteins C8 and C9 at membrane to prevent insertion polymerization of attack complex (MAC) pores. We present cryo-electron microscopy structures two inhibited MAC precursors known as C5b8 C5b9. discover in both complexes, pore-forming β-hairpins form intermolecular β-sheet prevents perforation. While bound C8, deflects cascading β-hairpins,...
The mechanism by which poliovirus infects the cell has been characterized a combination of biochemical and structural studies, leading to working model for entry. Upon receptor binding at physiological temperature, native virus (160S) undergoes conformational change 135S particle from VP4 N terminus VP1 are externalized. These components interact with membrane proposed form pore. An additional in is accompanied release infectious viral RNA genome its delivery, presumably through pore into...
Pore-forming proteins containing the structurally conserved membrane attack complex/perforin fold play an important role in immunity and host-pathogen interactions. Intermedilysin (ILY) is archetypal member of a cholesterol-dependent cytolysin subclass that hijacks complement receptor CD59 to make cytotoxic pores human cells. ILY directly competes for complex binding site on CD59, rendering cells susceptible lysis. To understand how these bacterial form lipid bilayers plays regulation, we...
Abstract Polypeptide aggregation into amyloid is linked with several debilitating human diseases. Despite the inherent risk of aggregation-induced cytotoxicity, bacteria control export amyloid-prone subunits and assemble adhesive fibres during biofilm formation. An Escherichia protein, CsgC potently inhibits formation curli proteins. Here we unlock its mechanism action, show that strongly primary nucleation via electrostatically-guided molecular encounters, which expands conformational...
Abstract Interleukin 27 (IL‐27) is a heterodimeric cytokine that elicits potent immunosuppressive responses. Comprised of EBI3 and p28 subunits, IL‐27 binds GP130 IL‐27Rα receptor chains to activate the JAK/STAT signaling cascade. However, how these receptors recognize form complex capable phosphorylating JAK proteins remains unclear. Here, we used cryo electron microscopy (cryoEM) AlphaFold modeling solve structure recognition complex. Our data show serves as bridge connecting (domains 1–2)...