A5021508521- Heat shock proteins research
- Enzyme Structure and Function
- Protein Structure and Dynamics
- Advanced Electron Microscopy Techniques and Applications
- Prion Diseases and Protein Misfolding
- Photoreceptor and optogenetics research
- Retinal Development and Disorders
- Alzheimer's disease research and treatments
- RNA and protein synthesis mechanisms
- Endoplasmic Reticulum Stress and Disease
- Toxin Mechanisms and Immunotoxins
- Bacterial Genetics and Biotechnology
- Photosynthetic Processes and Mechanisms
- Lipid Membrane Structure and Behavior
- Bacteriophages and microbial interactions
- Neurological diseases and metabolism
- Electron and X-Ray Spectroscopy Techniques
- Cellular transport and secretion
- Streptococcal Infections and Treatments
- Trace Elements in Health
- Clostridium difficile and Clostridium perfringens research
- Force Microscopy Techniques and Applications
- Complement system in diseases
- Mosquito-borne diseases and control
- Receptor Mechanisms and Signaling
Birkbeck, University of London
2015-2025
Institute of Structural and Molecular Biology
2015-2025
Rosalind Franklin Institute
2023
University College London
2009-2018
Diamond Light Source
2017
Max Planck Society
2010
National Institute for Biological Standards and Control
2010
King's College Hospital
2010
Guy's Hospital
2010
St Thomas' Hospital
2010
Under solution conditions where the native state is destabilized, largely helical polypeptide hormone insulin readily aggregates to form amyloid fibrils with a characteristic cross-β structure. However, there lack of information relating 4.8 Å β-strand repeat higher order assembly fibrils. We have used cryo-electron microscopy (EM), combining single particle analysis and reconstruction, characterize these study three-dimensional (3D) arrangement their component protofilaments. Low-resolution...
The cross-β amyloid form of peptides and proteins represents an archetypal widely accessible structure consisting ordered arrays β-sheet filaments. These complex aggregates have remarkable chemical physical properties, the conversion normally soluble functional forms into structures is linked to many debilitating human diseases, including several common age-related dementia. Despite their importance, however, fibrils proved be recalcitrant detailed structural analysis. By combining...
The chaperonin GroEL is a large, double-ring structure that, together with ATP and the cochaperonin GroES, assists protein folding in vivo. GroES forms an asymmetric complex which single ring binds one end of cylinder. Cross-linking studies reveal that polypeptide binding occurs exclusively to not occupied by (trans). During reaction, however, released can rebind containing (cis). held tightly proteolytically protected environment cis complexes, presence ADP. Single turnover experiments...
Chaperonin-assisted protein folding proceeds through cycles of ATP binding and hydrolysis by the large chaperonin GroEL, which undergoes major allosteric rearrangements. Interaction between two back-to-back seven-membered rings GroEL plays an important role in regulating release substrates small GroES. Using cryo-electron microscopy, we have obtained three-dimensional reconstructions to 30 Å resolution for GroEL–GroES complexes presence ADP, ATP, nonhydrolyzable analog, AMP-PNP. Nucleotide...
Huntington's disease is caused by an abnormally long polyglutamine tract in the huntingtin protein. This leads to generation and deposition of N-terminal exon1 fragments protein intracellular aggregates. We combined electron tomography quantitative fluorescence microscopy analyze structural material properties assemblies mammalian cells, yeast, vitro. found that proteins can form reversible liquid-like assemblies, a process driven huntingtin's polyQ proline-rich region. In cells vitro,...
Type IV secretion systems (T4SSs) are important virulence factors used by Gram-negative bacterial pathogens to inject effectors into host cells or spread plasmids harboring antibiotic resistance genes. We report the 15 angstrom resolution cryo–electron microscopy structure of core complex a T4SS. The is composed three proteins, each present in 14 copies and forming ∼1.1-megadalton two-chambered, double membrane–spanning channel. double-walled, with component apparently spanning large part...
A role for PrP in the toxic effect of oligomeric forms Aβ, implicated Alzheimer's disease (AD), has been suggested but remains controversial. Here we show that is required plasticity-impairing effects ex vivo material from human AD brain and standardized Aβ-derived diffusible ligand (ADDL) preparations disrupt hippocampal synaptic plasticity a PrP-dependent manner. We screened panel anti-PrP antibodies their ability to ADDL–PrP interaction. Antibodies directed principal PrP/Aβ-binding site...
Mammalian prions propagate as distinct strains and are composed of multichain assemblies misfolded host-encoded prion protein (PrP). Here, we present a near-atomic resolution cryo-EM structure PrP fibrils in highly infectious rod preparations isolated from the brains RML prion-infected mice. We found that rods comprise single-protofilament helical amyloid coexist with twisted pairs same protofilaments. Each rung protofilament is formed by single monomer ordered core comprising residues...
Abstract Recent cryogenic electron microscopy (cryo-EM) studies of infectious, ex vivo, prion fibrils from hamster 263K and mouse RML strains revealed a similar, parallel in-register intermolecular β-sheet (PIRIBS) amyloid architecture. Rungs the are composed individual protein (PrP) monomers that fold to create distinct N-terminal C-terminal lobes. However, disparity in hamster/mouse PrP sequence precludes understanding how divergent emerge an identical substrate. In this study, we...
Prion propagation involves the conversion of cellular prion protein (PrP C ) into a disease-specific isomer, PrP Sc , shifting from predominantly α-helical to β-sheet structure. Here, conditions were established in which recombinant human could switch between native α conformation, characteristic and compact, highly soluble, monomeric form rich β The soluble (β-PrP) exhibited partial resistance proteinase K digestion, was direct precursor fibrillar structures closely similar those isolated...
The double-ring chaperonin GroEL mediates protein folding in the central cavity of a ring bound by ATP and GroES, but it is unclear how cycles from one folding-active complex to next. We observe that hydrolysis within cis must occur before either nonnative polypeptide or GroES can bind trans ring, this associated with reorientation apical domains. Subsequently, formation new cis-ternary proceeds on open binding first, which stimulates ATP-dependent dissociation (by 20- 50-fold), followed...
The Tat system mediates Sec-independent transport of folded precursor proteins across the bacterial plasma membrane or chloroplast thylakoid membrane. involves distinct high-molecular-weight TatA and TatBC complexes. Here we report 3D architecture complex from Escherichia coli obtained by single-particle electron microscopy random conical tilt reconstruction. forms ring-shaped structures variable diameter in which internal channels are large enough to accommodate known substrate proteins....