A5041025844- Microtubule and mitosis dynamics
- RNA and protein synthesis mechanisms
- Endoplasmic Reticulum Stress and Disease
- Enzyme Structure and Function
- Heat shock proteins research
- RNA Research and Splicing
- Bacterial Genetics and Biotechnology
- Photosynthetic Processes and Mechanisms
- Chromosomal and Genetic Variations
- Protein Structure and Dynamics
- Cellular transport and secretion
- Mitochondrial Function and Pathology
- RNA modifications and cancer
- Genomics and Chromatin Dynamics
- Ubiquitin and proteasome pathways
- Nuclear Structure and Function
- Bacteriophages and microbial interactions
- PI3K/AKT/mTOR signaling in cancer
- Protist diversity and phylogeny
- DNA Repair Mechanisms
- DNA and Nucleic Acid Chemistry
- Advanced biosensing and bioanalysis techniques
- interferon and immune responses
- Transgenic Plants and Applications
- Immune Cell Function and Interaction
MRC Laboratory of Molecular Biology
2015-2025
Medical Research Council
2012-2023
The Francis Crick Institute
2022
University of Cambridge
2002-2020
Osaka University
2018
Novartis (Switzerland)
2014
Novartis Institutes for BioMedical Research
2014
Howard Hughes Medical Institute
2014
University of California, Berkeley
2014
Lawn Tennis Association
2008
Genetic information storage and processing rely on just two polymers, DNA RNA, yet whether their role reflects evolutionary history or fundamental functional constraints is currently unknown. With the use of polymerase evolution design, we show that genetic can be stored in recovered from six alternative polymers based simple nucleic acid architectures not found nature [xeno-nucleic acids (XNAs)]. We also select XNA aptamers, which bind targets with high affinity specificity, demonstrating...
Cells dynamically adjust their protein translation profile to maintain homeostasis in changing environments. During nutrient stress, the kinase general control nonderepressible 2 (GCN2) phosphorylates initiation factor eIF2α, initiating integrated stress response (ISR). To examine mechanism of GCN2 activation, we have reconstituted this process vitro, using purified components. We find that recombinant human is potently stimulated by ribosomes and, a lesser extent, tRNA. Hydrogen/deuterium...
Abstract Intermediate species in the assembly of amyloid filaments are believed to play a central role neurodegenerative diseases and may constitute important targets for therapeutic intervention 1,2 . However, structural information about intermediate has been scarce molecular mechanisms by which amyloids assemble remain largely unknown. Here we use time-resolved cryogenic electron microscopy study vitro recombinant truncated tau (amino acid residues 297–391) into paired helical Alzheimer’s...
Kinetochores assemble onto specialized centromeric CENP-A (centromere protein A) nucleosomes (CENP-A Nuc ) to mediate attachments between chromosomes and the mitotic spindle. We describe cryo–electron microscopy structures of human inner kinetochore constitutive centromere associated network (CCAN) complex bound reconstituted α-satellite DNA. CCAN forms edge-on contacts with , a linker DNA segment repeat emerges from fully wrapped end nucleosome thread through central CENP-LN channel that...
RbAp46 and RbAp48 (pRB-associated proteins p46 p48, also known as RBBP7 RBBP4, respectively) are highly homologous histone chaperones that play key roles in establishing maintaining chromatin structure. We report here the crystal structure of human bound to H4. folds into a seven-bladed β propeller binds H4 groove formed between an N-terminal α helix extended loop inserted blade six. Surprisingly, adopts different conformation when interacting with than it does either nucleosome or complex...
Phosphatidylinositol 4-kinases (PI4Ks) and small guanosine triphosphatases (GTPases) are essential for processes that require expansion remodeling of phosphatidylinositol 4-phosphate (PI4P)-containing membranes, including cytokinesis, intracellular development malarial pathogens, replication a wide range RNA viruses. However, the structural basis coordination PI4K, GTPases, their effectors is unknown. Here, we describe structures PI4Kβ (PI4KIIIβ) bound to GTPase Rab11a without with Rab11...
Polarised mRNA transport is a prevalent mechanism for spatial control of protein synthesis. However, the composition transported ribonucleoprotein particles (RNPs) and regulation their movement are poorly understood. We have reconstituted microtubule minus end-directed mRNAs using purified components. A Bicaudal-D (BicD) adaptor RNA-binding Egalitarian (Egl) sufficient long-distance by dynein motor its accessory complex dynactin, thus defining minimal transport-competent RNP. Unexpectedly,...
The point centromere of budding yeast specifies assembly the large kinetochore complex to mediate chromatid segregation. Kinetochores comprise centromere-associated inner (CCAN) and microtubule-binding outer KNL1-MIS12-NDC80 (KMN) network. also contains DNA binding centromere-binding factor 1 (CBF1) CBF3 complexes. We determined cryo–electron microscopy structure assembled onto centromere-specific protein A nucleosomes (CENP-A Nuc ). This revealed a central CENP-A with extensively unwrapped...
DNA crosslinks block replication and are repaired by the Fanconi anaemia pathway. The FANCD2-FANCI (D2-I) protein complex is central to this process as it initiates repair coordinating incisions around lesion
Cell surface Fc receptors activate inflammation and are tightly controlled to prevent autoimmunity. Antibodies also simulate potent immune signalling from inside the cell via cytosolic antibody receptor TRIM21, but how this is regulated unknown. Here we show that TRIM21 constitutively repressed by its B-Box domain activated phosphorylation. The occupies an E2 binding site on catalytic RING mimicking E2-E3 interactions, inhibiting ubiquitination preventing activation. derepressed IKKβ TBK1...
Transcription of transposable elements is tightly regulated to prevent genome damage. KRAB domain-containing zinc finger proteins (KRAB-ZFPs) and KRAB-associated protein 1 (KAP1/TRIM28) play a key role in regulating retrotransposons. KRAB-ZFPs recognize specific retrotransposon sequences recruit KAP1, inducing the assembly an epigenetic silencing complex, with chromatin remodeling activities that repress transcription targeted adjacent genes. Our biophysical structural data show tripartite...
Introduction Evolution and design of protein complexes are frequently viewed through the lens amino acid mutations at interfaces, but we showed previously that residues distant from interfaces also commonly involved in evolution alternative quaternary structures. We hypothesized these families, difference oligomeric state is due to a change intersubunit geometry. The indirect would act by changing conformation dynamics, similar way which allosteric small molecules introduce functional...
Vaccines in use against SARS-CoV-2 induce immune responses the spike protein. There is intense interest whether antibody response induced by vaccines will be robust new variants, as well next-generation for previously infected or immunized individuals.