A5085219320- DNA Repair Mechanisms
- Enzyme Structure and Function
- DNA and Nucleic Acid Chemistry
- Advanced Electron Microscopy Techniques and Applications
- CRISPR and Genetic Engineering
- RNA and protein synthesis mechanisms
- Protein Structure and Dynamics
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Bacterial Genetics and Biotechnology
- Extracellular vesicles in disease
- Photosynthetic Processes and Mechanisms
- Mitochondrial Function and Pathology
- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Heat shock proteins research
- RNA Research and Splicing
- RNA modifications and cancer
- Bacteriophages and microbial interactions
- Computational Drug Discovery Methods
- Plant Virus Research Studies
- Genomics and Chromatin Dynamics
- NF-κB Signaling Pathways
- Cellular transport and secretion
- Caveolin-1 and cellular processes
- PARP inhibition in cancer therapy
Human Technopole
2020-2025
The Francis Crick Institute
2016-2022
University of Milan
2017-2022
Foundation Jewish Contemporary Documentation Center
2017
University of Cambridge
2015
Cancer Research UK
2014
University of Padua
2011
Abstract Systemic light chain amyloidosis (AL) is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin chains (LC) in target organs. Severity heart involvement the most important factor determining prognosis. Here, we report 4.0 Å resolution cryo-electron microscopy map molecular model amyloid fibrils extracted from an AL patient with severe cardiomyopathy. The helical are composed single protofilament, showing typical 4.9 stacking cross-β...
The Cdc45/Mcm2-7/GINS (CMG) helicase separates DNA strands during replication in eukaryotes. How the CMG is assembled and engages substrates remains unclear. Using electron microscopy, we have determined structure of presence ATPγS a duplex bearing 3′ single-stranded tail. shows that MCM subunits bind preferentially to DNA, establishes polarity by which enters into Mcm2-7 pore, explains how Cdc45 helps prevent from dissociating helicase. subcomplex forms cracked-ring, right-handed spiral...
Bone marrow Mesenchymal Stem Cells (BM-MSCs), due to their strong protective and anti-inflammatory abilities, have been widely investigated in the context of several diseases for possible therapeutic role, based on release a highly proactive secretome composed soluble factors Extracellular Vesicles (EVs). BM-MSC-EVs, particular, convey many beneficial features parental cells, including direct indirect β-amyloid degrading-activities, immunoregulatory neurotrophic abilities. Therefore, EVs...
Retroviral integrase (IN) functions within the intasome nucleoprotein complex to catalyze insertion of viral DNA into cellular chromatin. Using cryo-electron microscopy, we now visualize functional maedi-visna lentivirus at 4.9 angstrom resolution. The comprises a homo-hexadecamer IN with tetramer-of-tetramers architecture featuring eight structurally distinct types protomers supporting two catalytically competent subunits. conserved intasomal core, previously observed in simpler retroviral...
The HCN1–4 channel family is responsible for the hyperpolarization-activated cation current If/Ih that controls automaticity in cardiac and neuronal pacemaker cells. We present cryoelectron microscopy (cryo-EM) structures of HCN4 presence or absence bound cAMP, displaying pore domain closed open conformations. Analysis cAMP-bound -unbound sheds light on how ligand-induced transitions cytosolic portion mediate effect cAMP gating highlights regulatory role a Mg2+ coordination site formed...
Amyloid fibrils are polymeric structures originating from aggregation of misfolded proteins. In vivo, proteolysis may modulate amyloidogenesis and fibril stability. light chain (AL) amyloidosis, fragmented chains (LCs) abundant components amyloid deposits; however, site timing debated. Identification the N C termini LC fragments is instrumental to understanding involved processes enzymes. We investigated terminome proteoforms in extracted hearts two AL cardiomyopathy patients, using a...
Activation of the main DNA interstrand crosslink repair pathway in higher eukaryotes requires mono-ubiquitination FANCI and FANCD2 by FANCL, E3 ligase subunit Fanconi anemia core complex. form a stable complex; however, molecular basis their ubiquitination is ill defined. FANCL stimulated presence FANCB FAAP100 complex components, through an unknown mechanism. How achieved remains unclear. Here, we use structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find...
Abstract Astrocytes‐derived extracellular vesicles (EVs) are key players in glia‐neuron communication. However, whether EVs interact with neurons at preferential sites and how reach these on remains elusive. Using optical manipulation to study single EV‐neuron dynamics, we here show that large scan the neuron surface use neuronal processes as highways move extracellularly. Large EV motion neurites is driven by binding of a receptor slides membrane, thanks actin cytoskeleton rearrangements....
Significance RecQ DNA helicases are critical enzymes for the maintenance of genome integrity. Here, we determined first complex structures, to our knowledge, human RECQ1 helicase. These structures provide new insight into helicase mechanism tracking, strand separation, annealing, and Holliday junction (HJ) branch migration. We identified a surface region in winged-helix domain that is important both dsDNA recognition HJ resolution, used combination biochemical, analytical...
Significance Bloom syndrome complex (BS complex) is necessary for maintenance of genome stability and suppression cancer-causing mutations. Composed a helicase, topoisomerase, two scaffolds, the BS implicated in several steps that ensure high fidelity DNA repair by recombination. One step, called “double Holliday junction dissolution,” ensures untangling at conclusion repair. Here, we used cross-link mass spectrometry to show how assembles. Using biochemical reactions cell complementation...
RNA can directly control protein activity in a process called riboregulation; only few mechanisms of riboregulation have been described detail, none which characterized on structural grounds. Here, we present comprehensive structural, functional, and phylogenetic analysis cytosolic serine hydroxymethyltransferase (SHMT1), the enzyme interconverting glycine one-carbon metabolism. We determined cryoelectron microscopy (cryo-EM) structure human SHMT1 its free- RNA-bound states, show that...
Fanconi anemia (FA) is a disorder associated with failure in DNA repair. FANCM (defective FA complementation group M) and its partner FAAP24 target other proteins to sites of damage. FANCM-FAAP24 related XPF/MUS81 endonucleases but lacks endonucleolytic activity. We report structure an C-terminal fragment (FANCMCTD) bound DNA. This S-shaped reveals the (HhH)2 domain buried, whereas engages identify second contact metal center within pseudo-nuclease demonstrate that mutations either region...
ABSTRACT Despite the availability of two attenuated vaccines, rotavirus (RV) gastroenteritis remains an important cause mortality among children in developing countries, causing about 215,000 infant deaths annually. Currently, there are no specific antiviral therapies available. RV is a nonenveloped virus with segmented double-stranded RNA genome. Viral genome replication and assembly transcriptionally active double-layered particles (DLPs) take place cytoplasmic viral structures called...
Abstract Cryo-focused ion beam milling has enabled groundbreaking structural discoveries in native cells. Progress toward medically relevant applications, however, been slow. We here present an adaptation of the cryo-lift out procedure for Serialized On-grid Lift-In Sectioning Tomography (SOLIST), which increases throughput, reduces ice contamination, and enhances sample stability. With these improvements, new specimens, ranging from high-pressure frozen reconstituted LLPS droplets to human...
In plant grana thylakoid membranes Photosystem II (PSII) associates with a variable number of antenna proteins (LHCII) to form different types supercomplexes (PSII-LHCII), whose organization is dynamically adjusted in response light cues, the C2S2 more abundant high-light and C2S2M2 low-light. Paired PSII-LHCII interacting at their stromal surface from adjacent were previously suggested mediate stacking. Here, we present cryo-electron microscopy maps paired isolated pea plants grown...
Nucleotide excision repair (NER) is a DNA pathway present in all domains of life. In bacteria, UvrA protein localizes the lesion, followed by verification UvrB helicase and UvrC double nuclease. senses deformations flexibility duplex without precisely localizing lesion damaged strand, an element essential for proper NER. Using combination techniques, we elucidate mechanism damage step bacterial dimer recruits two molecules to its sides. Each clamps different strand using β-hairpin element....