Francesco Zonta

Francesco Zonta
ShanghaiTech University · Shanghai Institute for Advanced Immunochemical Studies

PhD

About

54
Publications
4,744
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733
Citations
Introduction
Francesco Zonta currently works at the Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University. Francesco does research in Molecular Physics, Thermodynamics and Biophysics.
Additional affiliations
March 2015 - September 2016
ShanghaiTech University
Position
  • Professor (Associate)

Publications

Publications (54)
Article
Connexin (Cx) hemichannels (HCs) are large pore hexameric structures that allow the exchange of ions, metabolites and a variety of other molecules between the cell cytoplasm and extracellular milieu. HC inhibitors are attracting growing interest as drug candidates because deregulated fluxes through HCs have been implicated in a plethora of genetic...
Preprint
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The spread of SARS-CoV-2 has fueled the COVID-19 pandemic with its enduring medical and socioeconomic challenges due to subsequent waves and long-term consequences of great concern. Here we charted the molecular basis of COVID-19 pathogenesis, by analysing patients’ immune response at single-cell resolution across disease course and severity. This...
Article
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SARS-CoV-2 infects humans and causes Coronavirus disease 2019 (COVID-19). The S1 domain of the spike glycoprotein of SARS-CoV-2 binds to human angiotensin-converting enzyme 2 (hACE2) via its receptor-binding domain, while the S2 domain facilitates fusion between the virus and the host cell membrane for entry. The spike glycoprotein of circulating S...
Preprint
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Classical potentials are widely used to describe protein physics, due to their simplicity and accuracy, but they are continuously challenged as real applications become more demanding with time. Deep neural networks could help generating alternative ways of describing protein physics. Here we propose an unsupervised learning method to derive a neur...
Article
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This dataset contains a collection of molecular dynamics (MD) simulations of polyglutamine (polyQ) and glutamine-rich (Q-rich) peptides in the multi-microsecond timescale. Primary data from coarse-grained simulations performed using the SIRAH force field has been processed to provide fully atomistic coordinates. The dataset encloses MD trajectories...
Article
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Poly glutamine and glutamine-rich peptides play a central role in a plethora of pathological aggregation events. However, biophysical characterization of soluble oligomers the most toxic species involved in these processes- remains elusive due to their structural heterogeneity and dynamical nature. Here, we exploit the high spatio-temporal resoluti...
Article
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Background Connexin hemichannels have been implicated in pathology-promoting conditions, including inflammation, numerous widespread human diseases, including cancer and diabetes, and several rare diseases linked to pathological point mutations. Methods We analysed the literature focusing on antibodies capable of modulating hemichannel function, h...
Preprint
Full-text available
Poly glutamine and glutamine-rich peptides play a central role in a plethora of pathological aggregation events. However, biophysical characterization of soluble oligomers —the most toxic species involved in these processes— remains elusive due to their structural heterogeneity and dynamical nature. Here, we exploit the high spatio-temporal resolut...
Article
Full-text available
Background Numerous currently incurable human diseases have been causally linked to mutations in connexin (Cx) genes. In several instances, pathological mutations generate abnormally active Cx hemichannels, referred to also as “leaky” hemichannels. The goal of this study was to assay the in vivo efficacy of a potent antagonist antibody targeting Cx...
Article
Multidrug-resistant Gram-negative bacteria infection is particularly severe within the designated ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), which underscores the urgent need to explore alternative therapeutic strategies. The type...
Article
Full-text available
Connexin (Cx) gap junction channels comprise two hemichannels in neighboring cells, and their permeability is well described, but permeabilities of the single Cx hemichannel remain largely unresolved. Moreover, determination of isoform-specific Cx hemichannel permeability is challenging because of concurrent expression of other channels with simila...
Article
Full-text available
Connexin hemichannels, which are plasma membrane hexameric channels (connexons) composed of connexin protein protomers, have been implicated in a host of physiological processes and pathological conditions. A number of single point pathological mutations impart a "leaky" character to the affected hemichannels, i.e., make them more active or hyperac...
Article
DNA encoded chemical libraries (DELs) link the powers of genetics and chemical synthesis via combinatorial optimization. Through combinatorial chemistry DELs can grow to the unprecedented size of billions to trillions, providing a rich chemical diversity for biological and pharmaceutical research. While in most cases at the molecular level, the div...
Article
DNA encoded chemical libraries (DELs) link the powers of genetics and chemical synthesis via combinatorial optimization. Through combinatorial chemistry DELs can grow to the unprecedented size of billions to trillions, providing a rich chemical diversity for biological and pharmaceutical research. While in most cases at the molecular level, the div...
Article
Full-text available
Remodeling of the gene regulatory network in cells is believed to be a prerequisite for their lineage reprogramming. However, its key regulatory factors are not yet elucidated. In this paper we investigate the role of PIWI proteins and provide evidence that one of them, MIWI2, is elicited during trans‐differentiation of fibroblasts into hepatocyte‐...
Article
Acid-sensing ion channels (ASICs) have emerged as important, albeit challenging therapeutic targets for pain, stroke, etc. One approach to developing therapeutic agents could involve the generation of functional antibodies against these channels. To select such antibodies, we used channels assembled in nanodiscs, such that the target ASIC1a has a c...
Data
Excessively high electric fields destroy protein and membrane systems. The simulation was carried out applying an external field in the -z direction during 100 ns.
Data
Independent replicas of the Cx26 under external electric field. (Top) RMSD on the Cx26 hemichannel in absence (green) and presence of an external field (red: negative; blue: positive). The two columns identify independent replicas. The external field in either direction was applied immediately after the stabilization period re-generating a temperat...
Article
Full-text available
Connexin channels play numerous essential roles in virtually every organ by mediating solute exchange between adjacent cells, or between cytoplasm and extracellular milieu. Our understanding of the structure-function relationship of connexin channels relies on X-ray crystallographic data for human connexin 26 (hCx26) intercellular gap junction chan...
Article
Full-text available
Main conclusion The acetohydroxy acid synthase S627N mutation confers herbicide tolerance in rice, and the rice variety containing this mutation produces good yields. This variety is commercially viable at Shanghai and Jiangsu regions in China. Weedy rice is a type of rice that produces lower yields and poorer quality grains than cultivated rice. I...
Article
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Protein tyrosine phosphatase non-receptor 12 (PTPN12) is an important protein tyrosine phosphatase involved in regulating cell adhesion and migration as well as tumorigenesis. Here, we solved a crystal structure of the native PTPN12 catalytic domain with the catalytic cysteine (residue 231) in dual conformation (phosphorylated and unphosphorylated)...
Article
Mutations of the GJB1 gene encoding connexin 32 (Cx32) cause the X-linked form of Charcot-Marie-Tooth disease (CMTX1), a demyelinating peripheral neuropathy for which there is no cure. A growing body of evidence indicates that ATP release through Cx32 hemichannels in Schwann cells could be critical for nerve myelination, but it is unknown if CMTX1...
Article
Full-text available
Background: Mutations leading to changes in properties, regulation, or expression of connexin-made channels have been implicated in 28 distinct human hereditary diseases. Eight of these result from variants of connexin 26 (Cx26), a protein critically involved in cell-cell signaling in the inner ear and skin. Lack of non-toxic drugs with defined mec...
Article
The neuron-restricted isoform 3 of the plasma membrane Ca(2+) ATPase plays a major role in the regulation of Ca(2+) homeostasis in the brain, where the precise control of Ca(2+) signaling is a necessity. Several function-affecting genetic mutations in the PMCA3 pump associated to X-linked congenital cerebellar ataxias have indeed been described. In...
Article
The plasma membrane Ca2 + ATPases (PMCA pumps) have a long, cytosolic C-terminal regulatory region where a calmodulin-binding domain (CaM-BD) is located. Under basal conditions (low Ca2 +), the C-terminal tail of the pump interacts with autoinhibitory sites proximal to the active center of the enzyme. In activating conditions (i.e., high Ca2 +), Ca...
Article
Recent theoretical findings suggest that the local flexibility of a polymer, linked to the chemical details of the molecule, can affect both the position and the size of knots along the polymer itself. Being of relevance in biology and material science, we further investigate this issue by performing molecular dynamics simulations on a model of dib...
Article
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The mitochondrial thioredoxin system (NADPH, thioredoxin reductase, thioredoxin) is a major redox regulator. Here we have investigated the redox correlation between this system and the mitochondrial enzyme cyclophilin D. The peptidyl prolyl cis-trans isomerase activity of cyclophilin D was stimulated by the thioredoxin system, while it was decrease...
Article
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Human transthyretin (TTR) represents a notable example of an amyloidogenic protein, and several compounds that are able to stabilize its native state have been proposed as effective drugs in the therapy of TTR amyloidosis. The two thyroxine (T4) binding sites present in the TTR tetramer display negative binding cooperativity. Here, structures of TT...
Article
Full-text available
Mutations in the GJB2 gene, which encodes the gap junction protein connexin 26 (Cx26), are the primary cause of hereditary prelingual hearing impairment. Here, the p.Cys169Tyr missense mutation of Cx26 (Cx26C169Y), previously classified as a polymorphism, has been identified as causative of severe hearing loss in two Qatari families. We have analyz...
Article
Full-text available
Mutations of the GJB2 gene encoding the connexin 26 (Cx26) gap junction protein, which is widely expressed in the inner ear, are the primary cause of hereditary non-syndromic hearing loss in several populations. The deafness-associated single amino acid substitution of methionine 34 (M34) in the first transmembrane helix (TM1) with a threonine (T)...
Article
Full-text available
Connexin hemichannels are regulated by several gating mechanisms, some of which depend critically on the extracellular Ca2+ concentration ([Ca2+]e). It is well established that hemichannel activity is inhibited at normal (∼1 mM) [Ca2+]e, whereas lowering [Ca2+]e to micromolar levels fosters hemichannel opening. Atomic force microscopy imaging shows...
Article
Full-text available
The permeability of gap junction channels to metabolites, and not simply to small inorganic ions, is likely to play an important role in development, physiology as well as in etiology of several diseases. Here, we combined dual patch clamp and fluorescence imaging techniques with molecular dynamics (MD) simulations to investigate the permeation of...
Article
Full-text available
Mutations in the genes GJB2 and GJB6 encoding human connnexin26 (hCx26) and connexin30 (hCx30), respectively, are the leading cause of non-syndromic prelingual deafness in several human populations. In this work, we exploited the high degree (77%) of sequence similarity shared by hCx26 and hCx30 to create atomistic models of homomeric hCx26 and hCx...
Article
Channelrhodopsin-2 (ChR2) is a light-gated cation channel widely used as a biotechnological tool to control membrane depolarization in various cell types and tissues. Although several ChR2 variants with modified properties have been generated, the structural determinants of the protein function are largely unresolved. We used bioinformatic modeling...
Article
Full-text available
Channelrhodopsin-2 (ChR2) is a light-gated cation channel widely used as a biotechnological tool to control membrane depolarization in various cell types and tissues. Although several ChR2 variants with modified properties have been generated, the structural determinants of the protein function are largely unresolved. We used bioinformatic modeling...
Article
Full-text available
Simulations in which a globular ring polymer with delocalized knots is separated in two interacting loops by a slipping link, or in two noninteracting globuli by a wall with a hole, show how the minimal crossing number of the knots controls the equilibrium statistics. With slipping link the ring length is divided between the loops according to a si...
Data
Reconstruction and structural relaxation of the KcsA potassium channel from its Ca atoms. Global RMS deviations vs. time calculated using the crystallographic structure as reference. The four shoulders in the curve correspond to the time points in which constraints are applied (20 ps) or increased (120, 220 and 320 ps respectively). The inset shows...
Data
Figures S2a and S2c to S2h. Location and interactions of residues along TM2 taken from the averaged structure of the whole connexon. Figure S2b. The exposed side chain of Trp77 is in contact with the membrane phospholipids, i.e., in good position to interact with cholesterol molecules (not present in the simulation). Shown is a representative snaps...
Article
Full-text available
Connexins are plasma membrane proteins that associate in hexameric complexes to form channels named connexons. Two connexons in neighboring cells may dock to form a "gap junction" channel, i.e. an intercellular conduit that permits the direct exchange of solutes between the cytoplasm of adjacent cells and thus mediate cell-cell ion and metabolic si...
Article
Full-text available
We investigate the Rouse dynamics of a flexible ring polymer with a prime knot. Within a Monte Carlo approach, we locate the knot, follow its diffusion, and observe the fluctuations of its length. A topological time scale that is slower then the Rouse one, is found to determine the long time behaviour of several dynamical quantities. The value of t...
Article
We investigate the Rouse dynamics of a flexible ring polymer with a prime knot. Within a Monte Carlo approach, we locate the knot, follow its diffusion, and observe the fluctuations of its length. We characterise a topological time scale, and show that it is related to a self-reptation of the knotted region. The associated dynamical exponent, $z_T=...
Article
Full-text available
We give two different, statistically consistent definitions of the length l of a prime knot tied into a polymer ring. In the good solvent regime the polymer is modeled by a self avoiding polygon of N steps on cubic lattice and l is the number of steps over which the knot "spreads" in a given configuration. An analysis of extensive Monte Carlo data...
Article
Full-text available
We give statistical definitions of the length, 1, of a loose prime knot tied into a long, fluctuating ring macromolecule. Monte Carlo results for the equilibrium, good solvent regime show that (1) similar to N-t, where N is the ring length and t similar or equal to 0.75 is independent of the knot type. In the collapsed regime below the theta temper...

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