Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A toggle switch controls the low pH-triggered rearrangement and maturation of the dengue virus envelope proteins.

ABSTRACT: Immature dengue virus particles undergo a dramatic conformational change upon exposure to the acidic environment of the late secretory pathway. The interactions of the E fusion proteins and prM chaperone proteins on the virus envelope are reorganized to permit prM processing by a host protease, furin, thus priming virus for fusion and infection. Here we identify a pH-dependent toggle switch that controls this key conformational change during virus maturation. Our data show that the M region of prM interacts with E at neutral pH but is released at acidic pH, while the pr region interacts with E at acidic pH but is released at neutral pH. Alanine substitution of the conserved residue H98 in prM disrupts the switch by inhibiting dissociation of M from E at low pH, resulting in impaired prM processing and decreased virus infectivity. Thus, release of M-E interaction at low pH promotes formation of a furin-accessible intermediate.

SUBMITTER: Zheng A

PROVIDER: S-EPMC4063126 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

A toggle switch controls the low pH-triggered rearrangement and maturation of the dengue virus envelope proteins.

Zheng Aihua A Yuan Fei F Kleinfelter Lara M LM Kielian Margaret M

Nature communications 20140520

Immature dengue virus particles undergo a dramatic conformational change upon exposure to the acidic environment of the late secretory pathway. The interactions of the E fusion proteins and prM chaperone proteins on the virus envelope are reorganized to permit prM processing by a host protease, furin, thus priming virus for fusion and infection. Here we identify a pH-dependent toggle switch that controls this key conformational change during virus maturation. Our data show that the M region of p ...[more]

PMID: 24846574

Similar Datasets

Disulfide rearrangement triggered by translocon assembly controls lipopolysaccharide export.

Project description:The presence of lipopolysaccharide (LPS) on the cell surface of Gram-negative bacteria is critical for viability. A conserved ?-barrel membrane protein LptD (lipopolysaccharide transport protein D) translocates LPS from the periplasm across the outer membrane (OM). In Escherichia coli, this protein contains two disulfide bonds and forms the OM LPS translocon with the lipoprotein LptE. Here, we identified seven in vivo states on the oxidative-folding pathway of LptD. Proper assembly involved a nonfunctional intermediate containing non-native disulfides. Intermediate formation required the oxidase DsbA, and subsequent maturation to the active form with native disulfides was triggered by LptE. Thus, disulfide bond-dependent protein folding of LptD requires the proper assembly of a two-protein complex to promote disulfide bond rearrangement.

| S-EPMC3489181 | biostudies-literature

An electrogenetic toggle switch model.

Project description:Synthetic biology uses molecular biology to implement genetic circuits that perform computations. These circuits can process inputs and deliver outputs according to predefined rules that are encoded, often entirely, into genetic parts. However, the field has recently begun to focus on using mechanisms beyond the realm of genetic parts for engineering biological circuits. We analyse the use of electrogenic processes for circuit design and present a model for a merged genetic and electrogenetic toggle switch operating in a biofilm attached to an electrode. Computational simulations explore conditions under which bistability emerges in order to identify the circuit design principles for best switch performance. The results provide a basis for the rational design and implementation of hybrid devices that can be measured and controlled both genetically and electronically.

| S-EPMC9948229 | biostudies-literature

An IRF1-IRF4 Toggle-Switch Controls Tolerogenic and Immunogenic Transcriptional Programming in Human Langerhans Cells.

Project description:Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels, coordinating both immunogenic and tolerogenic immune responses. To determine molecular switches directing induction of LC immune activation, we performed mathematical modelling of gene regulatory networks identified by single cell RNA sequencing of LCs exposed to TNF-alpha, a key pro-inflammatory signal produced by the skin. Our approach delineated three programmes of LC phenotypic activation (immunogenic, tolerogenic or ambivalent), and confirmed that TNF-alpha enhanced LC immunogenic programming. Through regulon analysis followed by mutual information modelling, we identified IRF1 as the key transcription factor for the regulation of immunogenicity in LCs. Application of a mathematical toggle switch model, coupling IRF1 with tolerance-inducing transcription factors, determined the key set of transcription factors regulating the switch between tolerance and immunogenicity, and correctly predicted LC behaviour in LCs derived from different body sites. Our findings provide a mechanistic explanation of how combinatorial interactions between different transcription factors can coordinate specific transcriptional programmes in human LCs, interpreting the microenvironmental context of the local tissue microenvironments.

| S-EPMC8239435 | biostudies-literature

An electrically actuated molecular toggle switch.

Project description:Molecular electronics is considered a promising approach for future nanoelectronic devices. In order that molecular junctions can be used as electrical switches or even memory devices, they need to be actuated between two distinct conductance states in a controlled and reproducible manner by external stimuli. Here we present a tripodal platform with a cantilever arm and a nitrile group at its end that is lifted from the surface. The formation of a coordinative bond between the nitrile nitrogen and the gold tip of a scanning tunnelling microscope can be controlled by both electrical and mechanical means, and leads to a hysteretic switching of the conductance of the junction by more than two orders of magnitude. This toggle switch can be actuated with high reproducibility so that the forces involved in the mechanical deformation of the molecular cantilever can be determined precisely with scanning tunnelling microscopy.

| S-EPMC5347093 | biostudies-literature

An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.

Project description:The pharmacokinetic properties of antibodies are largely dictated by the pH-dependent binding of the IgG fragment crystallizable (Fc) domain to the human neonatal Fc receptor (hFcRn). Engineered Fc domains that confer a longer circulation half-life by virtue of more favorable pH-dependent binding to hFcRn are of great therapeutic interest. Here we developed a pH Toggle switch Fc variant containing the L309D/Q311H/N434S (DHS) substitutions, which exhibits markedly improved pharmacokinetics relative to both native IgG1 and widely used half-life extension variants, both in conventional hFcRn transgenic mice and in new knock-in mouse strains. engineered specifically to recapitulate all the key processes relevant to human antibody persistence in circulation, namely: (i) physiological expression of hFcRn, (ii) the impact of hFcγRs on antibody clearance and (iii) the role of competing endogenous IgG. DHS-IgG retains intact effector functions, which are important for the clearance of target pathogenic cells and also has favorable developability.

| S-EPMC6834678 | biostudies-literature

Structural transition of GP64 triggered by a pH-sensitive multi-histidine switch.

Project description:The fusion of viruses with cellular membranes is a critical step in the life cycle of enveloped viruses. This process is facilitated by viral fusion proteins, many of which are conformationally pH-sensitive. The specifics of how changes in pH initiate this fusion have remained largely elusive. This study presents the cryo-electron microscopy (cryo-EM) structures of a prototype class III fusion protein, GP64, in its prefusion and early intermediate states, revealing the structural intermediates accompanying the membrane fusion process. The structures identify the involvement of a pH-sensitive switch, comprising H23, H245, and H304, in sensing the low pH that triggers the initial step of membrane fusion. The pH sensing role of this switch is corroborated by assays of cell-cell syncytium formation and dual dye-labeling. The findings demonstrate that coordination between multiple histidine residues acts as a pH sensor and activator. The involvement of a multi-histidine switch in viral fusion is applicable to fusogens of human-infecting thogotoviruses and other viruses, which could lead to strategies for developing anti-viral therapies and vaccines.

| S-EPMC11372198 | biostudies-literature

Genetic toggle switch controlled by bacterial growth rate.

Project description:In favorable conditions bacterial doubling time is less than 20 min, shorter than DNA replication time. In E. coli a single round of genome replication lasts about 40 min and it must be accomplished about 20 min before cell division. To achieve such fast growth rates bacteria perform multiple replication rounds simultaneously. As a result, when the division time is as short as 20 min E. coli has about 8 copies of origin of replication (ori) and the average copy number of the genes situated close to ori can be 4 times larger than those near the terminus of replication (ter). It implies that shortening of cell cycle may influence dynamics of regulatory pathways involving genes placed at distant loci.We analyze this effect in a model of a genetic toggle switch, i.e. a system of two mutually repressing genes, one localized in the vicinity of ori and the other localized in the vicinity of ter. Using a stochastic model that accounts for cell growth and divisions we demonstrate that shortening of the cell cycle can induce switching of the toggle to the state in which expression of the gene placed near ter is suppressed. The toggle bistability causes that the ratio of expression of the competing genes changes more than two orders of magnitude for a two-fold change of the doubling time. The increasing stability of the two toggle states enhances system sensitivity but also its reaction time.By fusing the competing genes with fluorescent tags this mechanism could be tested and employed to create an indicator of the doubling time. By manipulating copy numbers of the competing genes and locus of the gene situated near ter, one can obtain equal average expression of both genes for any doubling time T between 20 and 120 min. Such a toggle would accurately report departures of the doubling time from T.

| S-EPMC5712128 | biostudies-literature

Biological signal processing with a genetic toggle switch.

Project description:Complex gene regulation requires responses that depend not only on the current levels of input signals but also on signals received in the past. In digital electronics, logic circuits with this property are referred to as sequential logic, in contrast to the simpler combinatorial logic without such internal memory. In molecular biology, memory is implemented in various forms such as biochemical modification of proteins or multistable gene circuits, but the design of the regulatory interface, which processes the input signals and the memory content, is often not well understood. Here, we explore design constraints for such regulatory interfaces using coarse-grained nonlinear models and stochastic simulations of detailed biochemical reaction networks. We test different designs for biological analogs of the most versatile memory element in digital electronics, the JK-latch. Our analysis shows that simple protein-protein interactions and protein-DNA binding are sufficient, in principle, to implement genetic circuits with the capabilities of a JK-latch. However, it also exposes fundamental limitations to its reliability, due to the fact that biological signal processing is asynchronous, in contrast to most digital electronics systems that feature a central clock to orchestrate the timing of all operations. We describe a seemingly natural way to improve the reliability by invoking the master-slave concept from digital electronics design. This concept could be useful to interpret the design of natural regulatory circuits, and for the design of synthetic biological systems.

| S-EPMC3712956 | biostudies-literature

Using a visible light-triggered pH switch to activate nanozymes for antibacterial treatment.

Project description:Here, we develop a visible light-triggered platform to activate the biomimetic activity of CuS nanoparticles by incorporating a photoacid generator. Under visible-light illumination, the remarkable pH decrease, caused by the intramolecular photoreaction of the photoacid generator, activates the peroxidase-like activity of the CuS nanoparticles. This visible light-triggered pH switch meets the antibacterial demands of peroxidase mimics perfectly in bacteria-infected wounds. Importantly, the built-in torches of mobile phones are able to replace the visible-light source to activate the peroxidase-mimicking activity of CuS nanoparticles to combat bacteria, which greatly promotes the utility and adaptability of this antibacterial platform.

| S-EPMC9048289 | biostudies-literature

A spatial toggle switch drives boundary formation in development.

Project description:Herein we introduce a multicellular network motif that performs as a spatial toggle switch and explains how boundary formation can be faithfully accomplished in developmental processes. Importantly, we show that expression and activity patterns of proteins must be simultaneously characterized for a proper understanding and description of the underlying mechanism. Our in silico experiments, in agreement with in vivo results, evaluate different genetic backgrounds and shed light on the dynamics of boundary formation. In addition, we provide an estimation of relevant biological parameters and a robustness analysis.

| S-EPMC2586583 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data