scholarly journals Blocker escape kinetics from a membrane channel analyzed by mapping blocker diffusive dynamics onto a two-site model

2019 ◽  
Vol 150 (19) ◽  
pp. 194103 ◽  
Author(s):  
Alexander M. Berezhkovskii ◽  
Sergey M. Bezrukov
Keyword(s):  
Membrane Channel ◽  
Site Model ◽  
Diffusive Dynamics

Diffusion model of solute dynamics in a membrane channel: Mapping onto the two-site model and optimizing the flux

2007 ◽  
Vol 127 (11) ◽  
pp. 115101 ◽  
Author(s):  
Sergey M. Bezrukov ◽  
Alexander M. Berezhkovskii ◽  
Attila Szabo
Keyword(s):  
Diffusion Model ◽  
Membrane Channel ◽  
Site Model ◽  
Solute Dynamics

A Phenotype–Genotype Codon Model for Detecting Adaptive Evolution

2019 ◽  
Vol 69 (4) ◽  
pp. 722-738 ◽  
Author(s):  
Christopher T Jones ◽  
Noor Youssef ◽  
Edward Susko ◽  
Joseph P Bielawski
Keyword(s):  
Positive Selection ◽  
Adaptive Evolution ◽  
Evolutionary History ◽  
Life History Trait ◽  
Molecular Adaptation ◽  
Simulation Studies ◽  
Site Model ◽  
Branch Site ◽  
A Site ◽  
Post Hoc

Abstract A central objective in biology is to link adaptive evolution in a gene to structural and/or functional phenotypic novelties. Yet most analytic methods make inferences mainly from either phenotypic data or genetic data alone. A small number of models have been developed to infer correlations between the rate of molecular evolution and changes in a discrete or continuous life history trait. But such correlations are not necessarily evidence of adaptation. Here, we present a novel approach called the phenotype–genotype branch-site model (PG-BSM) designed to detect evidence of adaptive codon evolution associated with discrete-state phenotype evolution. An episode of adaptation is inferred under standard codon substitution models when there is evidence of positive selection in the form of an elevation in the nonsynonymous-to-synonymous rate ratio $\omega$ to a value $\omega > 1$. As it is becoming increasingly clear that $\omega > 1$ can occur without adaptation, the PG-BSM was formulated to infer an instance of adaptive evolution without appealing to evidence of positive selection. The null model makes use of a covarion-like component to account for general heterotachy (i.e., random changes in the evolutionary rate at a site over time). The alternative model employs samples of the phenotypic evolutionary history to test for phenomenological patterns of heterotachy consistent with specific mechanisms of molecular adaptation. These include 1) a persistent increase/decrease in $\omega$ at a site following a change in phenotype (the pattern) consistent with an increase/decrease in the functional importance of the site (the mechanism); and 2) a transient increase in $\omega$ at a site along a branch over which the phenotype changed (the pattern) consistent with a change in the site’s optimal amino acid (the mechanism). Rejection of the null is followed by post hoc analyses to identify sites with strongest evidence for adaptation in association with changes in the phenotype as well as the most likely evolutionary history of the phenotype. Simulation studies based on a novel method for generating mechanistically realistic signatures of molecular adaptation show that the PG-BSM has good statistical properties. Analyses of real alignments show that site patterns identified post hoc are consistent with the specific mechanisms of adaptation included in the alternate model. Further simulation studies show that the covarion-like component of the PG-BSM plays a crucial role in mitigating recently discovered statistical pathologies associated with confounding by accounting for heterotachy-by-any-cause. [Adaptive evolution; branch-site model; confounding; mutation-selection; phenotype–genotype.]

scholarly journals Release mechanisms of major DAMPs

APOPTOSIS ◽  
2021 ◽  
Vol 26 (3-4) ◽  
pp. 152-162
Author(s):  
Atsushi Murao ◽  
Monowar Aziz ◽  
Haichao Wang ◽  
Max Brenner ◽  
Ping Wang
Keyword(s):  
Rna Binding ◽  
High Mobility ◽  
Live Cells ◽  
Membrane Channel ◽  
Membrane Rupture ◽  
Underlying Mechanisms ◽  
Shock Proteins ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Secretory Lysosomes

AbstractDamage-associated molecular patterns (DAMPs) are endogenous molecules which foment inflammation and are associated with disorders in sepsis and cancer. Thus, therapeutically targeting DAMPs has potential to provide novel and effective treatments. When establishing anti-DAMP strategies, it is important not only to focus on the DAMPs as inflammatory mediators but also to take into account the underlying mechanisms of their release from cells and tissues. DAMPs can be released passively by membrane rupture due to necrosis/necroptosis, although the mechanisms of release appear to differ between the DAMPs. Other types of cell death, such as apoptosis, pyroptosis, ferroptosis and NETosis, can also contribute to DAMP release. In addition, some DAMPs can be exported actively from live cells by exocytosis of secretory lysosomes or exosomes, ectosomes, and activation of cell membrane channel pores. Here we review the shared and DAMP-specific mechanisms reported in the literature for high mobility group box 1, ATP, extracellular cold-inducible RNA-binding protein, histones, heat shock proteins, extracellular RNAs and cell-free DNA.

scholarly journals Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Uday Tak ◽  
Terje Dokland ◽  
Michael Niederweis
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Pore Formation ◽  
Molecular Switches ◽  
Water Soluble ◽  
Host Cells ◽  
Solvent Exposure ◽  
Membrane Channel ◽  
Toxin Secretion ◽  
Outer Membrane Channel ◽  
Membrane Spanning

AbstractMycobacterium tuberculosis secretes the tuberculosis necrotizing toxin (TNT) to kill host cells. Here, we show that the WXG100 proteins EsxE and EsxF are essential for TNT secretion. EsxE and EsxF form a water-soluble heterodimer (EsxEF) that assembles into oligomers and long filaments, binds to membranes, and forms stable membrane-spanning channels. Electron microscopy of EsxEF reveals mainly pentameric structures with a central pore. Mutations of both WXG motifs and of a GXW motif do not affect dimerization, but abolish pore formation, membrane deformation and TNT secretion. The WXG/GXW mutants are locked in conformations with altered thermostability and solvent exposure, indicating that the WXG/GXW motifs are molecular switches controlling membrane interaction and pore formation. EsxF is accessible on the bacterial cell surface, suggesting that EsxEF form an outer membrane channel for toxin export. Thus, our study reveals a protein secretion mechanism in bacteria that relies on pore formation by small WXG proteins.

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