An Iris-Like Mechanism of Pore Dilation in the CorA Magnesium Transport System

AbstractMagnesium translocation across cell membranes is essential for numerous physiological processes. Three recently reported crystal structures of the CorA magnesium transport system revealed a surprising architecture, with a bundle of giant α-helices forming a 60-Å-long pore that extends beyond the membrane before widening into a funnel-shaped cytosolic domain. The presence of divalent cations in putative intracellular regulation sites suggests that these structures correspond to the closed conformation of CorA. To examine the nature of the conduction pathway, we performed 110-ns molecular-dynamics simulations of two of these structures in a lipid bilayer with and without regulatory ions. The results show that a 15-Å-long hydrophobic constriction straddling the membrane-cytosol interface constitutes a steric bottleneck whose location coincides with an electrostatic barrier opposing cation translocation. In one of the simulations, structural relaxation after the removal of regulatory ions led to concerted changes in the tilt of the pore helices, resulting in iris-like dilation and spontaneous hydration of the hydrophobic neck. This simple and robust mechanism is consistent with the regulation of pore opening by intracellular magnesium concentration, and explains the unusual architecture of CorA

One-loop approximation of Moller scattering in Krein-space quantization

It has been shown that the negative-norm states necessarily appear in a covariant quantization of the free minimally coupled scalar field in de Sitter spacetime [1,2]. In this processes ultraviolet and infrared divergences have been automatically eliminated [3]. A natural renormalization of the one-loop interacting quantum field in Minkowski spacetime ($\lambda\phi^4$) has been achieved through the consideration of the negative-norm states defined in Krein space. It has been shown that the combination of quantum field theory in Krein space together with consideration of quantum metric fluctuation, results in quantum field theory without any divergences [4]. Pursuing this approach, we express Wick's theorem and calculate M{\o}ller scattering in the one-loop approximation in Krein space. The mathematical consequence of this method is the disappearance of the ultraviolet divergence in the one-loop approximation.Comment: 10 page

Development of photocrosslinking probes based on Huwentoxin-IV to map the site of interaction on Nav1.7

Voltage-gated sodium (Nav) channels respond to changes in the membrane potential of excitable cells through the concerted action of four voltage-sensor domains (VSDs). Subtype Nav1.7 plays an important role in the propagation of signals in pain-sensing neurons and is a target for the clinical development of novel analgesics. Certain inhibitory cystine knot (ICK) peptides produced by venomous animals potently modulate Nav1.7, however the molecular mechanisms underlying their selective binding and activity remain elusive. This study reports on the design of a library of photoprobes based on the potent spider toxin Huwentoxin-IV and the determination of the toxin binding interface on VSD2 of Nav1.7 through a photocrosslinking and tandem mass spectrometry approach. Our Huwentoxin-IV probes selectively crosslink to extracellular loop S1-2 and helix S3 of VSD2 in a chimeric channel system. Our results provide a strategy that will enable mapping of sites of interaction of other ICK peptides on Nav channels

The link between plant-based diet indices with biochemical markers of bone turn over, inflammation, and insulin in Iranian older adults

Background: The association of plant-based diets and biomarkers of bone, insulin, and inflammation is still unclear. Objectives: We investigated the associations between biomarkers of bone, insulin, and inflammation and three plant-based diet indices: an overall plant-based diet index (PDI); a healthy plant-based diet index (hPDI); and an unhealthy plant-based diet index (uPDI). Methods: We included 178 elderly subjects who referred to health centers in Tehran. Blood and urine samples were collected to measure osteocalcin. The Human C-telopeptide of type â collagen (u-CTX-I), highly sensitive C-reactive protein (hs-CRP), parathyroid hormone (PTH), 25(OH) D, and insulin resistance and sensitivity. We created an overall PDI, hPDI, and uPDI from semi-quantitative food frequency questionnaire (FFQ) data. Results: Dietary groups of Vegetables (r =.15, p =.03), nuts (r =.16, p =.03), dairy (r =.25, p =.001), eggs (r =.27, p <.001), red meat, and animal products (r =.25, p =.001) were directly correlated with osteocalcin. Refined grains were also had a positive association with serum insulin concentration (r =.14, p =.04). PTH levels are inversely associated with PDI score (β = â��0.18, p =.01). Also, serum insulin concentration was negatively associated with PDI score (β = â��0.10, p =.04). Urine CTX-1 levels were significantly associated with hPDI score (β = â��0.06, p =.04). u-CTX-1 levels are inversely associated with uPDI score. This significance did not change with the adjustment of the confounders (β = â��0.28, p <.001). Conclusions: More adherence to PDI and hPDI and less in uPDI may have a beneficial effect on biomarkers of bone, inflammation, and insulin thus preserving chronic diseases. © 2021 The Authors. Food Science & Nutrition published by Wiley Periodicals LL

A review of the MSCA ITN ECOSTORE - Novel complex metal hydrides for efficient and compact storage of renewable energy as hydrogen and electricity

Hydrogen as an energy carrier is very versatile in energy storage applications. Developments in novel, sustainable technologies towards a CO2-free society are needed and the exploration of all-solid-state batteries (ASSBs) as well as solid-state hydrogen storage applications based on metal hydrides can provide solutions for such technologies. However, there are still many technical challenges for both hydrogen storage material and ASSBs related to designing low-cost materials with low-environmental impact. The current materials considered for all-solid-state batteries should have high conductivities for Na+, Mg2+ and Ca2+, while Al3+-based compounds are often marginalised due to the lack of suitable electrode and electrolyte materials. In hydrogen storage materials, the sluggish kinetic behaviour of solid-state hydride materials is one of the key constraints that limit their practical uses. Therefore, it is necessary to overcome the kinetic issues of hydride materials before discussing and considering them on the system level. This review summarizes the achievements of the Marie Skłodowska-Curie Actions (MSCA) innovative training network (ITN) ECOSTORE, the aim of which was the investigation of different aspects of (complex) metal hydride materials. Advances in battery and hydrogen storage materials for the efficient and compact storage of renewable energy production are discussed

Krein Regularization of \lambda\phi^4

We calculate the four-point function in \lambda\phi^4 theory by using Krein regularization and compare our result, which is finite, with the usual result in \lambda\phi^4 theory. The effective coupling constant (\lambda_\mu) is also calculated in this method

Characterization of the Prokaryotic Sodium Channel NavSp Pore with a Microfluidic Bilayer Platform

This paper describes the use of a newly-developed micro-chip bilayer platform to examine the electrophysiological properties of the prokaryotic voltage-gated sodium channel pore (NavSp) from Silicibacter pomeroyi. The platform allows up to 6 bilayers to be analysed simultaneously. Proteoliposomes were incorporated into suspended lipid bilayers formed within the microfluidic bilayer chips. The chips provide access to bilayers from either side, enabling the fast and controlled titration of compounds. Dose-dependent modulation of the opening probability by the channel blocking drug nifedipine was measured and its IC50 determined

Structure of the C-terminal domain of the Prokaryotic Sodium Channel Orthologue NsvBa

Crystallographic and electrophysiological studies have recently provided insight into the structure, function and drug binding of prokaryotic sodium channels. These channels exhibit significant sequence identities, especially in their transmembrane regions, with human voltage-gated sodium channels. However, rather than being single polypeptides with four homologous domains, they are tetramers of single domain polypeptides, with a C-terminal domain (CTD) composed of an inter-subunit four helix coiled-coil. The structures of the CTDs differ between orthologues. In NavBh and NavMs, the C-termini form a disordered region adjacent to the final transmembrane helix, followed by a coiled-coil region, as demonstrated by synchrotron radiation circular dichroism (SRCD) and double electron-electron resonance electron paramagnetic resonance spectroscopic measurements. In contrast, in the crystal structure of the NavAe orthologue, the entire C-terminus is comprised of a helical region followed by a coiled-coil. In this study we have examined the CTD of the NsvBa from Bacillus alcalophilus, which unlike other orthologues is predicted by different methods to have different types of structures: either a disordered adjacent to the transmembrane region, followed by a helical coiled-coil, or a fully helical CTD. To discriminate between the two possible structures we have used SRCD spectroscopy to experimentally determine the secondary structure of the C-terminus of this orthologue and used the results as the basis for modelling the transition between open and closed conformations of the channel

Mutagenesis of the NaChBac sodium channel discloses a functional role for a conserved S6 asparagine

Asparagine is conserved in the S6 transmembrane segments of all voltage-gated sodium, calcium, and TRP channels identified to date. A broad spectrum of channelopathies including cardiac arrhythmias, epilepsy, muscle diseases, and pain disorders is associated with its mutation. To investigate its effects on sodium channel functional properties, we mutated the simple prokaryotic sodium channel NaChBac. Electrophysiological characterization of the N225D mutant reveals that this conservative substitution shifts the voltage-dependence of inactivation by 25 mV to more hyperpolarized potentials. The mutant also displays greater thermostability, as determined by synchrotron radiation circular dichroism spectroscopy studies of purified channels. Based on our analyses of high-resolution structures of NaChBac homologues, we suggest that the side-chain amine group of asparagine 225 forms one or more hydrogen bonds with different channel elements and that these interactions are important for normal channel function. The N225D mutation eliminates these hydrogen bonds and the structural consequences involve an enhanced channel inactivation