Emerging View on the Molecular Functions of Sec62 and Sec63 in Protein Translocation

Most secreted and membrane proteins are targeted to and translocated across the endoplasmic reticulum (ER) membrane through the Sec61 protein-conducting channel. Evolutionarily conserved Sec62 and Sec63 associate with the Sec61 channel, forming the Sec complex and mediating translocation of a subset of proteins. For the last three decades, it has been thought that ER protein targeting and translocation occur via two distinct pathways: signal recognition particle (SRP)-dependent co-translational or SRP-independent, Sec62/Sec63 dependent post-translational translocation pathway. However, recent studies have suggested that ER protein targeting and translocation through the Sec translocon are more intricate than previously thought. This review summarizes the current understanding of the molecular functions of Sec62/Sec63 in ER protein translocation.

Integrated geological-geophysical characterization of the zone of the Kherson—Smolensk transregional tectonic suture — deep long-lived magma- and fluid-conducting channel

The transregional Kherson—Smolensk suture has been established to be located between large meridional faults of the crystalline crust of the Ukrainian Shield (USh) in a strip of 50—70 km width and separates two microplates of different composition of the Precambrian basement. It is traced by subcrustal mantle heterogeneity in the lithosphere and a change in the relief of the main geodynamic boundary. The suture controls the USh large multiphase magmatic massifs and manifestation of the basic mafic magmatism in the Dniepr-Donets Depressin (DDD), which age decreases from south to north from the Early Proterozoic in the shield to the Devonian in the depression. On both sides of it, the crystalline crust differs in a set of parameters including a zone of low velocities in the area of the Novokonstantinovsky ore field of the USh to the east of the Kherson—Smolensk suture, where from DSS data its maximum thickness is 10—15 km in the upper crust. It appears to bea source of abiogenic hydrogen manifestations recorded by mining operations on this field. The Kherson—Smolensk suture, being a transregional mantle feature, unites the existing hydrocarbon manifestation in the USh with the promising hydrocarbon areas of the DDD. The inhomogeneities of the crystalline crust and the uppermost mantle give strong evidences to classify reasonably the transregional tectonic suture Kherson—Smolensk as a powerful mantle long-lived magmatic and fluid-conducting channel. Ores hows and modern degassing of methane are related to it, with methane beingmain greenhouse gas.

Numerical Modeling of Pulse-Periodic Nanosecond Discharges

The first results of the numerical simulation of the Pulse-Periodic Nanosecond discharge in pin-to-pin configuration in 2Dt approximation of the full self-consist system of Navier-Stocks equation for real thermo-chemically non-equilibrium gases, drift-diffusion approximation of the low temperature plasma evolution in external electric and magnetic field and, alternative – arc (spark) discharge model of high-density energy input discharge. The intuitive criteria of the alternative discharge models re-switch are proposed and tested. The pin-to-pin the pulse-periodic nanosecond 5-MHz discharge has been considered for 1 microsecond interval. It was found that rather strong longitudinal non-uniformities of main physical parameters are created at the first corona stage of the interelectrode conducting channel. These nonuniformities reveal long-lived features that have define strong effect on the discharge performance

Structural basis of mitochondrial protein import by the TIM complex

Mitochondria import nearly all their ~1,000-2,000 constituent proteins from the cytosol across their double membrane envelope. Genetic and biochemical studies have shown that the conserved protein translocase, termed the TIM complex (also known as TIM23 complex), mediates import of presequence-containing proteins into the mitochondrial matrix and inner membrane. Among ~10 different subunits of the complex, the essential multi-pass membrane protein Tim23, together with the evolutionarily related protein Tim17, has long been postulated to form a protein-conducting channel. However, the mechanism of TIM-mediated protein import remains uncertain due to a lack of structural information on the complex. Here, we have determined the cryo-EM structure of the core TIM complex (Tim17-Tim23-Tim44) from Saccharomyces cerevisiae. We show that, contrary to the prevailing model, Tim23 and Tim17 do not form a water-filled channel, but instead have separate, lipid-exposed concave cavities that face in opposite directions. Remarkably, our data suggest that the cavity of Tim17 itself forms the protein translocation path whereas Tim23 plays a structural role. We also show how the Tim17-Tim23 heterodimer associates with the scaffold protein Tim44 and J-domain proteins to mediate Hsp70-driven polypeptide transport into the matrix. Our work provides the structural foundation to understand the mechanism of TIM-mediated protein import and sorting, a central pathway in mitochondrial biogenesis.

A revised mechanism for how Plasmodium falciparum recruits and exports proteins into its erythrocytic host cell.

Plasmodium falciparum exports ~10% of its proteome into its host erythrocyte to modify the host cell’s physiology. The Plasmodium export element (PEXEL) motif contained within the N-terminus of most exported proteins directs the trafficking of those proteins into the erythrocyte. To reach the host cell, the PEXEL motif of exported proteins are processed by the endoplasmic reticulum (ER) resident aspartyl protease plasmepsin V. Then, following secretion into the parasite-encasing parasitophorous vacuole, the mature exported protein must be unfolded and translocated across the parasitophorous vacuole membrane by the Plasmodium translocon of exported proteins (PTEX). PTEX is a protein-conducting channel consisting of the pore-forming protein EXP2, the protein unfoldase HSP101, and structural component PTEX150. The mechanism of how exported proteins are specifically trafficked from the parasite’s ER following PEXEL cleavage to PTEX complexes on the parasitophorous vacuole membrane is currently not understood. Here, we present evidence that EXP2 and PTEX150 form a stable subcomplex that facilitates HSP101 docking. We also demonstrate that HSP101 localises both within the parasitophorous vacuole and within the parasite’s ER throughout the ring and trophozoite stage of the parasite, coinciding with the timeframe of protein export. Interestingly, we found that HSP101 can form specific interactions with model PEXEL proteins in the parasite ER, irrespective of their PEXEL processing status. Collectively, our data suggest that HSP101 recognises and chaperones PEXEL proteins from the ER to the parasitophorous vacuole and given HSP101’s specificity for the EXP2-PTEX150 subcomplex, this provides a mechanism for how exported proteins are specifically targeted to PTEX for translocation into the erythrocyte.

Aquaporins in GtoPdb v.2021.3

Aquaporins and aquaglyceroporins are membrane channels that allow the permeation of water and certain other small solutes across the cell membrane, or in the case of AQP6, AQP11 and AQP12A, intracellular membranes, such as vesicles and the endoplasmic reticulum membrane [16]. Since the isolation and cloning of the first aquaporin (AQP1) [20], 12 additional mammalian members of the family have been identified, although little is known about the functional properties of one of these (AQP12A; Q8IXF9) and it is thus not tabulated. The other 12 aquaporins can be broadly divided into three families: orthodox aquaporins (AQP0,-1,-2,-4,-5, -6 and -8) permeable mainly to water, but for some additional solutes [4]; aquaglyceroporins (AQP3,-7 -9 and -10), additionally permeable to glycerol and for some isoforms urea [14], and superaquaporins (AQP11 and 12) located within cells [12]. Some aquaporins also conduct ammonia and/or H2O2 giving rise to the terms 'ammoniaporins' ('aquaammoniaporins') and 'peroxiporins', respectively. Aquaporins are impermeable to protons and other inorganic and organic cations, with the possible exception of AQP1, although this is controversial [14]. One or more members of this family of proteins have been found to be expressed in almost all tissues of the body [reviewed in Yang (2017) [26]]. AQPs are involved in numerous processes that include systemic water homeostasis, adipocyte metabolism, brain oedema, cell migration and fluid secretion by epithelia. Loss of function mutations of some human AQPs, or their disruption by autoantibodies further underscore their importance [reviewed by Verkman et al. (2014) [23], Kitchen et al. (2105) [14]]. Functional AQPs exist as homotetramers that are the water conducting units wherein individual AQP subunits (each a protomer) have six TM helices and two half helices that constitute a seventh 'pseudotransmembrane domain' that surrounds a narrow water conducting channel [16]. In addition to the four pores contributed by the protomers, an additional hydrophobic pore exists within the center of the complex [16] that may mediate the transport through AQP1. Although numerous small molecule inhibitors of aquaporins, particularly APQ1, have been reported primarily from Xenopus oocyte swelling assays, the activity of most has subsequently been disputed upon retesting using assays of water transport that are less prone to various artifacts [5] and they are therefore excluded from the tables [see Tradtrantip et al. (2017) [22] for a review].

Cancer associated mutations in Sec61γ alter the permeability of the ER translocase

Translocation of secretory and integral membrane proteins across or into the ER membrane occurs via the Sec61 complex, a heterotrimeric protein complex possessing two essential sub-units, Sec61p/Sec61α and Sss1p/Sec61γ and the non-essential Sbh1p/Sec61β subunit. In addition to forming a protein conducting channel, the Sec61 complex maintains the ER permeability barrier, preventing flow of molecules and ions. Loss of Sec61 integrity is detrimental and implicated in the progression of disease. The Sss1p/Sec61γ C-terminus is juxtaposed to the key gating module of Sec61p/Sec61α and is important for gating the translocon. Inspection of the cancer genome database identifies six mutations in highly conserved amino acids of Sec61γ/Sss1p. We identify that five out of the six mutations identified affect gating of the ER translocon, albeit with varying strength. Together, we find that mutations in Sec61γ that arise in malignant cells result in altered translocon gating dynamics, this offers the potential for the translocon to represent a target in co-therapy for cancer treatment.

Proton-mediated gating mechanism of anion channelrhodopsin-1

Anion channelrhodopsin from Guillardia theta (GtACR1) has Asp234 (3.2 Å) and Glu68 (5.3 Å) near the protonated Schiff base. Here we investigate mutant GtACR1s (e.g., E68Q/D234N) expressed in HEK293 cells. The influence of the acidic residues on the absorption wavelengths were also analyzed, using a quantum mechanical/molecular mechanical approach. The calculated protonation pattern indicates that Asp234 is deprotonated and Glu68 is protonated in the original crystal structures. The D234E mutation and the E68Q/D234N mutation shortens and lengthens the measured and calculated absorption wavelengths, respectively, which suggests that Asp234 is deprotonated in the wild type GtACR1. Molecular dynamics simulations show that upon mutation of deprotonated Asp234 to asparagine, deprotonated Glu68 reorients towards the Schiff base and the calculated absorption wavelength remains unchanged. The formation of the proton transfer pathway via Asp234 toward Glu68 and the disconnection of the anion conducting channel are likely a basis of the gating mechanism.

CARBON TUBE-BASED NANOTRANSISTORS

В статье рассмотрены нанотранзисторы и основные свойства нанотрубок. Представлен обзор CNTFET транзисторов и основные особенности технологии их изготовления. Полевые транзисторы из углеродных нанотрубок (CNTFET) являются перспективными наноразмерными устройствами для реализации высокопроизводительных схем с очень плотной и низкой мощностью. Проводящий канал CNTFET представляет собой углеродную нанотрубку. The article deals with nanotransistors and the main properties of nanotubes. An overview of CNTFET transistors and the main features of their manufacturing technology is presented. Carbon nanotube field effect transistors (CNTFETs) are promising nanoscale devices for implementing high-performance circuits with very dense and low power. The CNTFET conducting channel is a carbon nanotube.