Cells communicate with their external environment through physical and chemical processes that take place in the cell-surrounding membrane. The membrane serves as a barrier as well as a special ...environment in which membrane proteins are able to carry out important processes. Certain membrane proteins have the ability to detect the membrane voltage and regulate ion conduction or enzyme activity. Such voltage-dependent processes rely on the action of protein domains known as voltage sensors, which are embedded inside the cell membrane and contain an excess of positively charged amino acids, which react to an electric field. How does the membrane create an environment suitable for voltage sensors? Here we show under a variety of conditions that the function of a voltage-dependent K+ channel is dependent on the negatively charged phosphodiester of phospholipid molecules. A non-voltage-dependent K+ channel does not exhibit the same dependence. The data lead us to propose that the phospholipid membrane, by providing stabilizing interactions between positively charged voltage-sensor arginine residues and negatively charged lipid phosphodiester groups, provides an appropriate environment for the energetic stability and operation of the voltage-sensing machinery. We suggest that the usage of arginine residues in voltage sensors is an adaptation to the phospholipid composition of cell membranes.
Pathogens and cellular danger signals activate sensors such as RIG-I and NLRP3 to produce robust immune and inflammatory responses through respective adaptor proteins MAVS and ASC, which harbor ...essential N-terminal CARD and PYRIN domains, respectively. Here, we show that CARD and PYRIN function as bona fide prions in yeast and that their prion forms are inducible by their respective upstream activators. Likewise, a yeast prion domain can functionally replace CARD and PYRIN in mammalian cell signaling. Mutations in MAVS and ASC that disrupt their prion activities in yeast also abrogate their ability to signal in mammalian cells. Furthermore, fibers of recombinant PYRIN can convert ASC into functional polymers capable of activating caspase-1. Remarkably, a conserved fungal NOD-like receptor and prion pair can functionally reconstitute signaling of NLRP3 and ASC PYRINs in mammalian cells. These results indicate that prion-like polymerization is a conserved signal transduction mechanism in innate immunity and inflammation.
Display omitted
•MAVS and ASC exhibit hallmarks of prions in yeast and mammalian cells•The prion forms of MAVS and ASC activate downstream signaling•Mutations that impair MAVS and ASC prion formation abolish their functions•Signaling through prion-like polymerization is conserved from fungi to mammals
The adaptor proteins MAVS and ASC form self-perpetuating prion-like polymers to propagate innate immune and inflammatory signaling. Prion-like switch is a conserved mechanism of signal transduction from fungi to mammals.
In response to viral infection, RIG-I-like RNA helicases bind to viral RNA and activate the mitochondrial protein MAVS, which in turn activates the transcription factors IRF3 and NF-κB to induce type ...I interferons. We have previously shown that RIG-I binds to unanchored lysine-63 (K63) polyubiquitin chains and that this binding is important for MAVS activation; however, the mechanism underlying MAVS activation is not understood. Here, we show that viral infection induces the formation of very large MAVS aggregates, which potently activate IRF3 in the cytosol. We find that a fraction of recombinant MAVS protein forms fibrils that are capable of activating IRF3. Remarkably, the MAVS fibrils behave like prions and effectively convert endogenous MAVS into functional aggregates. We also show that, in the presence of K63 ubiquitin chains, RIG-I catalyzes the conversion of MAVS on the mitochondrial membrane to prion-like aggregates. These results suggest that a prion-like conformational switch of MAVS activates and propagates the antiviral signaling cascade.
Display omitted
► Viral infection induces the formation of MAVS aggregates that potently activate IRF3 ► Recombinant MAVS protein forms self-propagating fibrils ► MAVS fibrils are prion-like, converting endogenous MAVS into functional aggregates ► RIG-I and K63 polyUb chains trigger prion-like aggregates of MAVS on mitochondria
Simultaneous implementation of photodetector and neuromorphic vision sensor (NVS) on a single device faces a great challenge, due to the inherent speed discrepancy in their photoresponse ...characteristics. In this work, a trench‐bridged GaN/Ga2O3/GaN back‐to‐back double heterojunction array device is fabricated to enable the advanced functionalities of both devices on a single device. Interestingly, the device shows fast photoresponse and persistent photoconductivity behavior at low and high voltages, respectively, through the modulation of oxygen vacancy ionization and de‐ionization processes in Ga2O3. Consequently, the role of the optoelectronic device can be altered between the photodetector and NVS by simply adjusting the magnitude of bias voltage. As a photodetector, the device is able to realize fast optical imaging and optical communication functions. On the other hand, the device exhibits outstanding image sensing, image memory, and neuromorphic visual pre‐processing as an NVS. The utilization of NVS for image pre‐processing leads to a noticeable enhancement in both recognition accuracy and efficiency. The results presented in this work not only offer a new avenue to obtain complex functionality on a single optoelectronic device but also provide opportunities to implement advanced robotic vision systems and neuromorphic computing.
Trench‐bridged GaN/Ga2O3/GaN device is fabricated. According to the manipulation of the ionization and de‐ionization processe of oxygen vacancies within the Ga2O3, the device shows fast photoresponse at low voltages and persistent photoconductivity behavior at high voltages. Accordingly, various functions of the photodetector and neuromorphic vision sensor are achieved by one device and switched via bias voltage regulation.
Genome stability in eukaryotic cells relies on proper maintenance of telomeres at the termini of linear chromosomes. Human telomerase holoenzyme is required for maintaining telomere stability in a ...majority of proliferative human cells, making it essential for control of cell division and aging, stem cell maintenance, and development and survival of tumor or cancer. A dividing human cell usually contains a limited number of active telomerase holoenzymes. Recently, we discovered that a human telomerase catalytic site undergoes catalysis-dependent shut-off and an inactive site can be reactivated by cellular fractions containing human intracellular telomerase-activating factors (hiTAFs). Such ON-OFF control of human telomerase activity suggests a dynamic switch between inactive and active pools of the holoenzymes. In this review, we will link the ON-OFF control to the thermodynamic and kinetic properties of human telomerase holoenzymes, and discuss its potential contributions to the maintenance of telomere length equilibrium. This treatment suggests probabilistic fluctuations in the number of active telomerase holoenzymes as well as the number of telomeres that are extended in a limited number of cell cycles, and may be an important component of a fully quantitative model for the dynamic control of telomerase activities and telomere lengths in different types of eukaryotic cells.
Chloride is the most abundant inorganic anions in almost all cells and in human circulation systems. Its homeostasis is therefore important for systems physiology and normal cellular activities. This ...topic has been extensively studied with chloride loaders and extruders expressed in both cell surfaces and intracellular membranes. With the newly discovered, large-conductance, highly selective Cl- channel formed by membrane-bound chromogranin B (CHGB), which differs from all other known anion channels of conventional transmembrane topology, and is distributed in plasma membranes, endomembrane systems, endosomal, and endolysosomal compartments in cells expressing it, we will discuss the potential physiological importance of the CHGB channels to Cl- homeostasis, cellular excitability and volume control, and cation uptake or release at the cellular and subcellular levels. These considerations and CHGB's association with human diseases make the CHGB channel a possible druggable target for future molecular therapeutics.
Inorganic chalcogenides are traditional high-performance thermoelectric materials. However, they suffer from intrinsic brittleness and it is very difficult to obtain materials with both high ...thermoelectric ability and good flexibility. Here, we report a flexible thermoelectric material comprising highly ordered Bi
Te
nanocrystals anchored on a single-walled carbon nanotube (SWCNT) network, where a crystallographic relationship exists between the Bi
Te
<Formula: see text> orientation and SWCNT bundle axis. This material has a power factor of ~1,600 μW m
K
at room temperature, decreasing to 1,100 μW m
K
at 473 K. With a low in-plane lattice thermal conductivity of 0.26 ± 0.03 W m
K
, a maximum thermoelectric figure of merit (ZT) of 0.89 at room temperature is achieved, originating from a strong phonon scattering effect. The origin of the excellent flexibility and thermoelectric performance of the Bi
Te
-SWCNT material is attributed, by experimental and computational evidence, to its crystal orientation, interface and nanopore structure. Our results provide insight into the design and fabrication of high-performance flexible thermoelectric materials.
Inorganic chalcogenides are traditional high-performance thermoelectric materials. However, they suffer from intrinsic brittleness and it is very difficult to obtain materials with both high ...thermoelectric ability and good flexibility. Here, we report a flexible thermoelectric material comprising highly ordered Bi2Te3 nanocrystals anchored on a single-walled carbon nanotube (SWCNT) network, where a crystallographic relationship exists between the Bi2Te3 <\\bar{1}2\bar{1}0\> orientation and SWCNT bundle axis. This material has a power factor of ~1,600 μW m−1 K−2 at room temperature, decreasing to 1,100 μW m−1 K−2 at 473 K. With a low in-plane lattice thermal conductivity of 0.26 ± 0.03 W m−1 K−1, a maximum thermoelectric figure of merit (ZT) of 0.89 at room temperature is achieved, originating from a strong phonon scattering effect. The origin of the excellent flexibility and thermoelectric performance of the Bi2Te3–SWCNT material is attributed, by experimental and computational evidence, to its crystal orientation, interface and nanopore structure. Our results provide insight into the design and fabrication of high-performance flexible thermoelectric materials.
Potassium channels are present in every living cell and essential to setting up a stable, non-zero transmembrane electrostatic potential which manifests the off-equilibrium livelihood of the cell. ...They are involved in other cellular activities and regulation, such as the controlled release of hormones, the activation of T-cells for immune response, the firing of action potential in muscle cells and neurons, etc. Pharmacological reagents targeting potassium channels are important for treating various human diseases linked to dysfunction of the channels. High-resolution structures of these channels are very useful tools for delineating the detailed chemical basis underlying channel functions and for structure-based design and optimization of their pharmacological and pharmaceutical agents. Structural studies of potassium channels have revolutionized biophysical understandings of key concepts in the field - ion selectivity, conduction, channel gating, and modulation, making them multi-modality targets of pharmacological regulation. In this chapter, I will select a few high-resolution structures to illustrate key structural insights, proposed allostery behind channel functions, disagreements still open to debate, and channel-lipid interactions and co-evolution. The known structural consensus allows the inference of conserved molecular mechanisms shared among subfamilies of K
channels and makes it possible to develop channel-specific pharmaceutical agents.
Human body-surface epithelia coexist in close association with complex bacterial communities and are protected by a variety of antibacterial proteins. C-type lectins of the RegIII family are ...bactericidal proteins that limit direct contact between bacteria and the intestinal epithelium and thus promote tolerance to the intestinal microbiota. RegIII lectins recognize their bacterial targets by binding peptidoglycan carbohydrate, but the mechanism by which they kill bacteria is unknown. Here we elucidate the mechanistic basis for RegIII bactericidal activity. We show that human RegIIIα (also known as HIP/PAP) binds membrane phospholipids and kills bacteria by forming a hexameric membrane-permeabilizing oligomeric pore. We derive a three-dimensional model of the RegIIIα pore by docking the RegIIIα crystal structure into a cryo-electron microscopic map of the pore complex, and show that the model accords with experimentally determined properties of the pore. Lipopolysaccharide inhibits RegIIIα pore-forming activity, explaining why RegIIIα is bactericidal for Gram-positive but not Gram-negative bacteria. Our findings identify C-type lectins as mediators of membrane attack in the mucosal immune system, and provide detailed insight into an antibacterial mechanism that promotes mutualism with the resident microbiota.
PDF
