Mitochondrial antiviral signaling (MAVS) protein is required for innate immune responses against RNA viruses. In virus-infected cells MAVS forms prion-like aggregates to activate antiviral signaling ...cascades, but the underlying structural mechanism is unknown. Here we report cryo-electron microscopic structures of the helical filaments formed by both the N-terminal caspase activation and recruitment domain (CARD) of MAVS and a truncated MAVS lacking part of the proline-rich region and the C-terminal transmembrane domain. Both structures are left-handed three-stranded helical filaments, revealing specific interfaces between individual CARD subunits that are dictated by electrostatic interactions between neighboring strands and hydrophobic interactions within each strand. Point mutations at multiple locations of these two interfaces impaired filament formation and antiviral signaling. Super-resolution imaging of virus-infected cells revealed rod-shaped MAVS clusters on mitochondria. These results elucidate the structural mechanism of MAVS polymerization, and explain how an α-helical domain uses distinct chemical interactions to form self-perpetuating filaments. DOI: http://dx.doi.org/10.7554/eLife.01489.001.
The vanilloid receptor TRPV1 is an exquisite nociceptive sensor of noxious heat, but its temperature-sensing mechanism is yet to define. Thermodynamics dictate that this channel must undergo an ...unusually energetic allosteric transition. Thus, it is of fundamental importance to measure directly the energetics of this transition in order to properly decipher its temperature-sensing mechanism. Previously, using submillisecond temperature jumps and patch-clamp recording, we estimated that the heat activation for TRPV1 opening incurs an enthalpy change on the order of 100 kcal/mol. Although this energy is on a scale unparalleled by other known biological receptors, the generally imperfect allosteric coupling in proteins implies that the actual amount of heat uptake driving the TRPV1 transition could be much larger. In this paper, we apply differential scanning calorimetry to directly monitor the heat flow in TRPV1 that accompanies its temperature-induced conformational transition. Our measurements show that heat invokes robust, complex thermal transitions in TRPV1 that include both channel opening and a partial protein unfolding transition and that these two processes are inherently coupled. Our findings support that irreversible protein unfolding, which is generally thought to be destructive to physiological function, is essential to TRPV1 thermal transduction and, possibly, to other strongly temperature-dependent processes in biology.
An organic base-promoted chemoselective alkylation of lenalidomide with different halides was developed, which offers a novel approach to a highly functionalized lenalidomide-based PROTAC library ...under mild reaction conditions. DIPEA was found to act as an efficient base to trigger facile generation of arylamine alkylation products compared with inorganic bases. This library was successfully applied to BET PROTAC, which not only degraded BET protein but also effectively inhibited cancer cell proliferation.
Hot corrosion behavior of three nickel-based single crystal superalloys with different key alloying elements (including Re, Cr, Al and Ti) contents in molten Na2SO4 salt at 900 °C was investigated. ...Comparative study of hot corrosion resistance was conducted on two Re-free superalloys with 12 wt% Cr and different content of Al and Ti. By further adding Re, the experimental alloy with moderate Cr content (8.5 wt%) and Al/Ti > 1 in the present research also exhibited excellent hot corrosion resistance. The influence mechanism of Re on promoting hot corrosion resistance was attempted to be explored in combined with first-principle calculation. In addition, the potential design space of new-developed single crystal superalloys was also proposed.
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•Hot corrosion resistance of single crystal superalloys significantly depended on the ratio of Al/Ti in terms of the formation of a compact and protective NiTiO3 layer.•Re significantly improved hot corrosion resistance of the experimental single crystal superalloy.•The influence mechanism that adding Re may facilitate diffusion of Cr in γ phase and diffusion of Ti in γ' phase had been explored in combined with first-principle calculation.•Potential design space for developing new type of hot corrosion resistant single-crystal superalloys was proposed.
Cells are organized on length scales ranging from ångström to micrometres. However, the mechanisms by which ångström-scale molecular properties are translated to micrometre-scale macroscopic ...properties are not well understood. Here we show that interactions between diverse synthetic, multivalent macromolecules (including multi-domain proteins and RNA) produce sharp liquid-liquid-demixing phase separations, generating micrometre-sized liquid droplets in aqueous solution. This macroscopic transition corresponds to a molecular transition between small complexes and large, dynamic supramolecular polymers. The concentrations needed for phase transition are directly related to the valency of the interacting species. In the case of the actin-regulatory protein called neural Wiskott-Aldrich syndrome protein (N-WASP) interacting with its established biological partners NCK and phosphorylated nephrin, the phase transition corresponds to a sharp increase in activity towards an actin nucleation factor, the Arp2/3 complex. The transition is governed by the degree of phosphorylation of nephrin, explaining how this property of the system can be controlled to regulatory effect by kinases. The widespread occurrence of multivalent systems suggests that phase transitions may be used to spatially organize and biochemically regulate information throughout biology.
Developing highly efficient and stable photocatalysts for hydrogen (H
2
) evolution is a great challenge. Herein, a novel strategy using ultrathin black phosphorus (BP) as a bridge joint was proposed ...for controllable construction of a sandwich-type Pt-containing covalent triazine-based framework photocatalyst, CTF-BP-Pt. The as-prepared CTF-BP-Pt not only significantly enhances the stability of Pt nanoparticles but also dramatically improves the charge separation efficiency of the photocatalyst. For the first time, this work reveals that the unique Pt(
δ
+
)-P(
δ
−
)-N(
δ
+
) surface bonding states in CTF-BP-Pt lead to a greatly improved H
2
evolution rate (614.6 μmol g
−1
h
−1
) compared with that of CTF directly doped with Pt (CTF/Pt, 167.5 μmol g
−1
h
−1
). In addition, the Pt(
δ
+
)-P(
δ
−
)-N(
δ
+
) configurations enabled the reduction of loading amount of Pt from the normal 2 wt% to 0.05 wt% but did not remarkably decrease the H
2
evolution rate. It is noteworthy that the H
2
evolution rate and its turnover frequency (TOF) obtained over the CTF-BP-Pt with 0.05 wt% Pt are much higher than those of other Pt loaded carbonaceous materials. Finally, the improvement of photocatalytic performance of CTF-BP-Pt was well explained based on many characterization experiments. The present work marks a critical step toward developing high-performance and low-cost photocatalytic H
2
evolution materials.
Unique Pt(
δ
+
)-P(
δ
−
)-N(
δ
+
) bonding states were constructed on CTF-1 for efficient photocatalytic performance
via
using BP as a bridge joint.
Rare earth (RE) addition to steels to produce RE steels has been widely applied when aiming to improve steel properties. However, RE steels have exhibited extremely variable mechanical performances, ...which has become a bottleneck in the past few decades for their production, utilization and related study. Here in this work, we discovered that the property variation of RE steels stems from the presence of oxygen-based inclusions. We proposed a dual low-oxygen technology, and keeping low levels of oxygen content in steel melts and particularly in the raw RE materials, which have long been ignored, to achieve impressively stable and favourable RE effects. The fatigue life is greatly improved by only parts-per-million-level RE addition, with a 40-fold improvement for the tension–compression fatigue life and a 40% enhancement of the rolling contact fatigue life. We find that RE appears to act by lowering the carbon diffusion rate and by retarding ferrite nucleation at the austenite grain boundaries. Our study reveals that only under very low-oxygen conditions can RE perform a vital role in purifying, modifying and micro-alloying steels, to improve the performance of RE steels.The variation in the properties of rare earth (RE) steels is shown to stem from the presence of oxygen-based inclusions, and only under very-low-oxygen conditions can RE elements perform a vital role in purifying, modifying and micro-alloying steels.
Biomembranes separate a live cell from its environment and keep it in an off-equilibrium, steady state. They contain both phospholipids and nonphospholipids, depending on whether there are phosphate ...groups in the headgroup regions. Cholesterol (CHOL) is one type of nonphospholipids, and one of the most abundant lipid molecules in humans. Its content in plasma membranes and intracellular membranes varies and is tightly regulated. Voltage-gated ion channels are universally present in every cell and are fairly diversified in the eukaryotic domain of life. Our lipid-dependent gating hypothesis postulates that the controlled switch of the voltage-sensor domains (VSDs) in a voltage-gated potassium (Kv) channel between the "down" and the "up" state (gating) is sensitive to the ratio of phospholipids:nonphospholipids in the annular layer around the channel. High CHOL content is found to exert strong inhibitory effects on Kv channels. Such effects have been observed in in vitro membranes, cultured cells, and animal models for cholesterol metabolic defects. Thermodynamic analysis of the CHOL-dependent gating suggests that the inhibitory effects of CHOL result from collective interactions between annular CHOL molecules and the channel, which appear to be a more generic principle behind the CHOL effects on other ion channels and transporters. We will review the recent progress in the CHOL-dependent gating of voltage-gated ion channels, discuss the current technical limitations, and then expand briefly the learned principles to other ion channels that are known to be sensitive to the CHOL-channel interactions.
As a promising protein degradation strategy, PROTAC technology is increasingly becoming a new star in cancer treatment. Here we report the efficient construction of an IMiD-based azide library
via
a ...quick one-step conversion of the existing IMiD-based amine library. This new azide library can act as a kit to endow PROTAC libraries with triazole moieties for various POIs through a highly effective 'click reaction' and then help to rapidly screen out lead degraders that are valuable for drug development. Its power in fleetly identifying potent degraders has been verified on two oncogenic proteins, BCR-ABL and BET, the degraders of which showed comparable potency to or even higher potency than the reported PROTACs in degrading target proteins and effectively inhibiting cancer cell proliferation.
As a promising protein degradation strategy, PROTAC technology is increasingly becoming a new star in cancer treatment.
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