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Dysfunction of the intramembrane protease [gamma]-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human [gamma]-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of [gamma]-secretase function. The atomic structure of human [gamma]-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Human [gamma]-secretase structure The human [gamma]-secretase complex, comprising presenilin 1 (PS1), PEN-2, APH-1, and nicastrin, is a membrane-embedded protease that controls a number of important cellular functions through substrate cleavage. Dysfunction of the enzyme is thought to cause Alzheimer's disease. This paper reports the first atomic structure of an intact human [gamma]-secretase complex, determined at 3.4 Å resolution by cryo-electron microscopy. The structure illustrates how a remarkably plastic active site is positioned inside the membrane through specific interactions of four components of [gamma]-secretase. Alzheimer's disease-derived mutations affect residues that cluster at two hotspots, each located at the center of a distinct four-transmembrane segment bundle in PS1., Author(s): Xiao-chen Bai [sup.1] , Chuangye Yan [sup.2] , Guanghui Yang [sup.2] , Peilong Lu [sup.2] , Dan Ma [sup.2] , Linfeng Sun [sup.2] , Rui Zhou [sup.2] , Sjors [...]

The γ-secretase complex, comprising presenilin 1 (PS1), PEN-2, APH-1 and nicastrin, is a membrane-embedded protease that controls a number of important cellular functions through substrate cleavage. Aberrant cleavage of the amyloid precursor protein (APP) results in aggregation of amyloid-β, which accumulates in the brain and consequently causes Alzheimer's disease. Here we report the three-dimensional structure of an intact human γ-secretase complex at 4.5 Å resolution, determined by cryo-electron-microscopy single-particle analysis. The γ-secretase complex comprises a horseshoe-shaped transmembrane domain, which contains 19 transmembrane segments (TMs), and a large extracellular domain (ECD) from nicastrin, which sits immediately above the hollow space formed by the TM horseshoe. Intriguingly, nicastrin ECD is structurally similar to a large family of peptidases exemplified by the glutamate carboxypeptidase PSMA. This structure serves as an important basis for understanding the functional mechanisms of the γ-secretase complex., γ-Secretase is a membrane-embedded aspartyl protease that cleaves a large number of transmembrane substrate proteins within their membrane-spanning regions, with the cleavage products serving as signalling molecules (1,2). This process [...]

It is a major challenge to achieve a high‐performance anode for sodium‐ion batteries (SIBs) with high specific capacity, high rate capability, and cycling stability. Bismuth sulfide, which features a high theoretical specific capacity, tailorable morphology, and low cost, has been considered as a promising anode for SIBs. Nevertheless, due to a lack of direct atomistic observation, the detailed understanding of fundamental intercalation behavior and Bi2S3's (de)sodiation mechanisms remains unclear. Here, by employing in situ high‐resolution transmission electron microscopy, consecutive electron diffraction coupled with theoretical calculations, it is not only for the first time identified that Bi2S3 exhibits specific ionic transport pathways preferred to diffuse along the (110) direction instead of the (200) plane, but also tracks their real‐time phase transformations (de)sodiation involving multi‐step crystallographic tuning. The finite‐element analysis further disclosed multi‐reaction induced deformation and the relevant stress evolution originating from the combined effect of the mechanical and electrochemical interaction. These discoveries not only deepen the understanding of fundamental science about the microscopic reaction mechanism of metal chalcogenide anodes but also provide important implications for performance optimization. [ABSTRACT FROM AUTHOR]

Glucose transporters are essential for metabolism of glucose in cells of diverse organisms from microbes to humans, exemplified by the disease-related human proteins GLUT1, 2, 3 and 4. Despite rigorous efforts, the structural information for GLUT1-4 or their homologues remains largely unknown. Here we report three related crystal structures of XylE, an Escherichia coli homologue of GLUT1-4, in complex with D-xylose, d-glucose and 6-bromo-6-deoxy-d-glucose, at resolutions of 2.8, 2.9 and 2.6 Å, respectively. The structure consists of a typical major facilitator superfamily fold of 12 transmembrane segments and a unique intracellular four-helix domain. XylE was captured in an outward-facing, partly occluded conformation. Most of the important amino acids responsible for recognition of D-xylose or D-glucose are invariant in GLUT1-4, suggesting functional and mechanistic conservations. Structure-based modelling of GLUT1-4 allows mapping and interpretation of disease-related mutations. The structural and biochemical information reported here constitutes an important framework for mechanistic understanding of glucose transporters and sugar porters in general., Glucose is an essential fuel for most living organisms on Earth. Uptake of glucose into mammalian cells is mediated mainly by members of the GLUT (or SLC2A for solute carrier [...]

The major facilitator superfamily (MFS) transporters are an ancient and widespread family of secondary active transporters (1). In Escherichia coli, the uptake of L-fucose, a source of carbon for microorganisms, is mediated by an MFS proton symporter, FucP (2,3). Despite intensive study of the MFS transporters, atomic structure information is only available on three proteins and the outward-open conformation has yet to be captured (4-6). Here we report the crystal structure of FucP at 3.1 Å resolution, which shows that it contains an outward-open, amphipathic cavity. The similarly folded amino and carboxyl domains of FucP have contrasting surface features along the transport path, with negative electrostatic potential on the N domain and hydrophobic surface on the C domain. FucP only contains two acidic residues along the transport path, Asp 46 and Glu 135, which can undergo cycles of protonation and deprotonation. Their essential role in active transport is supported by both invivo and in vitro experiments. Structure-based biochemical analyses provide insights into energy coupling, substrate recognition and the transport mechanism of FucP., L-fucose is a major constituent of N-linked glycans on the cell surfaces of microbes, plants and animals (7). It can serve as the sole carbon source for some bacteria. In [...]

A large-size Bi2Se3 tape electrode (BTE) was prepared by peeling off a 2 × 1 × 0.5 cm high-quality single crystal. The feasibility of using the flexible BTE as an efficient bioplatform to load Au nanoparticles and probe DNA for HIV-1 DNA electrochemical sensing was explored. Differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) show that the resultant biosensor has a wide linear range from 0.1 fM to 1 pM, a low detection limit of 50 aM, excellent selectivity, reproducibility and stability, and is superior to the pM DNA detection level of Pt-Au, graphene-AuNPs hybrid biosensors. This outstanding performance is attributed to the intrinsic surface state of Bi2Se3 topological insulator in facilitating electron transfer. Therefore, BTE electrochemical biosensor platform has great potential in the application for sensitive detection of DNA biomarkers. [ABSTRACT FROM AUTHOR]

The negative photoconductance (NPC) effect, defined as an increase in resistance upon exposure to illumination, holds great potential for application in photoelectric devices. A prepared memristor with the structure of Ag|graphene quantum dots (GQDs)|TiOx|F‐doped SnO2 exhibits typical bipolar resistive switching (RS) memory behavior. The NPC effect is impressively observed in the high resistance state branch of the RS memory, enabling the memristor function to be extended to both memory logic display and multistate data storage. The observed NPC effect is attributed to the excitation, migration, and compensation of oxygen vacancy at the GQDs/TiOx interface, at which the electron transportation is efficiently restricted because of the variation in the charge distribution and electrostatic potential under illumination. Experiments, theoretical calculations, and physical models are used to provide engineer the interface with the aim of building the NPC effect in the memristive device. These results unveil a new horizon on extending the functionality of the memristor. [ABSTRACT FROM AUTHOR]