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1 Recognition of the amyloid precursor protein by human {gamma}-secretase 2019-01-12             

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Cleavage of amyloid precursor protein (APP) by the intramembrane protease -secretase is linked to Alzheimer’s disease. We report an atomic structure of human -secretase in complex with a transmembrane APP fragment at 2.6-Å resolution. The transmembrane helix (TM) of APP closely interacts with five surrounding TMs of PS1 (the catalytic subunit of -secretase). A hybrid β-sheet, which is formed by a β-strand from APP and two β-strands from PS1, guides -secretase to the scissile peptide bond of APP between its TM and β-strand. Residues at the interface between PS1 and APP are heavily targeted by recurring mutations from AD patients. This structure, together with that of -secretase bound to Notch, reveal contrasting features of substrate binding, which may be exploited toward design of substrate-specific inhibitors.

2 A loud quasi-periodic oscillation after a star is disrupted by a massive black hole 2019-01-12             

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The tidal forces close to massive black holes can rip apart stars that come too close to them. As the resulting stellar debris spirals toward the black hole, it heats up and emits x-rays. We report observations of a stable 131-s x-ray quasi-periodic oscillation from the tidal disruption event ASASSN-14li. Assuming the black hole mass indicated by host galaxy scaling relations, this implies that (i) the periodicity originates from close to the event horizon, and (ii) the black hole is rapidly spinning. Our findings demonstrate that tidal disruption events can generate quasi-periodic oscillations which encode information about the physical properties of their black holes.

3 H3K9me3-heterochromatin loss at protein-coding genes enables developmental lineage specification 2019-01-07             

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Gene silencing by chromatin compaction is integral to establishing and maintaining cell fates. H3K9me3-marked heterochromatin is reduced in embryonic stem cells compared to differentiated cells. However, the establishment and dynamics of closed regions of chromatin at protein coding genes, in embryologic development, remain elusive. We developed an antibody-independent method to isolate and map compacted heterochromatin from low cell number samples. We discovered high levels of compacted heterochromatin, H3K9me3-decorated, at protein coding genes in early, uncommitted cells at the germ layer stage, undergoing profound rearrangements and reduction upon differentiation, concomitant with cell type-specific gene expression. Perturbation of the three H3K9me3-related methyltransferases revealed a pivotal role for H3K9me3 heterochromatin during lineage commitment at the onset of organogenesis and for lineage fidelity maintenance.

4 Innate immune recognition of glycans targets HIV nanoparticle immunogens to germinal centers 2018-12-28             

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In vaccine design, arraying antigens in a multivalent nanoparticle form is often employed, but in vivo mechanisms underlying the enhanced immunity elicited by such vaccines remain poorly understood. Here we compared the fate of two different heavily glycosylated HIV antigens, a gp120-derived mini-protein and a large, stabilized envelope trimer, in protein nanoparticle or "free" forms following primary immunization. Unlike monomeric antigens, nanoparticles were rapidly shuttled to the follicular dendritic cell (FDC) network and then concentrated in germinal centers in a complement-, mannose-binding lectin (MBL)–, and immunogen glycan–dependent manner. Loss of FDC localization in MBL-deficient mice or via immunogen deglycosylation significantly impacted antibody responses. These findings identify an innate immune-mediated recognition pathway promoting antibody responses to particulate antigens, with broad implications for humoral immunity and vaccine design.

5 Concise total syntheses of (-)-jorunnamycin A and (-)-jorumycin enabled by asymmetric catalysis 2018-12-28             

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The bis-tetrahydroisoquinoline (bis-THIQ) natural products have been studied intensively over the past four decades for their exceptionally potent anticancer activity, in addition to strong gram-positive and -negative antibiotic character. Synthetic strategies toward these complex polycyclic compounds have relied heavily on electrophilic aromatic chemistry, such as the Pictet-Spengler reaction, that mimics their biosynthetic pathways. Herein we report an approach to two bis-THIQ natural products, jorunnamycin A and jorumycin, that instead harnesses the power of modern transition-metal catalysis for the three major bond-forming events and proceeds with high efficiency (15 and 16 steps, respectively). By breaking from biomimicry, this strategy allows for the preparation of a more diverse set of non-natural analogs.

6 Structural adaptations of photosynthetic complex I enable ferredoxin-dependent electron transfer 2018-12-28             

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Photosynthetic complex I enables cyclic electron flow around photosystem I, a regulatory mechanism for photosynthetic energy conversion. We report a 3.3-Å resolution cryo-EM structure of photosynthetic complex I from the cyanobacterium Thermosynechococcus elongatus. The model reveals structural adaptations that facilitate binding and electron transfer from the photosynthetic electron carrier ferredoxin. By mimicking cyclic electron flow with isolated components in vitro, we demonstrate that ferredoxin directly mediates electron transfer between photosystem I and complex I, instead of using intermediates such as NADPH. A large rate constant for association of ferredoxin to complex I indicates efficient recognition, with the protein subunit NdhS being the key component in this process.

 
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