Peptide backbone-copper ring structure:A molecular insight into copper-induced amyloid toxicity

Copper ions can promote amyloid diseases that are associated with amyloid peptides, such as type 2 diabetes(T2D),Alzheimer's disease(AD), Parkinson's disease(PD), and amyotrophic lateral sclerosis(ALS). However, the underlying molecular mechanism remains obscure. Here we present that Cu^(2+)is able to specifically bind to the backbone of T2D related human islet amyloid polypeptide(hIAPP) by forming a ring structure, which causes the reduction of Cu^(2+)to Cu^(+) to produce reactive oxygen species(ROS) and the modulation of hIAPP aggregation. Nuclear magnetic resonance spectroscopy showed that Cu^(2+)bound to the backbone of a turn region, His18-Ser21, which is critical for hIAPP aggregation.Ab initio calculations and x-ray absorption fine structure analyses revealed that Cu^(2+)simultaneously bound with both the amide nitrogen and carbonyl oxygen on the peptide backbone, resulting in a ring structure, and causing the reduction of Cu^(2+)to Cu^(+) to form a hIAPP-Cu^(+) complex. 2′,7′-dichlorodihydrofluorescin diacetate fluorescence measurements further indicated that this complex led to enhanced ROS levels in rat insulinoma cells. Additionally, thioflavin T fluorescence and atomic force microscopy measurements denoted that the backbone-Cu ring structure largely modulated hIAPP aggregation,including the inhibition of hIAPP fibrillation and the promotion of peptide oligomerization. These findings shed new light on the molecular mechanism of Cu^(2+)-induced amyloid toxicity involving both the enhancement of ROS and the modulation of hIAPP aggregation.

Maskless Microscopic Lithography through Shaping Ultraviolet Laser with Digital Micro-mirror Device

Laser shaping was introduced to maskless projection soft lithography by using digital micro-mirror device (DMD). The predesigned intensity pattern was imprinted onto the DMD and the input laser beam with a Gaussian or quasi-Gaussian distribution will carry the pattern on DMD to etch the resin. It provides a method of precise control of laser beam shapes and?photon-induced curing behavior of resin. This technology provides an accurate micro-fabrication of microstructures used for micro-systems. As a virtual mask generator and a binary-amplitude spatial light modulator, DMD is equivalent to the masks in the conventional exposure system. As the virtual masks and shaped laser beam can be achieved flexibly, it is a good method of precision soft lithography for 2D/3D microstructures.

Optical tape for high capacity three-dimensional optical data storage

In this Letter,a new approach of optical tape for high capacity multilayer data storage is proposed.We show that a length of 5 cm and width of 2 cm of soft and transparent optical tape can be used for two-photon three-dimensional bit data storage.We successfully demonstrate writing and reading of six layers of data storage with a transverse bit separation of 2μm and an axial separation of 2.5μm in a tetraphenylethylene-doped photobleaching polymer.The fluorescence intensity is insensitive to the storage depth of the photopolymer matrix.Thus,the optical tape that we put forward in the experiment can help people realize true large data storage in the future,like magnetic tape.This method significantly paves a novel way for solving big data storage problems.

Structural studies on MRG701 chromodomain reveal a novel dimerization interface of MRG proteins in green plants

MRG proteins are conserved during evolution in fungi, flies, mammals and plants, and they can exhibit diversified functions. The animal MRGs were found to form various complexes to activate gene expression. Plant MRGI/2 and MRG702 were reported to be involved in the regulation of flowering time via binding to H3K36me3- marked flowering genes. Herein, we determined the crystal structure of MRG701 chromodomain （MRG701CD）. MRG701co forms a novel dimerization fold both in crystal and in solution. Moreover, we found that the dimerization of MRG chromodomains is conserved in green plants. Our findings may provide new insights into the mechanism of MRGs in regulation of gene expression in green plants.

Fast dual-beam alignment method for stimulated emission depletion microscopy using aggregation-induced emission dye resin

A stimulated emission depletion is capable of breaking the diffraction limit by exciting fluorescent molecules with a solid Gaussian beam and quenching the excited molecules with another donut beam through stimulated emission.The coincidence degree of these two beams in three dimensions will significantly influence the spatial resolution of the microscope.However,the conventional alignment approach based on raster scanning of gold nanoparticles by the two laser beams separately suffers from a mismatch between fluorescence and scattering modes.To circumvent the above problems,we demonstrate a fast alignment design by scanning the second beam over the fabricated sample,which is made of aggregation-induced emission(AIE)dye resin.The relative positions of solid and donut laser beams can be represented by the fluorescent AIE from the labeled spots in the dye resin.This design achieves ultra-high resolutions of 22 nm in the x/y relative displacement and 27 nm in the z relative displacement for fast spatial matching of the two laser beams.This study has potential applications in scenarios that require the spatial matching of multiple laser beams,and the field of views of different objectives,for example,in a microscope with high precision.

Structural basis for DAXX interaction with ATRX

Alpha-thalassemia/mental retardation syndrome X-linked protein （ATRX） is a member of the switch 2/sucrose non- fermentable 2 （SWl2/SNF2） family of chromatin-remodelidg proteins （Clynes et al., 2013; Dyer et al., 2017）.

Crystal Structures of Arabidopsis thaliana Nudix Hydrolase NUDT7 Reveal a Previously Unobserved Conformation

Dear Editor,Nudix hydrolases are a superfamily of phylogenetically widespread enzymes that catalyze the hydrolysis of nucleoside diphosphate linked to another moiety X （NDP-X） to yield nucleoside monophosphate and P-X. Within the superfamily, at least four families are classified based on their substrate specificities： the Mutt family hydrolases, the ADPR pyrophosphatases, the NADH hydrolases, and the adenosine-（p）n-adenosine hydrolases （Bessman et al., 1996; Gabelii et al., 2001）. Arabidopsis thaliana contains 27 Nudix enzymes whose biological functions are not well understood except for NUDT7 （Ogawa et al., 2005）. NUDT7 belongs to the fibroblast growth factor type Nudix enzyme （FGFTNE） family and shares low sequence identity with other Nudix enzymes with known structures （Gunawardana et al., 2009）. The functional roles of NUDT7 in oxidative stress response and defense response have been demonstrated by genetic studies （Ge et al., 2007; Wang et al., 2013）. It has hydrolase activities toward ADPR and NADH; however, whether ADPR is a physiological substrate of NUDT7 remains obscure （Ge et al., 2007; Wang et al., 2013）.

A critical epitope in CD147 facilitates memory CD4^(+) T-cell hyper-activation in rheumatoid arthritis

The abnormal activation of CD4^(+)CD45RO+memory T(Tm)cells plays an important role in the pathogenesis of rheumatoid arthritis(RA).Previous studies have shown that CD147 participates in T-cell activation.However,it remains unclear whether CD147 is involved in abnormal Tm-cell activation in RA patients.In this study,we demonstrated that CD147 was predominantly upregulated in Tm cells derived from RA patients.The anti-CD147 mAb 5A12 specifically inhibited Tm-cell activation and proliferation and further restrained osteoclastogenesis.Using a structural–functional approach,we depicted the interface between 5A12 and CD147.This allowed us to identify two critical residues,Lys63 and Asp65,as potential targets for RA treatment,as the double mutation K63A/D65A inhibited Tm-cell activation,mimicking the neutralization by 5A12.This study provides not only a theoretical basis for a“CD147-Tm/Osteoclast-RA chain”for the potential prevention and treatment of RA or other T-cell-mediated autoimmune diseases but also a new target for related drug design and development.

Transcription factors AS1 and AS2 interact with LHP1 to repress KNOX genes in Arabidopsis

Polycomb group proteins are important repressors of numerous genes in higher eukaryotes. However, the mechanism by which Polycomb group proteins are recruited to specific genes is poorly understood. In Arabidopsis, LIKE HETEROCHROMATIN PROTEIN 1 （LHP1）, also known as TERMINAL FLOWER 2, was originally proposed as a subunit of polycomb repressive complex 1 （PRC1） that could bind the tri-methylated lysine 27 of histone H3 （H3K27me3） established by the PRC2. In this work, we show that LHP1 mainly functions with PRC2 to establish H3K27me3, but not with PRC1 to catalyze monoubiquitination at lysine 119 of histone H2A. Our results show that complexes of the transcription factors ASYMMETRIC LEAVES 1 （AS1） and AS2 could help to establish the H3K27me3 modification at the chromatin regions of Class-I KNOTTED＇t-like homeobox （KNOX） genes BREVIPEDICELLU5 and KNAT2 via direct interactions with LHP1. Additionally, our transcriptome analysis indicated that there are probably more common target genes of AS1 and LHP1 besides Class-I KNOX genes during leaf development in Arabidopsis.

4.4 A Resolution Cryo-EM structure of human mTOR Complex 1

Mechanistic target of rapamycin （mTOR） complex 1 （mTORC1） integrates signals from growth factors, cel- lular energy levels, stress and amino acids to control cell growth and proliferation through regulating trans- lation, autophagy and metabolism. Here we determined the cryo-electron microscopy structure of human mTORC1 at 4.4 A resolution. The mTORCI comprises a dimer of heterotrimer （mTOR-Raptor-mLST8） mediated by the mTOR protein. The complex adopts a hollow rhomboid shape with 2-fold symmetry. Notably, mTORC1 shows intrinsic conformational dynamics. Within the complex, the conserved N-terminal caspase- like domain of Raptor faces toward the catalytic cavity of the kinase domain of mTOR. Raptor shows no caspase activity and therefore may bind to TOS motif for sub- strate recognition. Structural analysis indicates that FKBP12-Rapamycin may generate steric hindrance forsubstrate entry to the catalytic cavity of mTORCI. The structure provides a basis to understand the assembly of mTORC1 and a framework to characterize the regu- latory mechanism of mTORC1 pathway.

The engagement of histone lysine methyltransferases with nucleosomes: structural basis, regulatory mechanisms, and therapeutic implications

Histone lysine methyltransferases(HKMTs)deposit methyl groups onto lysine residues on histones and play important roles in regulating chromatin structure and gene expression.The structures and functions of HKMTs have been extensively investigated in recent decades,significantly advancing our understanding of the dynamic regulation of histone methylation.Here,we review the recent progress in structural studies of representative HKMTs in complex with nucleosomes(H3K4,H3K27,H3K36,H3K79,and H4K20 methyltransferases),with emphasis on the molecular mechanisms of nucleosome recognition and trans-histone crosstalk by these HKMTs.These structural studies inform HKMTs'roles in tumorigenesis and provide the foundations for developing new therapeutic approachestargetingHKMTs incancers.

ORP8 acts as a lipophagy receptor to mediate lipid droplet turnover

Lipophagy,the selective engulfment of lipid droplets(LDs)by autophagosomes for lysosomal degradation,is critical to lipid and energy homeostasis.Here we show that the lipid transfer protein ORP8 is located on LDs and mediates the encapsulation of LDs by autophagosomal membranes.This function of oRP8 is independent of its lipid transporter activity and is achieved through direct interaction with phagophore-anchored LC3/GABARAPs.Upon lipophagy induction,ORP8 has increased localization on LDs and is phosphorylated by AMPK,thereby enhancing its affinity for LC3/GABARAPs.Deletion of ORP8 or interruption of ORP8-LC3/GABARAP interaction results in accumulation of LDs and increased intracellular triglyceride.Overexpression of ORP8 alleviates LD and triglyceride deposition in the liver of ob/ob mice,and Osbpl8 mice exhibit liver lipid clearance defects.Our results suggest that ORP8 is a lipophagy receptor that plays a key role in cellular lipid metabolism.

Staurosporine targets the Hippo pathway to inhibit cell growth

The Hippo signaling pathway was discovered to control organ size in Drosophila through regulating cell proliferation and apoptosis （Yu et al., 2015）. Arising studies over the past two decades have defined the core components and regulation mechanisms of the pathway in both Drosophila and mammals.

Dimeric G-quadruplex DNA Structure in the Proximal Promoter of VEGFR-2 Reveals a New Drug Target to Inhibit Tumor Angiogenesis

Vascular endothelial growth factor(VEGF)regulates tumor angiogenesis,which is active on the endothelium via VEGF receptor 2(VEGFR-2).The proximal promoter region of VEGFR-2(termed as VEGFR-2 DNA)is guanine-rich,forming G-quadruplex(G4)structures.Here,we demonstrate that VEGFR-2 DNA consists of one symmetrically dimeric 14-mer G4-DNA and one 12-mer sequence-palindromic dsDNA.This G4-DNA adopts an unprecedented folding with five stacked tetrads linked by four broken strands.Its 5’-end part contains an A-tetrad A^(1)•A^(4)•A^(1’)•A^(4’)and one G-tetrad G^(3)•G^(5)•G^(3’)•G^(5’)with two V-shaped loops and two one-nt edge-type loops.Its 3’-end part includes three G-tetrads G^(10)•G^(6)•G^(10’)•G^(6’),G^(11)•G^(7)•G^(11’)•G^(7’)(central)and G^(12)•G^(8)•G^(12’)•G^(8’)spanned by two double-chain-reversal one-nt(C^(9)or C^(9’))loops.Bases G^(13)and G^(13’)stack with G-tetrad G^(12)•G^(8)•G^(12’)•G^(8’).These characteristics make this G4-DNA more stable than reported VEGFR-17T G4 structure.The dsDNA connects with G4-DNA without any interactions,generating a linear assembly with G4-DNA structural bulges.These studies uncover new structural features of VEGFR-2 DNA as a potential drug target by inhibiting VEGFR-2 expression,thereby tumor angiogenesis.