Glycan heterogeneity and subunit composition of therapeutic glycoprotein complexes are challenging to define. In their Communication (e202213170), Di Wu and Carol V. Robinson present a native ...top‐down mass spectrometry approach, together with in silico modelling, to reveal the stabilization effect of interfacial N‐glycans on therapeutic cytokine and hormone assemblies.
Arc is a protein involved in neuronal plasticity, with the remarkable ability to assemble into virus‐like capsid structures. We have identified a coil interaction motif in the Arc N‐terminal domain, ...critical for protein self‐association and assembly into higher‐order oligomers. Exogenous RNA promotes higher‐order oligomerization, but this effect is abolished in the coil motif mutant.
Activity‐regulated cytoskeleton‐associated protein (Arc) is a protein interaction hub with diverse roles in intracellular neuronal signaling, and important functions in neuronal synaptic plasticity, memory, and postnatal cortical development. Arc has homology to retroviral Gag protein and is capable of self‐assembly into virus‐like capsids implicated in the intercellular transfer of RNA. However, the molecular basis of Arc self‐association and capsid formation is largely unknown. Here, we identified a 28‐amino‐acid stretch in the mammalian Arc N‐terminal (NT) domain that is necessary and sufficient for self‐association. Within this region, we identified a 7‐residue oligomerization motif, critical for the formation of virus‐like capsids. Purified wild‐type Arc formed capsids as shown by transmission and cryo‐electron microscopy, whereas mutant Arc with disruption of the oligomerization motif formed homogenous dimers. An atomic‐resolution crystal structure of the oligomerization region peptide demonstrated an antiparallel coiled‐coil interface, strongly supporting NT‐NT domain interactions in Arc oligomerization. The NT coil–coil interaction was also validated in live neurons using fluorescence lifetime FRET imaging, and mutation of the oligomerization motif disrupted Arc‐facilitated endocytosis. Furthermore, using single‐molecule photobleaching, we show that Arc mRNA greatly enhances higher‐order oligomerization in a manner dependent on the oligomerization motif. In conclusion, a helical coil in the Arc NT domain supports self‐association above the dimer stage, mRNA‐induced oligomerization, and formation of virus‐like capsids.
Database
The coordinates and structure factors for crystallographic analysis of the oligomerization region were deposited at the Protein Data Bank with the entry code 6YTU.
The AAA + ATPase p97 is a well-known hexametric enzyme that is evolutionary conserved in eukaryotes. p97 contains an amino-terminal N domain, two tandem ATPase domains (D1 and D2 domain) and a ...C-terminal unstructured extensive tail, involved in many cellular processes and plays important biological functions, but the structural basis of p97 for its biological roles still remain unclear. Here we report the Cryo-EM structure of full-length human p97 dodecamer in 3.0 Å resolution, the structure was captured in ADP-bound form but only D1 ATPase sites were well occupied by nucleotide and D2 sites are empty, furthermore, 12 non-ATP-competitive inhibitors of NMS-873 bound in the interface between each p97 monomer. We also found that the C-terminal S765-G779 (765-‘SRGFGSFRFPSGNQG’-779) peptide plays critical roles for the D2 ring oligomerization, biochemical and electron microscopy studies confirm that the S765-G779 peptide could induce the D2 ring itself to form the heptamer, this give new insights how p97 protomers assemble to the biological functional multimers.
•Cryo-EM structure of human full-length p97 dodecamer in ADP-bound form.•NMS-873 binds in the D1/D2 interface for allosteric inhibition.•D2 AAA domain in p97 is subject to form biological assembly.•C terminal S765-G779 of p97 plays critical role for D2 oligomerization.
Green and efficient synthesis of titanium‐containing molecular sieves is limited by the quantity of environmentally unfriendly additives and complicated synthesis procedures required. Oligomerization ...of Ti monomers into anatase TiO2 is the typical outcome of such procedures because of a mismatch between hydrolysis rates of Si and Ti precursors. We report a simple and generic additive‐free route for the synthesis of Ti‐containing molecular sieves (MFI, MEL, and BEA). This approach successfully reverses the formation of Ti oligomers to match hydrolysis rates of Ti and Si species with the assistance of hydroxyl free radicals generated in situ from ultraviolet irradiation. Moreover, fantastic catalytic performance for propene epoxidation with H2 and O2 was observed. Compared with the conventional hydrothermal method, this approach opens up new opportunities for high‐efficiency, environmentally benign, and facile production of pure titanium‐containing molecular sieves.
A reversed‐oligomerization approach was developed for preparation of titanium‐containing molecular sieves. The highly efficient and simple approach eliminates additives and it produces molecular sieves in high yield with improved titanium distribution, smaller particle sizes, and a higher surface area compared to previously reported methods. The approach is generic and can be applied in the synthesis of different molecular sieves (for example, MFI, MEL, BEA).
Cyclic peptides have been attracting a lot of attention in recent decades, especially in the area of drug discovery, as more and more naturally occurring cyclic peptides with diverse biological ...activities have been discovered. Chemical synthesis of cyclic peptides is essential when studying their structure–activity relationships. Conventional peptide cyclization methods via direct coupling have inherent limitations, like the susceptibility to epimerization at the C-terminus, poor solubility of fully protected peptide precursors, and low yield caused by oligomerization. In this regard, chemoselective ligation-mediated cyclization methods have emerged as effective strategies for cyclic peptide synthesis. The toolbox for cyclic peptide synthesis has been expanded substantially in the past two decades, allowing more efficient synthesis of cyclic peptides with various scaffolds and modifications. This Review will explore different chemoselective ligation technologies used for cyclic peptide synthesis that generate both native and unnatural peptide linkages. The practical issues and limitations of different methods will be discussed. The advance in cyclic peptide synthesis will benefit the biological and medicinal study of cyclic peptides, an important class of macrocycles with potentials in numerous fields, notably in therapeutics.
Ethylene, propylene, and benzene were investigated as molecules for extracting methoxy intermediate species formed during the cyclic partial oxidation of methane in Cu-exchanged zeolites, promising ...materials for the step-wise methane-to-methanol (MTM) reaction. 13C-labeled reaction studies reveal that alkenes preferentially undergo oligomerization followed by cracking, while benzene is successfully methylated, forming toluene. Benzene methylation further showcases the methyl species to behave similar to surface methoxy species formed on Brønsted acid sites in methanol-to-hydrocarbon (MTH) reaction. However, benzene is only able to extract a fraction of the methyl species compared to the methanol produced with water extraction, indicating either steric or intrinsic mechanistic effects to limit the full potential of the methyl pool inside the framework. We infer the presence of reactive methoxy species on Brønsted acid sites generated under reaction conditions, revealing their potential as a synthetic platform to form additional products from methane.
•Benzene reacts with the methoxy intermediate in the Cu-zeolite forming toluene.•Benzene and water access different amounts of methoxy; more than one type of methoxy.•Cu(I)-species formed after methane activation affect ethylene oligomerization.•Propylene oligomerizes independently of Cu species, BAS, or methoxy presence.
Neutrophils make up an essential part of the innate immune system, and are involved both in the initial responses to pathogens, and in orchestrating later immune responses. Neutrophils recognize ...pathogens through pattern-recognition receptors (PRRs), which are activated by microbial motifs. The Nod-like receptors (nucleotide-binding domain leucine-rich repeat containing family; NLRs) constitute a recently discovered group of PRRs whose role in the neutrophil immune responses is not yet characterized. The present study aimed to investigate the expression and function of NLRs in neutrophils. Neutrophils were isolated from human peripheral blood, and the presence of nucleotide-binding oligomerization domain 1 (NOD1), NOD2 and NACHT-LRR-PYD-containing protein 3 (NLRP3) was evaluated with flow cytometry and immunohistochemistry. The expression of NOD1, NOD2 and NLRP3 messenger RNA was determined using real-time reverse transcription-polymerase chain reaction. Changes in neutrophil cytokine secretion, phenotype and migration following agonist-induced activation were studied using enzyme-linked immunosorbent assay, flow cytometry and a chemotaxis assay, respectively. No expression of NOD1 was found in isolated neutrophils and stimulation with the NOD1 ligand γ- d-glutamyl-meso-diaminopimelic acid induced no signs of activity. In contrast, a marked expression of NOD2 and NLRP3 was found. NOD2 activation with MurNAc- l-Ala- d-isoGln (MDP) resulted in interleukin-8 secretion, CD62 ligand down-regulation, CD11b up-regulation and increased migration towards an inflammatory stimulus. NLRP3 activation with alum caused interleukin-1β secretion and facilitated migration. Altogether, this suggests that NLRs may be a previously unknown pathway for neutrophil activation.
The synthesis of reversible oligomer/polymers is fascinating both from the perspective of the fundamental understanding as well as their applications, ranging from biomedical to self‐healing smart ...materials. On the other hand, the reactions that occur in single‐crystal‐to‐single‐crystal (SCSC) fashion offer great details of the structure, geometry and stereochemistry of the product. However, SCSC 2+2 oligomerization is rather difficult and rare. Further, till date there are no reports for a reversible 2+2 oligomerization in SCSC fashion. In this work, four halogen‐substituted acrylic dienone molecules were deliberately designed and their ability to participate in 2+2 cycloaddition reaction in solid state was studied under visible light. Despite of having the required alignment of double bonds of dienes in all four crystal structures, they were found to exhibit variable reactivities given the differences in their weak intermolecular interactions such as halogen⋅⋅⋅halogen, halogen⋅⋅⋅π and C−H⋅⋅⋅O interactions. Notably, one of these materials exhibits reversible oligomerization in a SCSC manner.
The first single‐crystal‐to‐single‐crystal reversible 2+2 photo‐oligomerization of conjugated dienones under visible light is reported.
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•Addresses gaps in review literature by proposing a comprehensive mechanistic view for heterogenous nickel-acid catalysts.•Highlights relevant conditions to steer product ...distributions of ethylene oligomerization towards desirable products.•Focuses on environmentally-friendly and flexlble catalysts to produce a range of products for ever-changing market demands.
Light alkene oligomerization on heterogeneous acidic catalysts is widely and successfully used in current commercial processes. However, ethylene oligomerization remains inefficient due to ethylene’s inability to form reaction intermediates to a sufficient extent on acid sites. Adding Ni(II) on solid acids can more efficiently catalyze ethylene oligomerization and selectively produce butenes to fuel range products. The review proposes a complete and detailed mechanism of heterogenous Ni-catalyzed oligomerization, whose structures are supported by combining various studies throughout recent literature, and focuses on the bifunctional effects of the nickel and acid sites on ethylene oligomerization. Using experiments, first-principles calculations, and kinetic modeling, Ni2+ has been shown to selectively oligomerize ethylene to light, linear alkenes via the Cossee-Arlman mechanism, while Brønsted H+ sites catalyze further alkylation, cracking, and isomerization reactions. The effects of reaction conditions and catalyst properties on selectivity and activity for oligomerization are systematically discussed. Tuning the relative nickel-to-acid site ratio and the framework support can allow for an optimal catalyst design directed towards desirable products.
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