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The introduction of functional side groups and the application of the mixed-linker concept in divalent MIL-53(Ni) materials
No full textMetal–organic framework materials with functional side groups are commonly used for various purposes like post-synthetic modification reactions or the tuning of pore geometries. Additionally, the mixed-linker concept, in which different linkers are statistically distributed over equivalent lattice positions, is a versatile approach to adjust the number of functional groups within the framework. However, neither functional side groups nor the mixed-linker approach have been used in MIL-53 materials with divalent metal ions yet. In the present work, we report on the synthesis of MIL-53(Ni)-Br(100), which contains only 2-bromoterephthalate as a linker molecule, and mixed-linker MIL-53(Ni)-Br(50) containing both terephthalate and 2-bromoterephthalate. These two materials represent the first functionalized and mixed-linker MIL-53 materials in combination with a divalent metal. Consequently, the possibilities to tailor the properties of the still rarely used divalent MIL-53 materials were expanded
Discovery of a Regulatory Subunit of the Yeast Fatty Acid Synthase
No full textFatty acid synthases (FASs) are central to metabolism but are also of biotechnological interest for the production of fine chemicals and biofuels from renewable resources. During fatty acid synthesis, the growing fatty acid chain is thought to be shuttled by the dynamic acyl carrier protein domain to several enzyme active sites. Here, we report the discovery of a γ subunit of the 2.6 megadalton α6-β6 S. cerevisiae FAS, which is shown by high-resolution structures to stabilize a rotated FAS conformation and rearrange ACP domains from equatorial to axial positions. The γ subunit spans the length of the FAS inner cavity, impeding reductase activities of FAS, regulating NADPH turnover by kinetic hysteresis at the ketoreductase, and suppressing off-pathway reactions at the enoylreductase. The γ subunit delineates the functional compartment within FAS. As a scaffold, it may be exploited to incorporate natural and designed enzymatic activities that are not present in natural FAS
Albumin-neprilysin fusion protein: understanding stability using small angle X-ray scattering and molecular dynamic simulations
No full textFusion technology is widely used in protein-drug development to increase activity, stability, and bioavailability of protein therapeutics. Fusion proteins, like any other type of biopharmaceuticals, need to remain stable during production and storage. Due to the high complexity and additional intramolecular interactions, it is not possible to predict the behavior of fusion proteins based on the behavior the individual proteins. Therefore, understanding the stability of fusion proteins on the molecular level is crucial for the development of biopharmaceuticals. The current study on the albumin-neprilysin (HSA-NEP) fusion protein uses a combination of thermal and chemical unfolding with small angle X-ray scattering and molecular dynamics simulations to show a correlation between decreasing stability and increasing repulsive interactions, which is unusual for most biopharmaceuticals. It is also seen that HSA-NEP is not fully flexible: it is present in both compact and extended conformations. Additionally, the volume fraction of each conformation changes with pH. Finally, the presence of NaCl and arginine increases stability at pH 6.5, but decreases stability at pH 5.0
White Paper: ARIANNA-200 high energy neutrino telescope
No full textThe proposed ARIANNA-200 neutrino detector, located at sea-level on the Ross Ice Shelf, Antarctica, consists of 200 autonomous and independent detector stations separated by 1 kilometer in a uniform triangular mesh, and serves as a pathfinder mission for the future IceCube-Gen2 project. The primary science mission of ARIANNA-200 is to search for sources of neutrinos with energies greater than 10^17 eV, complementing the reach of IceCube. An ARIANNA observation of a neutrino source would provide strong insight into the enigmatic sources of cosmic rays. ARIANNA observes the radio emission from high energy neutrino interactions in the Antarctic ice. Among radio based concepts under current investigation, ARIANNA-200 would uniquely survey the vast majority of the southern sky at any instant in time, and an important region of the northern sky, by virtue of its location on the surface of the Ross Ice Shelf in Antarctica. The broad sky coverage is specific to the Moore's Bay site, and makes ARIANNA-200 ideally suited to contribute to the multi-messenger thrust by the US National Science Foundation, Windows on the Universe - Multi-Messenger Astrophysics, providing capabilities to observe explosive sources from unknown directions. The ARIANNA architecture is designed to measure the angular direction to within 3 degrees for every neutrino candidate, which too plays an important role in the pursuit of multi-messenger observations of astrophysical sources
EeV Astrophysical neutrinos from FSRQs?
No full textFlat Spectrum Radio Quasars (FSRQ) are the most powerful blazars in the gamma-ray band. Although they are supposed to be good candidates in producing high energy neutrinos, no secure detection of FSRQs has been obtained up to now, except for a possible case of PKS B1424-418. In this work, we compute the expected flux of high energy neutrinos from FSRQs using standard assumptions for the properties of the radiation fields filling the regions surrounding the central supermassive black hole. We obtain as a result that high energy neutrinos are naturally expected from FSRQs in the sub-EeV-EeV energy range and not at PeV energies. This justifies the non-observation of neutrinos from FSRQs with the present technology, since only neutrinos below 10 PeV have been observed. We found that for a non-negligible range of the parameters the cumulative flux from FSRQs is comparable to or even exceeds the expected cosmogenic neutrino flux. This result is intriguing and highlights the importance to disentangle these point-source emissions from the diffuse cosmogenic background
Structure of the ALS Mutation Target Annexin A11 Reveals a Stabilising N-Terminal Segment
No full textThe functions of the annexin family of proteins involve binding to Ca, lipid membranes, other proteins, and RNA, and the annexins share a common folded core structure at the C terminus. Annexin A11 (AnxA11) has a long N-terminal region, which is predicted to be disordered, binds RNA, and forms membraneless organelles involved in neuronal transport. Mutations in AnxA11 have been linked to amyotrophic lateral sclerosis (ALS). We studied the structure and stability of AnxA11 and identified a short stabilising segment in the N-terminal end of the folded core, which links domains I and IV. The crystal structure of the AnxA11 core highlights main-chain hydrogen bonding interactions formed through this bridging segment, which are likely conserved in most annexins. The structure was also used to study the currently known ALS mutations in AnxA11. Three of these mutations correspond to buried Arg residues highly conserved in the annexin family, indicating central roles in annexin folding. The structural data provide starting points for detailed structure–function studies of both full-length AnxA11 and the disease variants being identified in ALS
Orchestration of signaling by structural disorder in class 1 cytokine receptors
No full textBackground:Class 1 cytokine receptors (C1CRs) are single-pass transmembrane proteins responsible for transmitting signals between the outside and the inside of cells. Remarkably, they orchestrate key biological processes such as proliferation, differentiation, immunity and growth through long disordered intracellular domains (ICDs), but without having intrinsic kinase activity. Despite these key roles, their characteristics remain rudimentarily understood.Methods:The current paper asks the question of why disorder has evolved to govern signaling of C1CRs by reviewing the literature in combination with new sequence and biophysical analyses of chain properties across the family.Results:We uncover that the C1CR-ICDs are fully disordered and brimming with SLiMs. Many of these short linear motifs (SLiMs) are overlapping, jointly signifying a complex regulation of interactions, including network rewiring by isoforms. The C1CR-ICDs have unique properties that distinguish them from most IDPs and we forward the perception that the C1CR-ICDs are far from simple strings with constitutively bound kinases. Rather, they carry both organizational and operational features left uncovered within their disorder, including mechanisms and complexities of regulatory functions.Conclusions:Critically, the understanding of the fascinating ability of these long, completely disordered chains to orchestrate complex cellular signaling pathways is still in its infancy, and we urge a perceptional shift away from the current simplistic view towards uncovering their full functionalities and potential
p63 uses a switch-like mechanism to set the threshold for induction of apoptosis
No full textThe p53 homolog TAp63 is the transcriptional key regulator of genome integrity in oocytes. After DNA damage, TAp63 is activated by multistep phosphorylation involving multiple phosphorylation events by the kinase CK1, which triggers the transition from a dimeric and inactive conformation to an open and active tetramer that initiates apoptosis. By measuring activation kinetics in ovaries and single-site phosphorylation kinetics in vitro with peptides and full-length protein, we show that TAp63 phosphorylation follows a biphasic behavior. Although the first two CK1 phosphorylation events are fast, the third one, which constitutes the decisive step to form the active conformation, is slow. Structure determination of CK1 in complex with differently phosphorylated peptides reveals the structural mechanism for the difference in the kinetic behavior based on an unusual CK1/TAp63 substrate interaction in which the product of one phosphorylation step acts as an inhibitor for the following one
Spatially-resolved luminescence and crystal structure of single core–shell nanowires measured in the as-grown geometry
No full textWe report on the direct correlation between the structural and optical properties of single, as-grown core-multi-shell GaAs/InGaAs/GaAs/AlAs/GaAs nanowires. Fabricated by molecular beam epitaxy on a pre-patterned Si(111) substrate, on a row of well separated nucleation sites, it was possible to access individual nanowires in the as-grown geometry. The polytype distribution along the growth axis of the nanowires was revealed by synchrotron-based nanoprobe x-ray diffraction techniques monitoring the axial 111 Bragg reflection. For the same nanowires, the spatially-resolved emission properties were obtained by cathodoluminescence hyperspectral linescans in a scanning electron microscope. Correlating both measurements, we reveal a blueshift of the shell quantum well emission energy combined with an increased emission intensity for segments exhibiting a mixed structure of alternating wurtzite and zincblende stacking compared with the pure crystal polytypes. The presence of this mixed structure was independently confirmed by cross-sectional transmission electron microscopy
Floating layers and thin films of mesogenic mix-substituted phthalocyanine holmium complex
No full textThe supramolecular organization of the AB-type phthalocyanine holmium complex (AB–Ho) was investigated in floating layers at the air–water interface and in Langmuir-Schaefer thin films at the air–solid interface. The floating layers formed under different experimental conditions on the water subphase using the Langmuir technique. They were studied by Brewster angle microscopy, grazing incidence X-ray diffraction and X-ray reflectometry. It was established that molecules of AB–Ho form stable ordered floating monolayer on the water surface. Experimental conditions required for this monolayer formation were determined as following: the initial degree of coating of the water surface was 18%, the compression rate of barriers was 6 cm/min and the surface pressure was 0.4 mN/m. Under these conditions a stable crystalline monolayer structure was obtained with an area per one molecule 3.9 nm. It has a two-dimensional face-on packing with the intralayer period of 2.06 nm. The Langmuir-Schaefer thin film was obtained on the basis of the above mentioned monomolecular floating layer. The film possesses a single two-dimensional structure with the packing of the molecules parralel to the substrate surface that was revealed by electron diffraction. The lattice parameters of the monomolecular film were = 1.65 nm, = 1.92 nm, = 75. It was shown that the film preserves the structure of the floating monolayer