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327 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6, 7, 8 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I13-2-Diamond Manchester Imaging	Evaluating the morphology of the degradation layer of pure magnesium via 3D imaging at resolutions below 40 nm Berit Zeller-Plumhoff , Daniel Laipple , Hanna Slominska , Kamila Iskhakova , Elena Longo , Alexander Hermann , Silja Flenner , Imke Greving , Malte Storm , Regine Willumeit-Römer Bioactive Materials 6, 4368 - 4376 DOI: 10.1016/j.bioactmat.2021.04.009 Diamond Proposal Number(s): [22346, 21697] Open Access Show Abstract ▼ Abstract: Magnesium is attractive for the application as a temporary bone implant due to its inherent biodegradability, non-toxicity and suitable mechanical properties. The degradation process of magnesium in physiological environments is complex and is thought to be a diffusion-limited transport problem. We use a multi-scale imaging approach using micro computed tomography and transmission X-ray microscopy (TXM) at resolutions below 40 nm. Thus, we are able to evaluate the nanoporosity of the degradation layer and infer its impact on the degradation process of pure magnesium in two physiological solutions. Magnesium samples were degraded in simulated body fluid (SBF) or Dulbecco's modified Eagle's medium (DMEM) with 10% fetal bovine serum (FBS) for one to four weeks. TXM reveals the three-dimensional interconnected pore network within the degradation layer for both solutions. The pore network morphology and degradation layer composition are similar for all samples. By contrast, the degradation layer thickness in samples degraded in SBF was significantly higher and more inhomogeneous than in DMEM+10%FBS. Distinct features could be observed within the degradation layer of samples degraded in SBF, suggesting the formation of microgalvanic cells, which are not present in samples degraded in DMEM+10%FBS. The results suggest that the nanoporosity of the degradation layer and the resulting ion diffusion processes therein have a limited influence on the overall degradation process. This indicates that the influence of organic components on the dampening of the degradation rate by the suppression of microgalvanic degradation is much greater in the present study.	Dec 2021
I03-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Kinetoplastid kinetochore proteins KKT2 and KKT3 have unique centromere localization domains Gabriele Marciano , Midori Ishii , Olga O. Nerusheva , Bungo Akiyoshi Journal Of Cell Biology 220 DOI: 10.1083/jcb.202101022 Diamond Proposal Number(s): [18069] Open Access Show Abstract ▼ Abstract: The kinetochore is the macromolecular protein complex that assembles onto centromeric DNA and binds spindle microtubules. Evolutionarily divergent kinetoplastids have an unconventional set of kinetochore proteins. It remains unknown how kinetochores assemble at centromeres in these organisms. Here, we characterize KKT2 and KKT3 in the kinetoplastid parasite Trypanosoma brucei. In addition to the N-terminal kinase domain and C-terminal divergent polo boxes, these proteins have a central domain of unknown function. We show that KKT2 and KKT3 are important for the localization of several kinetochore proteins and that their central domains are sufficient for centromere localization. Crystal structures of the KKT2 central domain from two divergent kinetoplastids reveal a unique zinc-binding domain (termed the CL domain for centromere localization), which promotes its kinetochore localization in T. brucei. Mutations in the equivalent domain in KKT3 abolish its kinetochore localization and function. Our work shows that the unique central domains play a critical role in mediating the centromere localization of KKT2 and KKT3.	Aug 2021
I03-Macromolecular Crystallography	Structural properties and peptide ligand binding of the capsid homology domains of human Arc Erik I. Hallin , Clive R. Bramham , Petri Kursula Biochemistry And Biophysics Reports 26 DOI: 10.1016/j.bbrep.2021.100975 Diamond Proposal Number(s): [13440] Open Access Show Abstract ▼ Abstract: The activity-regulated cytoskeleton-associated protein (Arc) is important for synaptic plasticity and the normal function of the brain. Arc interacts with neuronal postsynaptic proteins, but the mechanistic details of its function have not been fully established. The C-terminal domain of Arc consists of tandem domains, termed the N- and C-lobe. The N-lobe harbours a peptide binding site, able to bind multiple targets. By measuring the affinity of human Arc towards various peptides from stargazin and guanylate kinase-associated protein (GKAP), we have refined its specificity determinants. We found two sites in the GKAP repeat region that bind to Arc and confirmed these interactions by X-ray crystallography. Phosphorylation of the stargazin peptide did not affect binding affinity but caused changes in thermodynamic parameters. Comparison of the crystal structures of three high-resolution human Arc-peptide complexes identifies three conserved C–H…π interactions at the binding cavity, explaining the sequence specificity of short linear motif binding by Arc. We further characterise central residues of the Arc lobe fold, show the effects of peptide binding on protein dynamics, and identify acyl carrier proteins as structures similar to the Arc lobes. We hypothesise that Arc may affect protein-protein interactions and phase separation at the postsynaptic density, affecting protein turnover and re-modelling of the synapse. The present data on Arc structure and ligand binding will help in further deciphering these processes.	Jul 2021
I22-Small angle scattering & Diffraction	Separating effects of bone-quality changes at multiple scales in steroid-induced osteoporosis: Combining multiscale experimental and modelling approaches Li Xi , Ettore Barbieri , Pan Wang , Wenwang Wu , Himadri Gupta Mechanics Of Materials 157 DOI: 10.1016/j.mechmat.2021.103821 Diamond Proposal Number(s): [9893, 11806, 12483] Show Abstract ▼ Abstract: Metabolic bone diseases have an impact on the multi-scale structure of bone and its mechanical properties. This study aims to conduct quantitative analysis of the link between specific material-level changes and mechanical alterations of bone tissue. We combine several scanning probe methods with an analytical multiscale model to investigate these links in a mouse model (𝐶𝑟h−120∕+) with endogenous steroid production. Experimental results from our prior study are used, which showed significant changes in spatial maps of nano-scale orientation, mineralization, and microporosity in 𝐶𝑟h−120∕+ mice bone. An analytical composite/continuum mechanical model is incorporated with these experimental parameters to predict the progressive reduction in elastic moduli. The largest fractional reduction in elastic modulus is found to arise from incorporation of microscale porosity, followed by the reduced nanoscale degree of orientation. Our work provides both insights into the altered structure-performance relations and a systematic analytical framework for linking scanning micro- and nanoprobe experimental data on hierarchical structural materials to macroscopic biomechanical outcomes.	Jun 2021
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Phosphorylation of the LIR domain of SCOC modulates ATG8 binding affinity and specificity Martina Wirth , Stephane Mouilleron , Wenxin Zhang , Eva Sjøttem , Yakubu Princely Abudu , Ashish Jain , Hallvard Lauritz Olsvik , Jack-Ansgar Bruun , Minoo Razi , Harold B. J. Jefferies , Rebecca Lee , Dhira Joshi , Nicola O'Reilly , Terje Johansen , Sharon A. Tooze Journal Of Molecular Biology 433 DOI: 10.1016/j.jmb.2021.166987 Diamond Proposal Number(s): [9826] Open Access Show Abstract ▼ Abstract: Autophagy is a highly conserved degradative pathway, essential for cellular homeostasis and implicated in diseases including cancer and neurodegeneration. Autophagy-related 8 (ATG8) proteins play a central role in autophagosome formation and selective delivery of cytoplasmic cargo to lysosomes by recruiting autophagy adaptors and receptors. The LC3-interacting region (LIR) docking site (LDS) of ATG8 proteins binds to LIR motifs present in autophagy adaptors and receptors. LIR-ATG8 interactions can be highly selective for specific mammalian ATG8 family members (LC3A-C, GABARAP, and GABARAPL1-2) and how this specificity is generated and regulated is incompletely understood. We have identified a LIR motif in the Golgi protein SCOC (short coiled-coil protein) exhibiting strong binding to GABARAP, GABARAPL1, LC3A and LC3C. The residues within and surrounding the core LIR motif of the SCOC LIR domain were phosphorylated by autophagy-related kinases (ULK1-3, TBK1) increasing specifically LC3 family binding. More distant flanking residues also contributed to ATG8 binding. Loss of these residues was compensated by phosphorylation of serine residues immediately adjacent to the core LIR motif, indicating that the interactions of the flanking LIR regions with the LDS are important and highly dynamic. Our comprehensive structural, biophysical and biochemical analyses support and provide novel mechanistic insights into how phosphorylation of LIR domain residues regulates the affinity and binding specificity of ATG8 proteins towards autophagy adaptors and receptors.	Jun 2021
I02-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Reviving lost binding sites: Exploring calcium binding‐site transitions between human and murine CD23 Veronica F. Ilkow , Anna M. Davies , Balvinder Dhaliwal , Andrew J. Beavil , Brian J. Sutton , James M. Mcdonnell Febs Open Bio DOI: 10.1002/2211-5463.13214 Diamond Proposal Number(s): [9495] Open Access Show Abstract ▼ Abstract: Immunoglobulin E (IgE) is a central regulatory and triggering molecule of allergic immune responses.IgE’s interaction with CD23 modulates both IgE production and functional activities.CD23 is a non-canonical immunoglobulin receptor, unrelated to receptors of other antibody isotypes. Human CD23 is a calcium-dependent (C-type) lectin-like domain that has apparently lost its carbohydrate binding capability. The calcium binding site classically required for carbohydrate binding in C-type lectins is absent in human CD23 but is present in the murine molecule.To determine if the absence of this calcium binding site affects the structure and function of human CD23, CD23 mutant proteins with increasingly ‘murine-like’ sequences were generated. Restoration of the calcium binding site was confirmed by NMR spectroscopy and structures of mutant human CD23 proteins were determined by X-ray crystallography, although no electron density for calcium was observed.This study offers insights into the evolutionary differences between murine and human CD23, and some of the functional differences between CD23 in different species.	Jun 2021
I24-Microfocus Macromolecular Crystallography	Activation of PARP2/ARTD2 by DNA damage induces conformational changes relieving enzyme autoinhibition Ezeogo Obaji , Mirko M. Maksimainen , Albert Galera-Prat , Lari Lehtio Nature Communications 12 DOI: 10.1038/s41467-021-23800-x Diamond Proposal Number(s): [19951] Open Access Show Abstract ▼ Abstract: Human PARP2/ARTD2 is an ADP-ribosyltransferase which, when activated by 5′-phosphorylated DNA ends, catalyses poly-ADP-ribosylation of itself, other proteins and DNA. In this study, a crystal structure of PARP2 in complex with an activating 5′-phosphorylated DNA shows that the WGR domain bridges the dsDNA gap and joins the DNA ends. This DNA binding results in major conformational changes, including reorganization of helical fragments, in the PARP2 regulatory domain. A comparison of PARP1 and PARP2 crystal structures reveals how binding to a DNA damage site leads to formation of a catalytically competent conformation. In this conformation, PARP2 is capable of binding substrate NAD+ and histone PARylation factor 1 that changes PARP2 residue specificity from glutamate to serine when initiating DNA repair processes. The structure also reveals how the conformational changes in the autoinhibitory regulatory domain would promote the flexibility needed by the enzyme to reach the target macromolecule for ADP-ribosylation.	Jun 2021
I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	An exploration of chemical properties required for cooperative stabilization of the 14-3-3 interaction with NF-κB—utilizing a reversible covalent tethering approach Madita Wolter , Dario Valenti , Peter J. Cossar , Stanimira Hristeva , Laura M. Levy , Thorsten Genski , Torsten Hoffmann , Luc Brunsveld , Dimitrios Tzalis , Christian Ottmann Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00401 Open Access Show Abstract ▼ Abstract: Protein–protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein–protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks established methodologies for drug design. Here, we report the systematic ″bottom-up″ development of a reversible covalent PPI stabilizer. An imine bond was employed to anchor the stabilizer at the interface of the 14-3-3/p65 complex, leading to a molecular glue that elicited an 81-fold increase in complex stabilization. Utilizing protein crystallography and biophysical assays, we deconvoluted how chemical properties of a stabilizer translate to structural changes in the ternary 14-3-3/p65/molecular glue complex. Furthermore, we explore how this leads to high cooperativity and increased stability of the complex.	Jun 2021
Krios I-Titan Krios I at Diamond	Gating and modulation of a hetero-octameric AMPA glutamate receptor Danyang Zhang , Jake F. Watson , Peter M. Matthews , Ondrej Cais , Ingo H. Greger Nature 62 DOI: 10.1038/s41586-021-03613-0 Diamond Proposal Number(s): [17434] Show Abstract ▼ Abstract: AMPA receptors (AMPARs) mediate the majority of excitatory transmission in the brain and enable the synaptic plasticity that underlies learning1. A diverse array of AMPAR signalling complexes are established by receptor auxiliary subunits, which associate with the AMPAR in various combinations to modulate trafficking, gating and synaptic strength2. However, their mechanisms of action are poorly understood. Here we determine cryo-electron microscopy structures of the heteromeric GluA1–GluA2 receptor assembled with both TARP-γ8 and CNIH2, the predominant AMPAR complex in the forebrain, in both resting and active states. Two TARP-γ8 and two CNIH2 subunits insert at distinct sites beneath the ligand-binding domains of the receptor, with site-specific lipids shaping each interaction and affecting the gating regulation of the AMPARs. Activation of the receptor leads to asymmetry between GluA1 and GluA2 along the ion conduction path and an outward expansion of the channel triggers counter-rotations of both auxiliary subunit pairs, promoting the active-state conformation. In addition, both TARP-γ8 and CNIH2 pivot towards the pore exit upon activation, extending their reach for cytoplasmic receptor elements. CNIH2 achieves this through its uniquely extended M2 helix, which has transformed this endoplasmic reticulum-export factor into a powerful AMPAR modulator that is capable of providing hippocampal pyramidal neurons with their integrative synaptic properties.	Jun 2021
B21-High Throughput SAXS I03-Macromolecular Crystallography	Periscope Proteins are variable-length regulators of bacterial cell surface interactions Fiona Whelan , Aleix Lafita , James Gilburt , Clement Degut , Samuel C. Griffiths , Huw Jenkins , Alexander N. St John , Emanuele Paci , James W. B. Moir , Michael J. Plevin , Christoph G. Baumann , Alex Bateman , Jennifer R. Potts Proceedings Of The National Academy Of Sciences 118 DOI: 10.1073/pnas.2101349118 Diamond Proposal Number(s): [9948] Open Access Show Abstract ▼ Abstract: Changes at the cell surface enable bacteria to survive in dynamic environments, such as diverse niches of the human host. Here, we reveal “Periscope Proteins” as a widespread mechanism of bacterial surface alteration mediated through protein length variation. Tandem arrays of highly similar folded domains can form an elongated rod-like structure; thus, variation in the number of domains determines how far an N-terminal host ligand binding domain projects from the cell surface. Supported by newly available long-read genome sequencing data, we propose that this class could contain over 50 distinct proteins, including those implicated in host colonization and biofilm formation by human pathogens. In large multidomain proteins, sequence divergence between adjacent domains appears to reduce interdomain misfolding. Periscope Proteins break this “rule,” suggesting that their length variability plays an important role in regulating bacterial interactions with host surfaces, other bacteria, and the immune system.	Jun 2021

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