8 research outputs found
Alzheimer’s Protective Cross-Interaction between Wild-Type and A2T Variants Alters Aβ<sub>42</sub> Dimer Structure
Whole
genome sequencing has recently revealed the protective effect
of a single A2T mutation in heterozygous carriers against Alzheimer’s
disease (AD) and age-related cognitive decline. The impact of the
protective cross-interaction between the wild-type (WT) and A2T variants
on the dimer structure is therefore of high interest, as the Aβ
dimers are the smallest known neurotoxic species. Toward this goal,
extensive atomistic replica exchange molecular dynamics simulations
of the solvated WT homo- and A2T hetero- Aβ<sub>1–42</sub> dimers have been performed, resulting into a total of 51 μs
of sampling for each system. Weakening of a set of transient, intrachain
contacts formed between the central and C-terminal hydrophobic residues
is observed in the heterodimeric system. The majority of the heterodimers
with reduced interaction between central and C-terminal regions lack
any significant secondary structure and display a weak interchain
interface. Interestingly, the A2T N-terminus, particularly residue
F4, is frequently engaged in tertiary and quaternary interactions
with central and C-terminal hydrophobic residues in those distinct
structures, leading to hydrophobic burial. This atypical involvement
of the N-terminus within A2T heterodimer revealed in our simulations
implies possible interference on Aβ<sub>42</sub> aggregation
and toxic oligomer formation, which is consistent with experiments.
In conclusion, the present study provides detailed structural insights
onto A2T Aβ<sub>42</sub> heterodimer, which might provide molecular
insights onto the AD protective effect of the A2T mutation in the
heterozygous state
Severe diffraction anisotropy, rotational pseudosymmetry and twinning complicate the refinement of a pentameric coiled-coil structure of NSP4 of rotavirus
The crystal structure of the region spanning residues 95-146 of the rotavirus nonstructural protein NSP4 from the asymptomatic human strain ST3 was determined at a resolution of 2.5 angstrom. Severe diffraction anisotropy, rotational pseudo-symmetry and twinning complicated the refinement of this structure. A systematic explanation confirming the crystal pathologies and describing how the structure was successfully refined is given in this report
De "l'incapacité littéraire des Belges". Complexe national et contrefaçon
info:eu-repo/semantics/publishe
A new pentameric structure of rotavirus NSP4 revealed by molecular replacement
The region spanning residues 95-146 of the rotavirus nonstructural protein NSP4 from the asymptomatic human strain ST3 has been purified and crystallized and diffraction data have been collected to a resolution of 2.6 angstrom. Several attempts to solve the structure by the molecular-replacement method using the available tetrameric structures of this domain were unsuccessful despite a sequence identity of 73% to the already known structures. A more systematic approach with a dimer as the search model led to an unexpected pentameric structure using the program Phaser. The various steps involved in arriving at this molecular-replacement solution, which unravelled a case of subtle variation between different oligomeric states unknown at the time of solving the structure, are presented in this paper
Novel Pentameric Structure of the Diarrhea-Inducing Region of the Rotavirus Enterotoxigenic Protein NSP4
A novel pentameric structure which differs from the previously reported tetrameric form of the diarrhea-inducing region of the rotavirus enterotoxin NSP4 is reported here. A significant feature of this pentameric form is the absence of the calcium ion located in the core region of the tetrameric structures. The lysis of cells, the crystallization of the region spanning residues 95 to 146 of NSP4 (NSP4(95-146)) of strain ST3 (ST3: NSP4(95-146)) at acidic pH, and comparative studies of the recombinant purified peptide under different conditions by size-exclusion chromatography (SEC) and of the crystal structures suggested pH-, Ca(2+)-, and protein concentration-dependent oligomeric transitions in the peptide. Since the NSP4(95-146) mutant lacks the N-terminal amphipathic domain (AD) and most of the C-terminal flexible region (FR), to demonstrate that the pentameric transition is not a consequence of the lack of the N- and C-terminal regions, glutaraldehyde cross-linking of the Delta N72 and Delta N94 mutant proteins, which contain or lack the AD, respectively, but possess the complete C-terminal FR, was carried out. The results indicate the presence of pentamers in preparations of these longer mutants. Detailed SEC analyses of Delta N94 prepared under different conditions, however, revealed protein concentration-dependent but metal ion-and pH-independent pentamer accumulation at high concentrations which dissociated into tetramers and lower oligomers at low protein concentrations. While calcium appeared to stabilize the tetramer, magnesium in particular stabilized the dimer. Delta N72 existed primarily in the multimeric form under all conditions. These findings of a calcium-free NSP4 pentamer and its concentration-dependent and largely calcium-independent oligomeric transitions open up a new dimension in an understanding of the structural basis of its multitude of functions
Insights into social insects from the genome of the honeybee Apis mellifera
Here we report the genome sequence of the honeybee Apis mellifera, a key model for social behaviour and essential to global ecology through pollination. Compared with other sequenced insect genomes, the A. mellifera genome has high A+T and CpG contents, lacks major transposon families, evolves more slowly, and is more similar to vertebrates for circadian rhythm, RNA interference and DNA methylation genes, among others. Furthermore, A. mellifera has fewer genes for innate immunity, detoxification enzymes, cuticle-forming proteins and gustatory receptors, more genes for odorant receptors, and novel genes for nectar and pollen utilization, consistent with its ecology and social organization. Compared to Drosophila, genes in early developmental pathways differ in Apis, whereas similarities exist for functions that differ markedly, such as sex determination, brain function and behaviour. Population genetics suggests a novel African origin for the species A. mellifera and insights into whether Africanized bees spread throughout the New World via hybridization or displacement