Structural rearrangement of amyloid-β upon inhibitor binding suppresses formation of Alzheimer’s disease related oligomers

The formation of oligomers of the amyloid-β peptide plays a key role in the onset of Alzheimer's disease. We describe herein the investigation of disease-relevant small amyloid-β oligomers by mass spectrometry and ion mobility spectrometry, revealing functionally relevant structural attributes. In particular, we can show that amyloid-β oligomers develop in two distinct arrangements leading to either neurotoxic oligomers and fibrils or non-toxic amorphous aggregates. Comprehending the key-attributes responsible for those pathways on a molecular level is a pre-requisite to specifically target the peptide's tertiary structure with the aim to promote the emergence of non-toxic aggregates. Here, we show for two fibril inhibiting ligands, an ionic molecular tweezer and a hydrophobic peptide that despite their different interaction mechanisms, the suppression of the fibril pathway can be deduced from the disappearance of the corresponding structure of the first amyloid-β oligomers.

Structure of the substrate-binding domain of Plasmodium falciparum heat-shock protein 70-x

The malaria parasite Plasmodium falciparum extensively modifies erythrocytes that it invades by exporting a large complement of proteins to the host cell. Among these exported components is a single heat-shock 70 kDa class protein, PfHsp70-x, that supports the virulence and growth rate of the parasite during febrile episodes. The ATP-binding domain of PfHsp70-x has previously been resolved and showed the presence of potentially druggable epitopes that differ from those on human Hsp70 chaperones. Here, the crystallographic structure of the substrate-binding domain (SBD) of PfHsp70-x is presented in complex with a hydrophobic peptide. The PfHsp70-x SBD is shown to be highly similar to the counterpart from a human erythrocytic Hsp70 chaperone. The binding of substrate at the interface between β-sandwich and α-helical subdomains of this chaperone segment is also conserved between the malaria parasite and humans. It is hypothesized that the parasite may partly exploit human chaperones for intra-erythrocytic trafficking and maintenance of its exported proteome.

Trigger, Signaling Mechanism and End Effector of Cardioprotective Effect of Remote Postconditioning of Heart

The hypothetical trigger of remote postconditioning (RPost) of the heart is the highmolecular weight hydrophobic peptide(s). Nitric oxide and adenosine serve as intermediaries between the peptide and intracellular structures. The role of the autonomic nervous system in RPost requires further study. In signaling mechanism RPost, kinases are involved: protein kinase C, PI3, Akt, JAK. The hypothetical end effector of RPost is aldehyde dehydrogenase-2, the transcription factors STAT, Nrf2, and also the BKCa channel.

A Novel Approach to Unzipped Tubes Synthesis Using Sulfanilic Acid as the Backbone Amino Acid

In this research, unzipped sulfanilic acid inspired hydrophobic peptide tube was synthesis by increasing the polarity of sulfanilic acid through nucleophilic attachment of aniline which then provided two reactive sites at the S-terminus. These two sites were then attached with the N-terminal of valine and alanine respectively at an intensity of 1000-1600 of 11 2θ (°). Through π-π stacking at the side chains, the opened ended peptide was linearly arranged to form the unzipped tube. Fourier transform infrared spectroscopy (FTIR) confirm the amine bond formation whiles X-ray diffraction test results confirmed D-spacing 7.36 and 4.44 corresponding 2θ (°)12 and 19.97 respectively whiles the torsion angles (Ø2) conformations was between-150.5°and-169.2° and-2 between-129.0° and-150.6°. The Thermogravimetric analysis result showed an increase in the rigidity of the bond with an increasing intensity. Finally, Differential scanning calorimetry (DSC) test was carried out to confirm the crystallinity of the structure. Keywords: Sulfanilic acid, hydrophobic Peptide, Unzipped tubes, Nanomaterial

Catestatin Induces Glucose Uptake and GLUT4 Trafficking in Adult Rat Cardiomyocytes

Catestatin is a cationic and hydrophobic peptide derived from the enzymatic cleavage of the prohormone Chromogranin A. Initially identified as a potent endogenous nicotinic–cholinergic antagonist, Catestatin has recently been shown to act as a novel regulator of cardiac function and blood pressure and as a cardioprotective agent in both pre- and postconditioning through AKT-dependent mechanisms. The aim of this study is to investigate the potential role of Catestatin also on cardiac metabolism modulation, particularly on cardiomyocytes glucose uptake. Experiments were performed on isolated adult rat cardiomyocytes. Glucose uptake was assessed by fluorescent glucose incubation and confocal microscope analysis. Glut4 plasma membrane translocation was studied by immunofluorescence experiments and evaluation of the ratio peripheral vs internal Glut4 staining. Furthermore, we performed immunoblot experiments to investigate the involvement of the intracellular pathway AKT/AS160 in the Catestatin dependent Glut4 trafficking. Our results show that 10 nM Catestatin induces a significant increase in the fluorescent glucose uptake, comparable to that exerted by 100 nM Insulin. Moreover, Catestatin stimulates Glut4 translocation to plasma membrane and both AKT and AS160 phosphorylation. All these effects were inhibited by Wortmannin. On the whole, we show for the first time that Catestatin is able to modulate cardiac glucose metabolism, by inducing an increase in glucose uptake through Glut4 translocation to the plasma membrane and that this mechanism is mediated by the AKT/AS160 intracellular pathway.