Protein Interactions Between the C-Terminus of Aβ-Peptide and Phospholipase A₂ - A Structure Biology Based Approach to Identify Novel Alzheimer’s Therapeutics

Abstract

Amyloid β (Aβ) polypeptide plays a key role in determining the state of protein aggregation in Alzheimer's disease. The hydrophobic C-terminal part of the Aβ peptide is critical in triggering the transformation from α-helical to β- sheet structure. We hypothesized that phospholipase A2 (PLA2) may inhibit the aggregation of Aβ peptide by interacting with the peptide and keeping the two peptide chains apart. In order to examine the nature of interactions between PLA2 and Aβ peptide, we prepared and crystallized complex of Naja naja sagittifera PLA2 with the C-terminal hepta-peptide Val-Gly-Gly-Val-Val-Ile-Ala. The X-ray intensity data were collected to 2.04 A resolution and the structure was determined by molecular replacement and refined to the crystallographic R factor of 0.186. The structural analysis revealed that the peptide binds to PLA2 at the hydrophobic substrate binding cavity forming at least eight hydrogen bonds and approximately a two dozen Van der Waals interactions. The number and nature of interactions indicate that the affinity between PLA2 and the hepta-peptide is greater than the affinity between two Aβ peptide chains. Therefore, PLA2 is proposed as a probable ligand to prevent the aggregation of Aβ peptides.

Interactions of the Aβ(1–42) Peptide with Boron Nitride Nanoparticles of Varying Curvature in an Aqueous Medium: Different Pathways to Inhibit β-Sheet Formation

“…The aromatic residues of Phe4 from N-terminal and Phe20 from CHC and most of the other residues of Glu22, Asp23, Ile31, Leu34, Met35, Val36, Val40, and Ile41 from the CHC and C-terminal regions are found to contribute significantly to the total binding energy between the peptide and BNNS. In addition to π–π stacking interactions of aromatic residues with the hexagonal rings of BNNS, the hydrophobic CHC and C-terminal residues, which are otherwise mostly responsible for β-sheet formation, ,,,,− are also found to bind with the nanoparticle surfaces in our study and prevent the conformational transition of the peptide to its β-sheet structure.…”

Amyloid beta: structure, biology and structure-based therapeutic development

“…Approximately 25% of the surface is uninterruptedly hydrophobic, and the compact coil structure is meta-stable, which may lead to a global conformational rearrangement and the formation of an intermolecular beta-sheet secondary structure caused by fibrillization. The 3D NMR structures of Aβ peptide (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and Aβ peptide (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) show two helical regions connected by a regular type I β-turn. Aβ peptide (25-35) is a highly toxic synthetic derivative of Aβ peptides.…”

“…However, the most recent NMR structure of Aβ40 shows significant secondary and tertiary structure [35] . The hydrophobic C-terminal of the Aβ is critical in triggering the transformation from α-helical to β-sheet structure and plays a key role in determining the state of protein aggregation in Alzheimer's disease [36] .…”

Second Sphere Interactions in Amyloidogenic Diseases

“…Recently derived NMR structure of Aβ(1–40) also exhibited substantial secondary as well as tertiary structure . The conformational transformation from α-helix to β-sheet and the aggregation state of Aβ in AD is tuned by the peptide’s hydrophobic C-terminus …”

“…144 The conformational transformation from α-helix to β-sheet and the aggregation state of Aβ in AD is tuned by the peptide's hydrophobic Cterminus. 145 Aβ monomers can aggregate to form low molecular weight oligomers like dimers to pentamers, midrange molecular weight oligomers such as hexamers, nonamers, and dodecamers, protofibrils, and ultimately fibrils. The transient nature of the oligomeric states and the nontrivial preparation of a homogeneous population of oligomers render their structural characterization very difficult.…”