Structure of N-Terminal Sequence Asp-Ala-Glu-Phe-Arg-His-Asp-Ser of Aβ-Peptide with Phospholipase A2 from Venom of Andaman Cobra Sub-Species Naja naja sagittifera at 2.0 Å Resolution

Abstract

Alzheimer’s disease (AD) is one of the most significant social and health burdens of the present century. Plaques formed by extracellular deposits of amyloid β (Aβ) are the prime player of AD’s neuropathology. Studies have implicated the varied role of phospholipase A2 (PLA2) in brain where it contributes to neuronal growth and inflammatory response. Overall contour and chemical nature of the substrate-binding channel in the low molecular weight PLA2s are similar. This study involves the reductionist fragment-based approach to understand the structure adopted by N-terminal fragment of Alzheimer’s Aβ peptide in its complex with PLA2. In the current communication, we report the structure determined by X-ray crystallography of N-terminal sequence Asp-Ala-Glu-Phe-Arg-His-Asp-Ser (DAEFRHDS) of Aβ-peptide with a Group I PLA2 purified from venom of Andaman Cobra sub-species Naja naja sagittifera at 2.0 Å resolution (Protein Data Bank (PDB) Code: 3JQ5). This is probably the first attempt to structurally establish interaction between amyloid-β peptide fragment and hydrophobic substrate binding site of PLA2 involving H bond and van der Waals interactions. We speculate that higher affinity between Aβ and PLA2 has the therapeutic potential of decreasing the Aβ–Aβ interaction, thereby reducing the amyloid aggregation and plaque formation in AD.

Molecular Science for Drug Development and Biomedicine

“…The article entitled with “Structure of N -Terminal Sequence Asp-Ala-Glu-Phe-Arg-His-Asp-Ser of Aβ-Peptide with Phospholipase A 2 from Venom of Andaman Cobra Sub-Species Naja naja sagittifera at 2.0 Å Resolution” authored by Professor Dr. Zeenat Mirza, and coauthors reported the structure from Alzheimer’s Aβ-peptide in complex with phospholipase A 2 , which was determined by X-ray crystallography at 2.0 Å resolution [ 9 ]. Their findings suggest the possibility of interactions between N -terminus residues (DAEFRHDS) and phospholipase A 2 .…”

Imidazole improves cognition and balances Alzheimer's‐like intracellular calcium homeostasis in transgenic Drosophila model

“…Some results have been indicated that the Aβ forms an ion channel and is responsible for an elevation of cytoplasmic Ca 2+ . The Aβ channel hypothesis proposes that the hydrophilic N‐terminus third (residues 1‐14, S1) of amyloid peptide composes the lining of the Aβ channel's pore, which encompasses the His13‐His14 diad around the axis . The channel is electronegative, characterized by its selective affinity with cations including Ca 2+ .…”

Molecular Science for Drug Development and Biomedicine

“…The article entitled with "Structure of N-Terminal Sequence Asp-Ala-Glu-Phe-Arg-His-Asp-Ser of Aβ-Peptide with Phospholipase A2 from Venom of Andaman Cobra Sub-Species Naja naja sagittifera at 2.0 Å Resolution" authored by Professor Dr. Zeenat Mirza, and coauthors reported the structure from Alzheimer's Aβ-peptide in complex with phospholipase A2, which was determined by X-ray crystallography at 2.0 Å resolution [9]. Their findings suggest the possibility of interactions between N-terminus residues (DAEFRHDS) and phospholipase A2.…”