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

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

Volume: 13 Issue: 7

Author(s): Zeenat Mirza, Vikram G. Pillai and Mohammad A. Kamal

Affiliation:

Keywords: Alzheimer's disease, Aβ peptide, C-terminus, co-crystallization, phospholipase A₂, VGGVVIA.

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.

Cite this article as:

Mirza Zeenat, Pillai G. Vikram and Kamal A. Mohammad, Protein Interactions Between the C-Terminus of Aβ-Peptide and Phospholipase A₂ - A Structure Biology Based Approach to Identify Novel Alzheimer's Therapeutics, CNS & Neurological Disorders - Drug Targets 2014; 13 (7) . https://dx.doi.org/10.2174/1871527313666140917112248