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.
Keywords: Alzheimer's disease, Aβ peptide, C-terminus, co-crystallization, phospholipase A2, VGGVVIA.
CNS & Neurological Disorders - Drug Targets
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.
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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
DOI https://dx.doi.org/10.2174/1871527313666140917112248 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
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