title: 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.
authors.forename: Zeenat
authors.initials: Z
authors.lastname: Mirza
authors.forename: Vikram G
authors.initials: VG
authors.lastname: Pillai
authors.affiliation: King Fahd Medical Research Center, P.B. No. 80216, King Abdulaziz University, Jeddah -21589, Saudi Arabia. zmirza1@kau.edu.sa.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Kamal
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D017815:Elapidae; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D054467:Phospholipases A2 / Q000378:metabolism*; D020836:Protein Structure, Quaternary
chemical_list: D016229:Amyloid beta-Peptides; D054467:Phospholipases A2; D002118:Calcium