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BMC Genomics

Open Access

Crystallography based structure elucidation of the complex of C-terminal fragment of Aβ polypeptide of Alzheimer’s disease with phospholipase A2

  • Zeenat Mirza1, 2Email author,
  • Vikram Gopalakrishna Pillai2, 3,
  • Sujata Sharma2,
  • Punit Kaur2,
  • Alagiri Srinivasan2 and
  • Tej P. Singh2
BMC Genomics201415(Suppl 2):P10

https://doi.org/10.1186/1471-2164-15-S2-P10

Published: 2 April 2014

Background

Aggregation of Aβ polypeptide plays an important role in pathogenesis of Alzheimer’s disease, the most common form of dementia [1]. Therapies based on rationally designed aggregation inhibitors require knowledge of molecular structure [2]; because of high aggregation tendency of Aβ, it has not been possible to obtain complete structural information by X-ray crystallography. The hydrophobic C-terminal part of the Aβ peptide is critical in triggering transformation from α-helical to β-sheet structure. Phospholipases are an important enzyme involved in the inflammatory cascade mechanism having a conserved globular structure with active site, calcium binding loop, and hydrophobic channel. It has been speculated that phospholipase A2 (PLA2) inhibits the aggregation of Aβ peptide by interacting with the peptide and keeping the two peptide chains apart.

Material and methods

PLA2 was purified to homogeneity from cobra venom. In order to examine the nature of interactions between PLA2 and Aβ36-42 peptide 1:1 complex of PLA2 with the C-terminal heptapeptide Val-Gly-Gly-Val-Val-Ile-Ala was prepared and co-crystallized. It is in tetragonal space group P41 with unit cell dimensions, a=b=42.6 Å, c=65.8Å. X-ray intensity data were collected to 2.04 Å resolution. Structure has been determined by molecular replacement and refined to the crystallographic R factor of 0.193. Structural co-ordinates were deposited at RCSB’s PDB (3GCI).

Results

Peptide binds to PLA2 at the hydrophobic substrate binding site and forms at least eight hydrogen bonds and about a two dozen Van der Waals interactions indicating that the affinity between PLA2 and the heptapeptide is far greater than the affinity between two Aβ peptide chains. Therefore, PLA2 may have a potential role to prevent the aggregation of Aβ peptides. Calcium has been found in the calcium binding site and has pentagonal bipyramidal geometry. Kinetic studies showed that the peptide VGGVVIA binds to PLA2 in a competitive manner with a binding constant of 5.2 x 10-7 M.

Conclusions

This is the first attempt to structurally establish the interaction between Aβ peptide and PLA2. Results indicate that the peptide mainly adopts β-sheet secondary structure. Understanding the mechanism and effects of PLA2 upregulation in AD brain may help in the development of novel strategies to inhibit the inflammatory responses and delay AD progression. Preventing the folding of nascent Aβ monomer into toxic conformers or oligomers would have therapeutic benefits.

Authors’ Affiliations

(1)
King Fahd Medical Research Center, King Abdulaziz University
(2)
Department of Biophysics, All India Institute of Medical Sciences
(3)
Long Zheng Lab, Division of Pathology, 803I Abramson Research Center, The Children’s Hospital of Philadelphia

References

  1. Yao F, Zhang R, Tian H, Li X: Studies on the interactions of Copper and Zinc ions with β-Amyloid peptides by a surface plasmon resonance biosensor. International Journal of Molecular Sciences. 2012, 13 (9): 11832-11843.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Tjernberg LO, Tjernberg A, Bark N, Shi Y, Ruzsicska BP, Bus Z, Thyberg J, Callaway DJE: Assembling amyloid fibrils from designed structures containing a significant amyloid β-peptide fragment. Biochem. J. 2002, 366: 343-351.PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Mirza et al; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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