| Autor: |
Chang YJ; Genomics Research Center, Academia Sinica, Taiwan , 128, Academia Road, Sec. 2, Nankang Dist., Taipei 115, Taiwan., Linh NH; Institute for Computational Science and Technology , SBI Building, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam., Shih YH; Genomics Research Center, Academia Sinica, Taiwan , 128, Academia Road, Sec. 2, Nankang Dist., Taipei 115, Taiwan., Yu HM; Genomics Research Center, Academia Sinica, Taiwan , 128, Academia Road, Sec. 2, Nankang Dist., Taipei 115, Taiwan., Li MS; Institute of Physics Polish Academy of Sciences , Al. Lotnikow 32/46, 02-668 Warsaw, Poland., Chen YR; Genomics Research Center, Academia Sinica, Taiwan , 128, Academia Road, Sec. 2, Nankang Dist., Taipei 115, Taiwan. |
| Abstrakt: |
Amyloid-β (Aβ), the main constituent in senile plaques found in the brain of patients with Alzheimer's disease (AD), is considered as a causative factor in AD pathogenesis. The clinical examination of the brains of patients with AD has demonstrated that caspase-3 colocalizes with senile plaques. Cellular studies have shown that Aβ can induce neuronal apoptosis via caspase-3 activation. Here, we performed biochemical and in silico studies to investigate possible direct effect of Aβ on caspase-3 to understand the molecular mechanism of the interaction between Aβ and caspase-3. We found that Aβ conformers can specifically and directly sequester caspase-3 activity in which freshly prepared Aβ42 is the most potent. The inhibition is noncompetitive, and the C-terminal region of Aβ plays an important role in sequestration. The binding of Aβ to caspase-3 was examined by cross-linking and proteolysis and by docking and all-atom molecular dynamic simulations. Experimental and in silico results revealed that Aβ42 exhibits a higher binding affinity than Aβ40 and the hydrophobic C-terminal region plays a key role in the caspase-Aβ interaction. Overall, our study describes a novel mechanism demonstrating that Aβ sequesters caspase-3 activity via direct interaction and facilitates future therapeutic development in AD. |
