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Is the novel amyloid-β tetramer fold a stable conformation?
Journal of Cheminformatics volume 5, Article number: P10 (2013)
In the pathogenesis of Alzheimer's disease (AD), the most common neurodegenerative disorder, the amyloid-β (Aβ) peptide plays a key role. Originally, the Aβ fibrils were postulated to be the neurotoxic agents for a long time, because an increased presence of extracellular amyloid plaques, composed primarily of insoluble Aβ fibrils, is found in the brain of affected patients. Recent studies, however, showed a higher cytotoxicity for small Aβ oligomers than for the Aβ fibrils so that these soluble Aβ oligomers are moving to the centre of interest now [1, 2].
Because of the unstable and noncrystalline nature of these species, obtaining structural information for small oligomers is an experimentally challenging task. Novel structural insight was obtained from a recent crystal structure of a tetramer formed by the amyloidogenic residues 18-41 of the Aβ peptide. To enhance stability, this fragment was genetically engineered into the CDR3 loop region of a shark Ig single variable domain antibody .
Since the respective crystal structure is stabilized by the antibody moiety, we investigated, whether the respective topology also represents a stable fold for the isolated Aβ-peptide.
We performed molecular dynamics simulations in explicit solvent for the isolated tetrameric amyloid-β fragment in two different lengths (17-40 and 17-42) and the derived dimer and monomer structures. In contrast to Aβ17-40, we observed a stable dynamical behaviour for the tetramer of Aβ17-42: the extension of the antiparallel β-sheet through the residues 41 and 42 is responsible for the enhanced structural stability.
In summary, our results suggest that the novel tetrameric structure represents a stable oligomer conformation for the longer and more neurotoxic Aβ42 species and thus could be a new target in rational drug design aiming at the prevention of toxic oligomer formation.
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Stroud JC, Liu C, Teng PK, Eisenberg D: Toxic fibrillar oligomers of amyloid-β have cross-β structure. PNAS. 2012, 109: 7717-7722. 10.1073/pnas.1203193109.
Streltsov VA, Varghese JN, Masters CL, Nuttall SD: Crystal structure of the amyloid-β p3 fragment provides a model for oligomer formation in Alzheimer's disease. J Neurosci. 2011, 31: 1419-1426. 10.1523/JNEUROSCI.4259-10.2011.
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Socher, E., Horn, A.H. & Sticht, H. Is the novel amyloid-β tetramer fold a stable conformation?. J Cheminform 5 (Suppl 1), P10 (2013). https://doi.org/10.1186/1758-2946-5-S1-P10
- Recent Crystal Structure
- CDR3 Loop
- Extracellular Amyloid Plaque
- Stable Fold
- Toxic Oligomer