Amyloid fibrils and their implication
Beside the native state, another thermodynamically stable conformation, the so called amyloid fibrils, can form. These fibrils consist of many-chain aggregates. Surprisingly, irrespective of the given amino acid sequence, fibrils formed by different polypeptides have very similar morphologies. Hence, a protein can exist in a stable non-toxic, as well as a stable toxic form, which seems to be a generic feature of polypeptide chains. The difference can be found in the secondary and tertiary structure of the molecules and the mutual interaction between different groups of amino acids.
Fibril forming peptides such as amyloid-β peptides consist of 36-43 amino acids (see Figure 1). The arrows indicate the β-strands and are pointing in the direction of an amino acid with a free carboxyl group (COOH), the C-terminus, in the polypeptide.
Figure 1: Schematic depiction of the backbone structure (“β-hair pin”) of an
amyloid-β(1– 40) peptide in a mature fibril. The corresponding β-strands reach
from the amino acids Glu-11 to Glu-22 (yellow arrow) and from Ala-30 to Val-
40 (green arrow); adapted from Scheidt, H. A., Morgado, I. & Huster, D. Dynamics
of Amyloid β Fibrils Revealed by Solid-state NMR. J Biol Chem 287, 2017–2021
(2012).
The unbranched and often twisted fibrillar structure with 10-20 nm in diameter are up to a few micrometers long. Two densely packed β-sheets (all yellow and all green arrows in Figure 2), whose strands run perpendicular to the fibre axis lead to the so called β-cross structure with a characteristic X-ray diffraction pattern. The intermolecular interactions between the polymer chains differ from the intramolecular ones within the same chain and dominate the formation of the protein aggregates. Thus, β-strands of different peptides within the fibril interact via H-bonds which are parallel to the fibril axis. In Figure 2, the corresponding β-strands (yellow and green arrows) of the example amyloid-β(1-40) are parallel aligned to each other in each sheet.
Figure 2: Scheme of the cross-β structure of a mature amyloid fibril with a
densely packed two-layer
β-sheet structure. Each β-sheet is indicated by yellow
or green color and shows a parallel alignment of the β-strands (yellow and green
arrows).
The mature fibrils are the final product of a formation process which is not fully understood. The toxic intermediates (oligomers and protofibrils) of the amyloid fibrils are associated with fatal diseases.
These amyloid diseases (e.g. Alzheimer’s disease) involve predominantly the aggregation of proteins. This can lead to extracellular deposits of amyloid plaque in the affected tissue, such as the brain, in the range of almost undetectable amounts up to literally kilograms of proteins.
However, the question “What happens to the structure during the formation of amyloid fibrils and which changes occur to the bonds?” is still under debate. Therefore the tertiary structure of amyloid-β (1-40) protofibrils, the pre stage of mature fibrils, has been investigated by researcher in the group of Daniel Huster at University of Leipzig within the CRC project A06.