The common architecture of cross-beta amyloid.
Amyloid fibril deposition is central to the pathology of more than 30 unrelated diseases including Alzheimer's disease and Type 2 diabetes. It is generally accepted that amyloid fibrils share common structural features despite each disease being characterised by the deposition of an unrelated protein or peptide. The structure of amyloid fibrils has been studied using X-ray fibre diffraction and crystallography, solid-state NMR and electron paramagnetic resonance, and many different, sometimes opposing, models have been suggested. Many of these models are based on the original interpretation of the cross-beta diffraction pattern for cross-beta silk in which beta-strands run perpendicular to the fibre axis, although alternative models include beta-helices and natively structured proteins. Here, we have analysed opposing model structures and examined the necessary structural elements within the amyloid core structure, as well as producing idealised models to test the limits of the core conformation. Our work supports the view that amyloid fibrils share a number of common structural features, resulting in characteristic diffraction patterns. This pattern may be satisfied by structures in which the strands align close to perpendicular to the fibre axis and are regularly arranged to form beta-sheet ribbons. Furthermore, the fibril structure contains several beta-sheets that associate via side-chain packing to form the final protofilament structure.
Jahn
Thomas R
TR
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Makin
O Sumner
OS
Morris
Kyle L
KL
Marshall
Karen E
KE
Tian
Pei
P
Sikorski
Pawel
P
Serpell
Louise C
LC
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D014961:X-Ray Diffraction
D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments