From the polymorphism of amyloid fibrils to their assembly mechanism and cytotoxicity.
Extracellular amyloid deposits are present in a variety of diseases. They contain amyloid fibrils that arise from the association of proteins or peptides. At the molecular level, all these fibrils share a common assembly principle based on a conformational change of the protein precursor leading to the formation of a cross-beta sheet structure. The smallest observed fibrils in vitro, often called protofibrils, are 4-5 nm in diameter. An amyloid fibril is generally composed of several of these protofibrils and may adopt different morphologies such as ribbons, sheets, or multistranded cables. This polymorphism was observed with many different amyloid-forming peptides and proteins using electron microscopy. The need to understand the molecular origin of this effect as well as the desire to find inhibitors of fibril formation has driven researchers toward the dissection of amyloid fibril assembly pathways. We review the current knowledge on amyloid polymorphism and discuss recent findings in the field concerning amyloid fibril assembly pathways and cytotoxicity mechanisms.
Kreplak
Laurent
L
M.E. Müller Institute for Structural Biology, Biozentrum, University of Basel, CH-4056, Basel, Switzerland.
Aebi
Ueli
U
D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D009474:Neurons / Q000187:drug effects; D020836:Protein Structure, Quaternary
D000682:Amyloid; D008055:Lipids