In Vitro Creation of Amyloid Fibrils from Native and Arg124Cys Mutated βIGH3(110–131) Peptides, and Its Relevance for Lattice Corneal Amyloid Dystrophy Type I
Clair‐Florent Schmitt‐BernardAlain ChavanieuJean DerancourtBernard ArnaudJacques DemailleBernard CalasÀngel Argilés
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Amyloid fibrils are responsible for pathogenesis of various diseases and exhibit the structural feature of an ordered, hierarchical structure such as multi-stranded helical structure. As the multi-strandedness of amyloid fibrils has recently been found to be highly correlated with their toxicity and infectivity, it is necessary to study how the hierarchical (i.e. multi-stranded) structure of amyloid fibril is formed. Moreover, although it has recently been reported that the nanomechanics of amyloid proteins plays a key role on the amyloid-induced pathogenesis, a critical role that the multi-stranded helical structure of the fibrils plays in their nanomechanical properties has not fully characterized. In this work, we characterize the morphology and mechanical properties of multi-stranded amyloid fibrils by using equilibrium molecular dynamics simulation and elastic network model. It is shown that the helical pitch of multi-stranded amyloid fibril is linearly proportional to the number of filaments comprising the amyloid fibril, and that multi-strandedness gives rise to improving the bending rigidity of the fibril. Moreover, we have also studied the morphology and mechanical properties of a single protofilament (filament) in order to understand the effect of cross-β structure and mutation on the structures and mechanical properties of amyloid fibrils. Our study sheds light on the underlying design principles showing how the multi-stranded amyloid fibril is formed and how the structure of amyloid fibrils governs their nanomechanical properties.
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This review will focus on the process of amyloid-type protein aggregation. Amyloid fibrils are an important hallmark of protein misfolding diseases and therefore have been investigated for decades. Only recently, however, atomic or near-atomic resolution structures have been elucidated from various in vitro and ex vivo obtained fibrils. In parallel, the process of fibril formation has been studied in vitro under highly artificial but comparatively reproducible conditions. The review starts with a summary of what is known and speculated from artificial in vitro amyloid-type protein aggregation experiments. A partially hypothetic fibril selection model will be described that may be suitable to explain why amyloid fibrils look the way they do, in particular, why at least all so far reported high resolution cryo-electron microscopy obtained fibril structures are in register, parallel, cross-β-sheet fibrils that mostly consist of two protofilaments twisted around each other. An intrinsic feature of the model is the prion-like nature of all amyloid assemblies. Transferring the model from the in vitro point of view to the in vivo situation is not straightforward, highly hypothetic, and leaves many open questions that need to be addressed in the future.
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Cryoelectron microscopy (cryo-EM) has provided unprecedented insights into amyloid fibril structures, including those associated with disease. However, these structures represent the endpoints of long assembly processes, and their relationship to fibrils formed early in assembly is unknown. Consequently, whether different fibril architectures, with potentially different pathological properties, form during assembly remains unknown. Here, we used cryo-EM to determine structures of amyloid fibrils at different times during in vitro fibrillation of a disease-related variant of human islet amyloid polypeptide (IAPP-S20G). Strikingly, the fibrils formed in the lag, growth, and plateau phases have different structures, with new forms appearing and others disappearing as fibrillation proceeds. A time course with wild-type hIAPP also shows fibrils changing with time, suggesting that this is a general property of IAPP amyloid assembly. The observation of transiently populated fibril structures has implications for understanding amyloid assembly mechanisms with potential new insights into amyloid progression in disease.
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