Abstract
Amyloid fibrils are highly polymorphic structures formed by many different proteins. They provide biological function but also abnormally accumulate in numerous human diseases. The physicochemical principles of amyloid polymorphism are not understood due to lack of structural insights at the single-fibril level. To identify and classify different fibril polymorphs and to quantify the level of heterogeneity is essential to decipher the precise links between amyloid structures and their functional and disease associated properties such as toxicity, strains, propagation and spreading. Employing gentle, force-distance curve-based AFM, we produce detailed images, from which the 3D reconstruction of individual filaments in heterogeneous amyloid samples is achieved. Distinctive fibril polymorphs are then classified by hierarchical clustering, and sample heterogeneity is objectively quantified. These data demonstrate the polymorphic nature of fibril populations, provide important information regarding the energy landscape of amyloid self-assembly, and offer quantitative insights into the structural basis of polymorphism in amyloid populations.
Highlights
Amyloid fibrils are highly polymorphic structures formed by many different proteins
The results show that variation in the degree of structural polymorphism and the heterogeneity of amyloid fibril samples are highly sequence specific
Considerable heterogeneity has been displayed in several amyloid fibril samples previously[26,27], including in samples made from Waltz peptide amyloid assembly reactions[40]
Summary
Amyloid fibrils are highly polymorphic structures formed by many different proteins They provide biological function and abnormally accumulate in numerous human diseases. Recent cryo-EM and ssNMR structures of Aβ17,20,21 and tau[16,22,23] reveal parallel, in register organisation of the proteins within the cross-β core These advances have provided molecular information on the 3D fold of the monomeric subunits within the core of distinct fibril types in addition to information about the intermolecular interactions between amino acid residues[24]. On a mesoscopic (micrometre to nanometre) scale, amyloid fibrils display a high degree of polymorphism and amyloid populations are often highly heterogeneous This has been demonstrated in disease related amyloid fibrils in both in vitro and ex vivo samples, as well as in samples of functional amyloid[25,26,27]. Structural characterisation has revealed that many amyloidogenic proteins can form polymorphic structures, revealing that, for example, AA can fold into different conformations dependent on the species, as well as the individual patients[29], while tau has been shown to form different polymorphs in different tauopathies[16,22,30]
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