A structural analysis of amyloid polymorphism in disease: clues for selective vulnerability?

Abstract

The increasing amount of amyloid structures offers an opportunity to investigate the general principles determining amyloid stability and polymorphism in disease. We find that amyloid stability is dominated by about 30% of residues localized in few segments interspersed with regions that are often structurally frustrated in the cross-β conformation. These stable segments correspond to known aggregation-nucleating regions and constitute a cross-β structural framework that is shared among polymorphs. Alternative tertiary packing of these segments within the protofibril results in conformationally different but energetically similar polymorphs. This combination of a conserved structural framework along the axis and energetic ambiguity across the axis results in polymorphic plasticity that explains a number of fundamental amyloid properties, including fibril defects and brittleness but also the polymorphic instability of amyloids in simple aqueous buffers. Together these findings suggest a structural model for in vivo polymorphic bias and selective cellular vulnerability whereby (1) polymorphic bias is induced by particular templating interactions in susceptible cells, (2) once formed specific polymorphs are entropically primed to selectively bind similar targets in neighbouring cells, (3) conservation of polymorphic bias during pathological spreading implies the continued presence of similar templating interactions in successive susceptible cells and (4) absence of templating interactions relaxes polymorphic bias possibly allowing for the modification of cellular susceptibilities during disease progression by novel templating interactions.

Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers

“…This notion comes to add to our recent thermodynamic profiling of the fibril cores of full-length amyloid fibrils, which highlighted that these APR segments provide an extremely conserved framework that commonly stabilises different polymorphs. Furthermore, the same analysis revealed that although additional segments of the polypeptide chain participate in hetero-packing when incorporated in the fibril core, these segments are described by energetically degenerative tertiary packing 40 , thus supporting our findings on the limitations of cross-aggregation interactions within amyloid cores.…”

“…1a-1c ). We limited our search to single variants of major APRs as: (i) APRs are the kinetic drivers that promote self-assembly of amyloids 41-44 , (ii) individual amyloid polymorphs share energetic profiles in a sense that they depend on APRs as a common framework of high structural stability to counteract longer regions of structural frustration in their core 40 and (iii) this approach also supports a deeper understanding of potential tendencies, as assignments are performed at a single residue level.…”

“…For this, we selected a well-known and thoroughly described APR from tau as a case study 85 . The VQIVYK (PHF6) stretch, located in the C-terminal repeat domain of tau, has been demonstrated to be crucial for tau aggregation 86,87 and is a dominant stabiliser of all tau amyloid polymorphs 40 ( Fig. 4a ).…”

“…Regardless of their protein of origin and self-assembly conditions, however, amyloid fibrils share a common structural cross-β architecture 36-39 . Further to this, disease-related amyloid conformers share overlapping thermodynamic distribution profiles, as specific segments that also drive their nucleation predominantly stabilise their amyloid framework 40 . These regions, previously identified as aggregation prone regions (APRs) 41-45 , form thermodynamically stable steric zipper interfaces that staple together amyloid fibril structures.…”

Structural analysis of the bacterial amyloid curli

“…Although once considered an implausible target for structural biology, recent developments in cryo-electron microscopy (cryoEM) and helical processing have facilitated the structure determination of amyloid fibrils at near atomic resolution 1 . A plethora of experimentally determined structures of both in vitro generated and ex vivo isolated amyloids has revealed a bewildering structural diversity of fiber architectures, including the concept of fiber polymorphs or “strains” of otherwise identical or closely related sequences 2–5 .…”