Amyloid-forming proteins aggregate within and between neuronal cells, and the resulting deposits are associated with neurodegenerative diseases. The amyloidogenic property of these proteins, in fact, arises from a relatively short part of the whole amino acid sequence. Recent studies have also shown that some short subsequences drive amorphous aggregation; the resulting aggregates are structurally distinct from amyloid aggregates and may thus play different functional and pathogenic roles than amyloid aggregates. Although the process of conformational conversion between amyloid and amorphous aggregates has attracted much attention, the detailed molecular mechanism underlying such a conformational conversion is not yet clear. In this mini-review, I review some aggregation studies that employ the concept of nucleated polymerization to describe early stage on-pathway protein aggregation. I specifically look into one of the most important aggregation properties, critical nucleus size, for a variety of amyloid proteins/fragments and demonstrate that this quantity can be used to help understand the molecular mechanism of early stage protein aggregation. I argue that a similar nucleated polymerization scheme can be applied to study functional/amorphous aggregates without a fundamental difference from a theoretical perspective. I hypothesize that the physical principle underlying the conformational conversion between pathogenic and functional aggregates is associated with several morphological properties (e.g., lateral alignment and intrinsic polymorphism) that can be modulated through proline-mediated conformational rigidity of the sequence. This phenomenon may thus be responsible for the length-dependent amyloidogenesis of amyloid-forming proteins. This notion may shed light on predicting amyloidogenic propensity by correlating the change of a protein’s mechanical properties with the resulting protein morphologies at the sequence level.
Relation:
Research on Chemical Intermediates 45, p.5357–5373
