Self-Templated Nucleation in Peptide and Protein aggregation

TL;DR

This paper introduces a self-templated nucleation mechanism in peptide and protein aggregation, explaining how disordered oligomers transition into fibrillar structures, with implications for neurodegenerative diseases.

Contribution

It reveals a novel self-templated nucleation process where oligomer surfaces catalyze the transition to fibrils, advancing understanding of aggregation pathways.

Findings

Disordered oligomers can reorder into fibrils via surface templating.

Fibril surfaces stabilize disordered assemblies.

Mechanism links oligomer reordering to disease-related aggregation.

Abstract

Peptides and proteins exhibit a common tendency to assemble into highly ordered fibrillar aggregates, whose formation proceeds in a nucleation-dependent manner that is often preceded by the formation of disordered oligomeric assemblies. This process has received much attention because disordered oligomeric aggregates have been associated with neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Here we describe a self-templated nucleation mechanism that determines the transition between the initial condensation of polypeptide chains into disordered assemblies and their reordering into fibrillar structures. The results that we present show that at the molecular level this transition is due to the ability of polypeptide chains to reorder within oligomers into fibrillar assemblies whose surfaces act as templates that stabilise the disordered assemblies.