Non-native beta-sheet formation: insights into protein amyloidosis

TL;DR

This paper presents a theoretical framework explaining how sequence-independent beta-sheet aggregation occurs in protein amyloidosis, highlighting the role of inter-sheet stacking and predicting critical polymer lengths relevant to disease.

Contribution

It introduces a novel theoretical model linking hydrogen-bond cooperativity to in vivo beta-sheet aggregation and disease-related polymer length thresholds.

Findings

Aggregation driven by inter-sheet stacking dynamics

Prediction of minimal polymer length for aggregation

Correlation with critical lengths in poly-glutamine diseases

Abstract

Protein amyloidosis is a cytopathological process characterized by the formation of highly beta-sheet-rich fibrils. How this process occurs and how to prevent/treat the associated diseases are not completely understood. Here, we carry out a theoretical investigation of sequence-independent beta-sheet formation, based on recent findings regarding the cooperativity of hydrogen-bond network formation. Our results strongly suggest that in vivo beta-sheet aggregation is induced by inter-sheet stacking dynamics. This leads to a prediction for the minimal length of susceptible polymer needed to form such an aggregate. Remarkably, the prediction corresponds quite well with the critical lengths detected in poly-glutamine-related diseases. Our work therefore provides a theoretical framework capable of understanding the underlying mechanism and shedding light on therapy strategies of protein amyloidosis.