Stop-and-go kinetics in amyloid fibrillation

TL;DR

This study investigates the intermittent growth behavior of amyloid fibrils during protein aggregation, revealing a Markovian switching mechanism between growth and pause states with a consistent probability distribution.

Contribution

It introduces real-time single-fibril measurements and proposes a Markovian model explaining the stochastic switching between growth and pause states in amyloid fibrillation.

Findings

Fibrils grow intermittently with exponential stop and growth time distributions.

The probability of fibrils being in the growth state is approximately 1/4.

The data suggest four independent conformations of the fibril tip.

Abstract

Many human diseases are associated with protein aggregation and fibrillation. We present experiments on in vitro glucagon fibrillation using total internal reflection fluorescence microscopy, providing real-time measurements of single-fibril growth. We find that amyloid fibrils grow in an intermittent fashion, with periods of growth followed by long pauses. The observed exponential distributions of stop and growth times support a Markovian model, in which fibrils shift between the two states with specific rates. Remarkably, the probability of being in the growing (stopping) state is very close to 1/4 (3/4) in all experiments, even if the rates vary considerably. This finding suggests the presence of 4 independent conformations of the fibril tip; we discuss this possibility in terms of the existing structural knowledge.