Deciphering the structural basis for amyloid secondary nucleation and its inhibition

Amyloid is a fibrillar structure formed by misfolding and aggregation of peptides or protein segments. Amyloid aggregation is linked to a range of severe diseases, e.g. Alzheimer’s disease and type 2 diabetes.

The root cause of disease appears to be the surface-catalysed accumulation of large amounts of cytotoxic amyloid intermediates in a process called secondary nucleation.

The small BRICHOS domain, found in 13 unrelated type protein families, is a powerful and promiscuous anti-amyloid chaperone, and BRICHOS domains from different protein families, with only limited sequence homology, are able to inhibit secondary nucleation of unrelated amyloids.

In this project we aim to understand the structural basis for secondary nucleation, and its BRICHOS-mediated inhibition.

To this end, we will employ X-ray crystallography, cryo-electron microscopy, and state-of-the art fibrillation kinetics together with a completely novel and general approach based on the design of single-chain recombinant amyloid-like proteins (SCRAPs) that will allow us to decode the determinants of these processes.

The results will not only provide new inroads to blocking production of disease-causing cytotoxic amyloid intermediates as potential treatments for amyloid diseases, but also shed light on a fundamental recognition problem in structural biology: How can promiscuous protein-protein interactions that result in specific activities (in this case surface-catalysis and its inhibition) be achieved?