Ion mobility–mass spectrometry reveals a conformational conversion from random assembly to β-sheet in amyloid fibril formation

Abstract

Amyloid cascades leading to peptide β-sheet fibrils and plaques are central to many important diseases. Recently, intermediate assemblies of these cascades were identified as the toxic agents that interact with the cellular machinery. The location and cause of the transformation from natively unstructured assembly to the beta-sheet oligomers found in all fibrils is important in understanding disease onset and the development of therapeutic agents. Research on this early oligomeric region has largely been unsuccessful since all traditional techniques measure only ensemble average oligomer properties. Here, ion mobility methods are utilized to deduce the peptide self-assembly mechanism. We look at a series of amyloid forming peptides clipped from larger peptides or proteins associated with disease. We provide unambiguous evidence for structural transitions in each of these fibril forming peptide systems establishing the potential of this method for the development of therapeutic agents and drug evaluation.