Antiparallel triple-strand architecture for prefibrillar A?42 oligomers.

ABSTRACT: A?42 oligomers play key roles in the pathogenesis of Alzheimer disease, but their structures remain elusive partly due to their transient nature. Here, we show that A?42 in a fusion construct can be trapped in a stable oligomer state, which recapitulates characteristics of prefibrillar A?42 oligomers and enables us to establish their detailed structures. Site-directed spin labeling and electron paramagnetic resonance studies provide structural restraints in terms of side chain mobility and intermolecular distances at all 42 residue positions. Using these restraints and other biophysical data, we present a novel atomic-level oligomer model. In our model, each A?42 protein forms a single ?-sheet with three ?-strands in an antiparallel arrangement. Each ?-sheet consists of four A?42 molecules in a head-to-tail arrangement. Four ?-sheets are packed together in a face-to-back fashion. The stacking of identical segments between different ?-sheets within an oligomer suggests that prefibrillar oligomers may interconvert with fibrils via strand rotation, wherein ?-strands undergo an ?90° rotation along the strand direction. This work provides insights into rational design of therapeutics targeting the process of interconversion between toxic oligomers and non-toxic fibrils.

SUBMITTER: Gu L 

PROVIDER: S-EPMC4175361 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature