Structural details of amyloid beta oligomers in complex with human prion protein as revealed by solid-state MAS NMR spectroscopy

Abstract

Human PrP (huPrP) is a high-affinity receptor for oligomeric Aβ. Synthetic oligomeric Aβ species are known to be heterogeneous, dynamic and transient, rendering their structural investigation particularly challenging. Here, we used huPrP to preserve Aβ oligomers by coprecipitating them into large hetero-assemblies to investigate the conformation of Aβ(1-42) oligomers and huPrP in the complex by solid-state MAS NMR spectroscopy. The disordered N-terminal region of huPrP becomes immobilized in the complex and therefore visible in dipolar spectra without adopting chemical shifts characteristic of a regular secondary structure. Most of the well-defined C-terminal part of huPrP is part of the rigid complex, and solid-state NMR spectra suggest a loss in regular secondary structure in the last two αhelices. For Aβ(1-42) oligomers in complex with huPrP, secondary chemical shifts reveal a substantial β-strand content. Importantly, not all Aβ(1-42) molecules within the complex have identical conformations. Comparison with the chemical shifts of synthetic A fibrils suggests that the Aβ oligomer preparation represents a heterogeneous mixture of -strandrich assemblies, of which some have the potential to evolve and elongate into different fibril polymorphs, reflecting a general propensity of Aβ to adopt variable β-structure conformers.

The N-terminal domain of the prion protein is required and sufficient for liquid–liquid phase separation: A crucial role of the Aβ-binding domain

“…First, binding of Aβ oligomers or other neurotoxic β-sheet-rich conformers to the polybasic motif is expected to interfere with LLPS of full-length PrPs and the N-terminal fragments, similarly to the deletion of the lysines. In support of this notion, it has been reported that binding of Aβ oligomers modulates phase separation and alters the conformation of full-length PrPs (44,53). Second, it is tempting to speculate that LLPS of PrPs is linked to both its conversion into prions or neurotoxic conformers and its physiological function.…”