Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains

Area of Science:

• Structural Biology
• Neuroscience
• Biochemistry

Background:

• Prion diseases are associated with misfolded prion proteins, but the structural basis of different prion strains remains poorly understood.
• Understanding prion strain structures is crucial for developing targeted therapeutics and diagnostics.

Purpose of the Study:

• To determine the high-resolution structure of infectious brain-derived fibrils from the mouse anchorless RML scrapie strain.
• To compare the structural features of the anchorless RML strain with other known prion strains, such as hamster 263K.

Main Methods:

• High-resolution (3.0 Å) cryo-electron microscopy was employed to visualize the fibril structure.
• Comparative structural analysis was performed between the determined anchorless RML structure and existing prion strain structures.

Main Results:

• The anchorless RML scrapie strain exhibits a parallel in-register β-sheet-based core, similar to the hamster 263K strain.
• Shared structural motifs, including a steric zipper and β-arches, were identified, but with notable variations in topology.
• Absence of glycophosphatidylinositol anchors and N-linked glycans in anchorless RML did not significantly alter the amyloid core conformation compared to wildtype RML.

Conclusions:

• Prion strains share common structural elements in their amyloid core, suggesting conserved mechanisms of aggregation.
• Divergent features in shared structural motifs highlight the structural basis for prion strain diversity.
• Post-translational modifications have a limited impact on the fundamental amyloid core structure of prion fibrils.