Structural consequences of sequence variation in mammalian prion β2α2 loop segments

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• The β2α2 loop of mammalian prion protein (PrP) is crucial for its structure.
• Sequence variations in this loop can affect protein folding and aggregation.

Purpose of the Study:

• To investigate how sequence variations in the PrP β2α2 loop impact its structure and amyloid packing.
• To understand the biochemical and biophysical consequences of natural and artificial loop variants.

Main Methods:

• Microcrystal electron diffraction (MicroED) was used to determine atomic resolution structures of β2α2 loop segments.
• Biochemical and biophysical analyses were performed on various PrP loop sequences.
• Negative stain electron microscopy evaluated fibril morphology of recombinant PrP segments.

Main Results:

• Two dominant amyloid packing polymorphisms, 'clasped' and 'interdigitated,' were identified.
• The identity of residue 174 significantly influences the adopted packing.
• Single residue substitutions in the β2α2 loop impacted fibril morphology.

Conclusions:

• Prion protein β2α2 loop sequence variations dictate distinct amyloid packing structures.
• Residue 174 and overall loop sequence are critical for prion assembly stability and morphology.
• These findings highlight sequence-specific polymorphisms in prion diseases.