Sub-ångström cryo-EM structure of a prion protofibril reveals a polar clasp

Area of Science:

• Structural Biology
• Biochemistry
• Neuroscience

Background:

• The atomic structure of infectious mammalian prion protein remains elusive.
• Prions are known for their protease resistance, β-sheet-rich, and fibrillar nature.
• Understanding prion structure is crucial for deciphering their infectious mechanism.

Purpose of the Study:

• To determine the high-resolution atomic structure of a prion protofibril.
• To elucidate the structural basis of prion stability and infectivity.
• To identify novel structural motifs within prion aggregates.

Main Methods:

• Cryo-electron microscopy (cryo-EM) with Microcrystal Electron Diffraction (MicroED).
• Analysis of a wild-type segment from the β2-α2 loop of the bank vole prion protein.
• Sub-ångström-resolution structural determination.

Main Results:

• The sub-ångström-resolution structure of a prion protein protofibril was determined.
• A stabilizing network of hydrogen bonds, termed 'polar clasps', was identified within the protofibril structure.
• These 'polar clasps' link polar zippers within the β-sheet structure, contributing to stability.

Conclusions:

• The study reveals the atomic architecture of a key prion structural unit.
• The identified 'polar clasps' offer insights into the stability of infectious prion aggregates.
• This structural information may guide the development of therapeutic strategies against prion diseases.