Structure of prion β-oligomers as determined by short-distance crosslinking constraint-guided discrete molecular...

Area of Science:

• Structural Biology
• Neurodegenerative Diseases
• Biochemistry

Background:

• Prion diseases involve the conversion of native cellular prion protein (PrP^C) into pathological aggregates (PrP^β, PrP^Sc).
• The precise structure of these aggregates and the molecular mechanisms driving the conformational changes remain largely unknown.
• Understanding these mechanisms is crucial for deciphering prion disease pathogenesis.

Purpose of the Study:

• To characterize the structural differences between native PrP^C and urea+acid-converted PrP^β oligomers.
• To elucidate the molecular mechanisms underlying PrP conversion and aggregation.
• To determine the structure of the monomer and dimer units within the β-oligomer.

Main Methods:

• Applied mass spectrometry combined with chemical crosslinking, hydrogen/deuterium exchange, limited proteolysis, and surface modification.
• Utilized a de novo protein structure determination approach integrating crosslinking data with discrete molecular dynamics (CL-DMD) simulations.
• Determined structures of monomer and dimer units of the β-oligomer.

Main Results:

• Differential structural characterization of native and converted prion β-oligomers was achieved.
• The study determined the structure of the monomer and dimer units of the β-oligomer.
• A potential assembly model for the β-oligomer was proposed based on experimental and computational data.

Conclusions:

• The proposed β-oligomer assembly model offers insights into the β-sheet nucleation site.
• The findings provide clues on how template-based conversion of native prion protein occurs.
• The study sheds light on the growth and maturation of prion aggregates into fibrils.