Insight into Early-Stage Unfolding of GPI-Anchored Human Prion Protein

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Prion diseases involve misfolded prion protein (PrPSc) accumulation.
• Normal cellular prion protein (PrPC) is α-helical; PrPSc is β-sheet rich.
• Understanding PrPC structural stability is key to prion disease mechanisms.

Purpose of the Study:

• Investigate the impact of N-glycosylation and membrane environment on PrPC secondary structure stability.
• Elucidate the molecular mechanisms underlying PrPC conformational changes.

Main Methods:

• Extensive microsecond molecular dynamics simulations were employed.
• Analyzed conformational changes and secondary structure stability of PrPC.

Main Results:

• PrPC's C-terminal fragment (residues 173-194) unfolds in solution due to competing hydrogen bonds and intrinsic instability.
• This unfolding initiates loop extension (residues 195-199), potentially triggering further conformational changes.
• Membrane interactions stabilize PrPC by constraining conformation and reducing solvent accessibility.
• N-glycosylation further enhances stability through interactions with the membrane surface.

Conclusions:

• Membrane presence and N-glycosylation are critical for stabilizing cellular prion protein (PrPC) structure.
• PrPC's intrinsic instability in solution contributes to initial unfolding events.
• These findings offer insights into prion protein misfolding and disease pathogenesis.