Structural and Computational Study of the GroEL-Prion Protein Complex

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• The molecular chaperone GroEL facilitates protein folding and prevents aggregation.
• Prion protein (PrP^C) misfolding and aggregation are linked to neurodegenerative diseases.
• Interactions between chaperones and PrP^C may influence its conversion to the pathogenic PrP^Sc form.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying the interaction between GroEL and PrP.
• To understand how GroEL binding affects PrP structure and its potential for aggregation.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structure of the GroEL-PrP complex.
• Molecular dynamics (MD) simulations to analyze the dynamic interactions and conformational changes.

Main Results:

• Cryo-EM revealed PrP binding to the apical domains of multiple GroEL subunits.
• MD simulations indicated extensive contacts between GroEL and the disordered N-domain of PrP.
• GroEL binding induced helical structure formation in PrP's N-domain and partial unfolding of its C-domain's α2-helix.
• These conformational changes occurred on the nanosecond to microsecond timescale in the absence of nucleotides.

Conclusions:

• GroEL binding induces specific structural alterations in PrP, particularly in its N-domain.
• These GroEL-induced changes in PrP conformation may be critical in the initial steps of prion pathogenesis.
• The findings provide insights into chaperone-mediated prion protein conversion and potential therapeutic targets.