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Multiple folding pathways for heterologously expressed human prion protein.

G S Jackson¹, A F Hill, C Joseph

¹Prion Disease Group, Department of Neurogenetics, Imperial College School of Medicine at St. Mary's, London W2 1NY, UK.

Biochimica Et Biophysica Acta

|April 21, 1999

Summary

Human prion protein (PrP) adopts different structures based on pH and redox conditions. These findings offer insights into prion protein misfolding and potential disease mechanisms.

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Area of Science:

Biochemistry
Structural Biology
Neuroscience

Background:

The human prion protein (PrP) is implicated in neurodegenerative diseases.
Understanding PrP conformation is crucial for elucidating disease mechanisms.

Purpose of the Study:

To investigate the conformational flexibility of human PrP under varying solution conditions.
To explore the relationship between PrP structure and potential fibril formation.

Main Methods:

Expression of human PrP (residues 91-231) in E. coli.
Analysis of protein conformation using techniques sensitive to pH, redox state, and denaturant concentration.
Differential Scanning Calorimetry (DSC) to study unfolding thermodynamics.

Main Results:

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Oxidized PrP at neutral pH exists as a soluble alpha-helical monomer (PrPC).
PrP unfolding is pH-dependent, with a stable intermediate at pH 4.0 or below.
Reduced PrP exhibits distinct conformations, including a beta-sheet-rich form at acidic pH, which is inter-convertible with the alpha-helical form.

Conclusions:

Human PrP can adopt multiple conformations, some prone to fibril formation.
Solvent conditions significantly influence PrP conformation and unfolding pathways.
These findings provide a model for studying PrP structural rearrangements relevant to prion disease pathogenesis.