Autonomous and reversible folding of a soluble amino-terminally truncated segment of the mouse prion protein.

Prion diseases are assumed to be caused by the infectious isoform, PrPsc, of a single cellular surface protein, PrPc. PrPsc is an insoluble form of PrPc and is believed to possess a different three-dimensional fold. It may propagate by causing PrPc to adopt its own infectious conformation by an unknown mechanism. Studies on folding and thermodynamic stability of prion proteins are essential for understanding the processes underlying the conversion from PrPc to PrPsc, but have so far been hampered by the low solubility of prion proteins in the absence of detergents. Here, we show that the amino-terminally truncated segment of mouse PrP comprising residues 121 to 231 is an autonomous folding unit. It consists predominantly of alpha-helical secondary structure and is soluble at high concentrations up to 1 mM in distilled water. PrP(121-231) undergoes a cooperative and completely reversible unfolding/refolding transition in the presence of guanidinium chloride with a free energy of folding of -22 kJ/mol at pH 7. The intrinsic stability of segment 121-231 is not in accordance with present models of the structure of PrPc and PrPsc PrP(121-231) may represent the only part of PrPc with defined three-dimensional structure.