Background: Folding intermediates of proteins are known to initiate misfolding. Results: Two partially unfolded forms (PUFs) of the prion protein have been characterized structurally and energetically. Conclusion: One of the PUFs is structurally similar to an initial intermediate in prion misfolding. Significance: Identification of aggregation-prone intermediates on the prion protein's folding pathway is the key to understanding its amyloidogenic propensity.

The prion protein appears to be unusually susceptible to conformational change, and unlike nearly all other proteins, it can easily be made to convert to alternative misfolded conformations. To understand the basis of this structural plasticity, a detailed thermodynamic characterization of two variants of the mouse prion protein (moPrP), the full-length moPrP (23-231) and the structured C-terminal domain, moPrP (121-231), has been carried out. All thermodynamic parameters governing unfolding, including the changes in enthalpy, entropy, free energy, and heat capacity, were found to be identical for the two protein variants. The N-terminal domain remains unstructured and does not interact with the C-terminal domain in the full-length protein at pH 4. Moreover, the enthalpy and entropy of unfolding of moPrP (121-231) are similar in magnitude to values reported for other proteins of similar size. However, the protein has an unusually high native-state heat capacity, and consequently, the change in heat capacity upon unfolding is much lower than that expected for a protein of similar size. It appears, therefore, that the native state of the prion protein undergoes substantial fluctuations in enthalpy and hence, in structure.

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