Peptide Fragment Approach to Prion Misfolding: The Alpha-2 Domain

The mechanism that underlies a multitude of human disorders, including type II diabetes, Parkinson’s, Huntington’s and Alzheimer’s, and the prion encephalopathies, is β-structure expansion through a pathogenic aggregation-prone monomeric form. β-sheet expansion disorders share intermolecular association as a common determinant, being therefore collectively identified as conformational diseases, but little is known about the underlying mechanism. Transmissible spongiform encephalopathies, also known as prion diseases, are all characterised by progressive neuronal degeneration associated to marked extracellular accumulation of an amyloidogenic conformer of the normal cellular prion protein (PrP^C), referred to as the scrapie isoform (PrP^Sc), which is thought to be responsible for the disease symptoms. PrP^C is a ubiquitous 231-amino acid glycoprotein, whose physiological role is still elusive. It is organised as an N-terminal disordered region and a compact C-terminal domain, where secondary structure elements consist of three α-helices (α1, α2 and α3), with an α2-α3 disulphide bridge, and two short β-strands (β1 and β2). Evidence accumulated so far suggests that the protein possesses one or several ‘spots’ of intrinsic conformational weakness, which may trigger generic folding, leading the whole architecture to adopt aggregation-prone conformations. One of such spots is suspected to be the C-terminal side of the α-helix 2, which has recently gained the attention of several investigations because it gathers several disease-associated point mutations, can be strongly fibrillogenic and toxic to neuronal cells, and possesses chameleon conformational behaviour. This paper briefly reviews recent literature on α-2 domain-derived model peptides.