Models of structural transition in prion protein (PrP) focus on the domain visualised by solution NMR. Accumulating evidence suggests that the adjacent and highly conserved nonpolar segment, as well as PrP-membrane interactions, should also be considered. Calculations predict that membrane-induced structural destabilisation is mediated by stabilisation of the unfolded form. Comparative analysis of PrP structures leads to a model for PrP dimerisation that incorporates the nonpolar segment. A prediction that PrP will interact with the PrP-like protein (Dpl) to form a heterodimer, but that Dpl will not form a homodimer, can be tested. Modelling is discussed in the context of ataxias associated with the expression of Dpl or truncated PrP in transgenic animals lacking wild-type PrP. A PrPC dimer model forms the basis for considering the geometry of PrPSc fibril formation.