Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases associated with progressive oligo- and multimerization of the prion protein (PrP C ), its conformational conversion, aggregation and precipitation. We recently proposed that PrP C serves as a cell surface scaffold protein for a variety of signaling modules, the effects of which translate into wide-range functional consequences. Here we review evidence for allosteric functions of PrP C , which constitute a common property of scaffold proteins. The available data suggest that allosteric effects among PrP C and its partners are involved in the assembly of multi-component signaling modules at the cell surface, impose upon both physiological and pathological conformational responses of PrP C , and that allosteric dysfunction of PrP C has the potential to entail progressive signal corruption. These properties may be germane both to physiological roles of PrP C , as well as to the pathogenesis of the TSEs and other degenerative/non-communicable diseases.